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Tryptophan catabolism in females with irritable bowel syndrome: Relationship to interferon-gamma, severity of symptoms and psychiatric co-morbidity
Neurogastroenterology & Motility
Abstract
Irritable bowel syndrome (IBS) has been linked with abnormal serotonin functioning and immune activation. Tryptophan forms the substrate for serotonin biosynthesis, but it can alternatively be catabolized to kynurenine (Kyn) by the enzyme indoleamine 2,3-dioxygenase (IDO), the main inducer of which is interferon-gamma. The primary aim of this study was to test the hypothesis that IBS is associated with increased tryptophan (Trp) catabolism along the Kyn pathway due to increased IFN-gamma levels. Plasma Kyn, Trp and IFN-gamma levels were measured in 41 female IBS subjects and 33 controls. Indoleamine 2,3-dioxygenase activity was assessed using the Kyn to Trp ratio. Psychiatric co-morbidity was assessed using the Patient Health Questionnaire, and severity of IBS assessed using self-report ordinal scales. Irritable bowel syndrome subjects had increased Kyn concentrations compared with controls (P = 0.039) and there was a trend for Kyn:Trp to be increased in the IBS group (P = 0.09). There was a positive correlation between IBS severity and Kyn:Trp (r = 0.57, P < 0.001). Those with severe IBS symptoms had increased Kyn:Trp (P < 0.005) compared to those with less severe symptoms and controls, and were over twice as likely to have depression or anxiety compared to those with less severe IBS (RR = 2.2, 95% CI 1.2-3.9). No difference in IFN-gamma levels was observed between groups; however, IFN-gamma was positively correlated with Kyn:Trp in IBS (r = 0.58, P = 0.005) but not controls (r = 0.12, P = 0.5). Females with IBS have abnormal Trp catabolism. The Kyn:Trp is related to symptom severity, and those with severe IBS symptoms have increased shunting of Trp along the Kyn pathway which contributes to the abnormal serotonergic functioning in this syndrome.
... Evidence shows that IBS is linked with heightened levels of kynurenine, the kynurenine/tryptophan ratio, and quinolinic acid, alongside reduced levels of kynurenic acid and the kynurenic acid/kynurenine ratio. [147][148][149][150] Moreover, neopterin levels are elevated in IBS patients compared to controls. 150 These findings suggest heightened activity of IDO in IBS patients, indicating immune-mediated alterations in tryptophan metabolism. ...
... Although IFN-γ levels did not differ among groups, a positive correlation with the kynurenine/tryptophan ratio was noted in IBS subjects. 147 Furthermore, there was a positive correlation between quinolinic acid levels and intestinal symptoms and depression scale scores, and a negative correlation between kynurenic acid levels and intestinal symptoms and depression scale scores in IBS-C and IBS-D patients. 149,153 Keszthelyi et al. demonstrated that individuals with IBS displayed lower mucosal concentrations and higher systemic levels of kynurenic acid and serotonin compared to healthy controls. ...
Chronic pain is a debilitating symptom with a significant negative impact on the quality of life and socioeconomic status, particularly among adults and the elderly. Major Depressive Disorder (MDD) stands out as one of the most important comorbid disorders accompanying chronic pain. The kynurenine pathway serves as the primary route for tryptophan degradation and holds critical significance in various biological processes, including the regulation of neurotransmitters, immune responses, cancer development, metabolism, and inflammation. This review encompasses key research studies related to the kynurenine pathway in the context of headache, neuropathic pain, gastrointestinal disorders, fibromyalgia, chronic fatigue syndrome, and MDD. Various metabolites produced in the kynurenine pathway, such as kynurenic acid and quinolinic acid, exhibit neuroprotective and neurotoxic effects, respectively. Recent studies have highlighted the significant involvement of kynurenine and its metabolites in the pathophysiology of pain. Moreover, pharmacological interventions targeting the regulation of the kynurenine pathway have shown therapeutic promise in pain management. Understanding the underlying mechanisms of this pathway presents an opportunity for developing personalized, innovative, and non-opioid approaches to pain treatment. Therefore, this narrative review explores the role of the kynurenine pathway in various chronic pain disorders and its association with depression and chronic pain.
... In the same way, clinical studies have shown that IBS patients have increased kynurenine concentrations compared to controls. 51,52 Furthermore, a positive correlation was found between IBS severity (including CHS and anxiety) and the kynurenine/Trp ratio. 51 This ratio reflects the indoleamine-2.3-dioxygenase ...
... 51,52 Furthermore, a positive correlation was found between IBS severity (including CHS and anxiety) and the kynurenine/Trp ratio. 51 This ratio reflects the indoleamine-2.3-dioxygenase (IDO) enzyme activity, which catalyzes the breakdown of Trp into kynurenine and whose expression is induced during inflammatory process. ...
Alterations in brain/gut/microbiota axis are linked to Irritable Bowel Syndrome (IBS) physiopathology. Upon gastrointestinal infection, chronic abdominal pain and anxio-depressive comorbidities may persist despite pathogen clearance leading to Post-Infectious IBS (PI-IBS). This study assesses the influence of tryptophan metabolism, and particularly the microbiota-induced AhR expression, on intestinal homeostasis disturbance following gastroenteritis resolution, and evaluates the efficacy of IL-22 cytokine vectorization on PI-IBS symptoms. The Citrobacter rodentium infection model in C57BL6/J mice was used to mimic Enterobacteria gastroenteritis. Intestinal homeostasis was evaluated as low-grade inflammation, permeability, mucosa-associated microbiota composition, and colonic sensitivity. Cognitive performances and emotional state of animals were assessed using several tests. Tryptophan metabolism was analyzed by targeted metabolomics. AhR activity was evaluated using a luciferase reporter assay method. One Lactococcus lactis strain carrying an eukaryotic expression plasmid for murine IL-22 (L. lactisIL−22) was used to induce IL-22 production in mouse colonic mucosa. C. rodentium-infected mice exhibited persistent colonic hypersensitivity and cognitive impairments and anxiety-like behaviors after pathogen clearance. These post-infectious disorders were associated with low-grade inflammation, increased intestinal permeability, decrease of Lactobacillaceae abundance associated with the colonic layer, and increase of short-chain fatty acids (SCFAs). During post-infection period, the indole pathway and AhR activity were decreased due to a reduction of tryptophol production. Treatment with L. lactisIL−22 restored gut permeability and normalized colonic sensitivity, restored cognitive performances and decreased anxiety-like behaviors. Data from the video-tracking system suggested an upgrade of welfare for mice receiving the L.lactisIL−22 strain. Our findings revealed that AhR/IL-22 signaling pathway is altered in a preclinical PI-IBS model. IL-22 delivering alleviate PI-IBS symptoms as colonic hypersensitivity, cognitive impairments, and anxiety-like behaviors by acting on intestinal mucosa integrity. Thus, therapeutic strategies targeting this pathway could be developed to treat IBS patients suffering from chronic abdominal pain and associated well-being disorders.
... demonstrated that RB supplementation favorably modulated the GLP-2 serum EED biomarker and impacted a variety of chemical classes of serum and stool metabolites without major changes to targeted trace element concentrations. In our study, serum metabolites from the tryptophan metabolic pathway were significantly increased with RB supplementation, including tryptophan (1.18-fold), N-acetylkynurenine (2.8-fold), serotonin (1.81-fold), and 5bromotryptophan (1.2-fold).Tryptophan is an essential amino acid and principal component of the human diet with relevance to the enteric neurological system while also playing a substantial role in the functionality of the gut-brain axis(47)(48)(49). Several studies have demonstrated direct relationships between the concentration of tryptophan and its metabolites with various disorders such as irritable bowel syndrome(47), obesity(50), cardiovascular diseases (51), anorexia nervosa(52,53), and others(54). ...
... In our study, serum metabolites from the tryptophan metabolic pathway were significantly increased with RB supplementation, including tryptophan (1.18-fold), N-acetylkynurenine (2.8-fold), serotonin (1.81-fold), and 5bromotryptophan (1.2-fold).Tryptophan is an essential amino acid and principal component of the human diet with relevance to the enteric neurological system while also playing a substantial role in the functionality of the gut-brain axis(47)(48)(49). Several studies have demonstrated direct relationships between the concentration of tryptophan and its metabolites with various disorders such as irritable bowel syndrome(47), obesity(50), cardiovascular diseases (51), anorexia nervosa(52,53), and others(54). Further, serotonin is thought to mediate the vomiting reflex in children with rotavirus and norovirus(55).Kosek et al. reported associations between tryptophan concentration and linear growth in two longitudinal birth cohorts, and increased concentrations of tryptophan was associated with LAZ gain in those infants(56). ...
Background
Environmental enteric dysfunction (EED) is associated with chronic gut inflammation affecting nutrient absorption and development of children, primarily in low- and middle-income countries. Several studies have shown that rice bran (RB) supplementation provides nutrients and modulates gut inflammation that may reduce risk for undernutrition.
Objectives
To evaluate daily RB dietary supplementation for six months on serum biomarkers in weaning infants and associated changes in serum and stool metabolites.
Methods
A 6-month, randomized-controlled dietary intervention was conducted in a cohort of weaning 6-month-old infants in León, Nicaragua. Anthropometric indices were obtained at 6, 8, and 12 months. Serum and stool ionomics and metabolomics were completed at the end of the six-month intervention using Inductively coupled plasma mass spectrometry and Ultra-performance liquid chromatography tandem mass spectroscopy. The Alpha-1-acid glycoprotein, C-reactive protein and Glucagon-like peptide-2 serum EED biomarkers were measured by Enzyme-Linked Immunosorbant Assay ELISA.
Results
Twenty-four infants in the control group and 23 in the RB group successfully completed the 6-month dietary intervention with 90% dietary compliance. RB participants had higher concentrations of GLP-2 as compared to control participants at 12 months (median, (IQR): 743.53 (380.54) pg/ml vs. 592.50 (223.59) pg/ml; P = 0.04). Metabolite profiles showed significant fold differences of 39 serum metabolites and 44 stool metabolites from infants consuming RB compared to control, and with significant metabolic pathway enrichment scores of 4.7 for the tryptophan metabolic pathway, 5.7 for polyamine metabolism and 5.7 for fatty acid/acylcholine metabolic pathway in the RB group. No differences were detected in serum and stool trace elements or heavy metals following daily RB intake for six months.
Conclusions
RB consumption influences a suite of metabolites associated with growth promotion and development, while also supporting nutrient absorption as measured by changes in serum glucagon-like peptide-2 in Nicaraguan infants. This clinical trial was registered at: https://clinicaltrials.gov (NCT02615886).
Rice bran modulates glucagon-like peptide-2, serum and stool metabolites in weaning Nicaraguan infants.
Clinical Trial Registry: NCT02615886 https://clinicaltrials.gov/ct2/show/NCT02615886
... Trp is an essential amino acid that acts as a precursor to serotonin but can also be metabolized via the kynurenine pathway, resulting in the production of other neuroactive compounds [150]. Variation of Trp metabolism has been shown to influence mood and cognition within the central nervous system as well as secretion, motility, and perception in the enteric nervous system [224]. The gut microbiota has shown to be able to metabolize Trp that, in combination with host GI metabolism, are key factors in the systemic availability of Trp, as well as indoles, kynurenine, and serotonin [148,225]. ...
Irritable bowel syndrome is a common functional gastrointestinal disorder characterized by recurrent abdominal discomfort, bloating, cramping, flatulence, and changes in bowel movements. The pathophysiology of IBS involves a complex interaction between motor, sensory, microbiological, immunological, and psychological factors. Diversity, stability, and metabolic activity of the gut microbiota are frequently altered in IBS, thus leading to a situation of gut dysbiosis. Therefore, the use of probiotics and probiotic-derived metabolites may be helpful in balancing the gut microbiota and alleviating irritable bowel syndrome symptoms. This review aimed to report and consolidate recent progress in understanding the role of gut dysbiosis in the pathophysiology of IBS, as well as the current studies that have focused on the use of probiotics and their metabolites, providing a foundation for their potential beneficial effects as a complementary and alternative therapeutic strategy for this condition due to the current absence of effective and safe treatments.
... The role of Trp metabolites in IBS has been demonstrated by Fitzgerald et al. when comparing patients with IBS to healthy controls. They found that IBS patients' blood had more kynurenine than the control group, and that there was a positive link between the severity of IBS symptoms and the kynurenine/tryptophan (Kyn/Trp) ratio [52]. A shift in Trp metabolism toward kynurenine production has also been observed by Han et al. along with a link between a Trp dysregulated metabolism and the severity of IBS depression [53]. ...
Recently, the role of the gut microbiome has become more prominent in gut-brain interactions. The microbiota-gut-brain axis homeostasis is responsible for our emotional behavior, stress response, and brain neurotransmitter balance. This bidirectional communication axis between the gut and the brain is influenced by the effect of the microbiome on the metabolic pathways of the host. Intestinal bacteria intervene directly in Trp metabolism, generating signaling molecules and specific metabolites with physiological effects on both the brain and the intestine. Trp is also metabolized under the influence of the microbiome and suffers three major pathways in the organism: The serotonin (5-HT), kynurenine, and indole pathway resulting in the production of neuro-active metabolites. This current chapter aims to cover the most recent data referring to the Trp metabolites and the microbiome-gut-brain axis in major gut disorders, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and celiac disease. These diseases are frequently associated with mood disorders.
... Bacteria and pro-inflammatory cytokines also activate the kynurenine pathway, but the role of its metabolites in the pathogenesis of IBS is little known. Higher levels of plasma kynurenine were found in these patients [41][42][43][44], but these changes were related to accompanying mental disorders. ...
Patients with a mixed type of irritable bowel syndrome (IBS-M) experience constipation and diarrhea, which alternate between weeks or months. The pathogenesis of this syndrome is still little understood. The aim of the study was mainly to evaluate the urinary excretion of selected tryptophan (TRP) metabolites during the constipation and diarrhea periods of this syndrome. In 36 patients with IBS-M and 36 healthy people, serum serotonin level was measured by ELISA and urinary levels of 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN) and indican (3-IS) were determined using the LC-MS/MS method. The levels of all above metabolites were higher in the patient group, and increased significantly during the diarrheal period of IBS-M. In particular, the changes concerned 5-HIAA (3.67 ± 0.86 vs. 4.59 ± 0.95 mg/gCr, p < 0.001) and 3-IS (80.2 ± 17.4 vs. 93.7 ± 25.1 mg/g/Cr, p < 0.001). These changes coexisted with gut microbiome changes, assessed using hydrogen-methane and ammonia breath tests. In conclusion, the variability of TRP metabolism and the gut microbiome may cause the alternation of IBS-M symptoms.
... Alterations in the KP have been documented in several diseases linked to a disrupted microbiome. Patients diagnosed with irritable bowel syndrome (IBS) have reported heightened KP metabolism and altered microbiome [54][55][56], providing evidence of a connection between these two systems. The roles of altered microbiome and oxidative stress have also been described in patients with Crohn's disease [57,58]. ...
The intestinal flora has been the focus of numerous investigations recently, with inquiries not just into the gastrointestinal aspects but also the pathomechanism of other diseases such as nervous system disorders and mitochondrial diseases. Mitochondrial disorders are the most common type of inheritable metabolic illness caused by mutations of mitochondrial and nuclear DNA. Despite the intensive research, its diagnosis is usually difficult, and unfortunately, treating it challenges physicians. Metabolites of the kynurenine pathway are linked to many disorders, such as depression, schizophrenia, migraine, and also diseases associated with impaired mitochondrial function. The kynurenine pathway includes many substances, for instance kynurenic acid and quinolinic acid. In this review, we would like to show a possible link between the metabolites of the kynurenine pathway and mitochondrial stress in the context of intestinal flora. Furthermore, we summarize the possible markers of and future therapeutic options for the kynurenine pathway in excitotoxicity and mitochondrial oxidative stress.
... TRP can be metabolized through these three pathways into various bioactive compounds such as serotonin, melatonin, NAD + and NAPD, which have important physiological functions for the body 25,26 . A growing number of studies also have found that TRP metabolites are associated with many diseases and dysfunctions such as Alzheimer's disease 5 , psychiatric disorders 27 , functional bowel disease 28 , and aging 29 . In recent years, some progress has been made in the study of TRP metabolism in the field of reproduction. ...
Tryptophan (TRP) and its indole metabolites exhibit numerous biological effects, especially their antioxidant properties. This study used untargeted metabolomics in conjunction with targeted metabolomics to investigate the differential expression of tryptophan and its indole metabolites in follicular fluid (FF) of diminished ovarian reserve (DOR) and normal ovarian reserve (NOR) populations. This study included patients with DOR (n = 50) and females with NOR (n = 35) who received in vitro fertilization and embryo transfer. Untargeted metabolomics suggests that diminished ovarian reserve affects the metabolic profile of FF, TRP and indole metabolites were significantly down-regulated in the DOR group. Targeted metabolomics quantification revealed that the levels of TRP, IPA and IAA in the FF of the DOR group were significantly lower than those of the NOR group (P < 0.01). The concentration of TRP in FF is positively correlated with the available embryo rate in NOR females. These results provide data support to explore the pathogenesis of DOR and to look for new biomarkers and ovarian protectors. Additionally, alterations in TRP and its indole metabolites in FF may indirectly reflect the interaction between intestinal flora and the follicular microenvironment.
... In our trial, IPA correlated with the IBS symptom of abdominal pain and quality of life, albeit weakly [38]. Mechanisms may involve microbiota shifting the metabolism of tryptophan towards the kynurenine pathway [41,42], or it may be that IPA itself affects the kynuerine pathway [43], which is suggested to be involved in the pathogenesis of IBS [44]. Gluten was shown to affect lipid-related metabolites only modestly, including carnitine derivates, an acyl-CoA derivate, a medium chain fatty acid, and an unknown lipid, but with no meaningful correlation with IBS symptoms. ...
Background:
A mechanistic understanding of the effects of dietary treatment in irritable bowel syndrome (IBS) is lacking. Our aim was therefore to investigate how fermentable oligo- di-, monosaccharides, and polyols (FODMAPs) and gluten affected gut microbiota and circulating metabolite profiles, as well as to investigate potential links between gut microbiota, metabolites, and IBS symptoms.
Methods:
We used data from a double-blind, randomized, crossover study with week-long provocations of FODMAPs, gluten, and placebo in participants with IBS. To study the effects of the provocations on fecal microbiota, fecal and plasma short-chain fatty acids, the untargeted plasma metabolome, and IBS symptoms, we used Random Forest, linear mixed model and Spearman correlation analysis.
Results:
FODMAPs increased fecal saccharolytic bacteria, plasma phenolic-derived metabolites, 3-indolepropionate, and decreased isobutyrate and bile acids. Gluten decreased fecal isovalerate and altered carnitine derivatives, CoA, and fatty acids in plasma. For FODMAPs, modest correlations were observed between microbiota and phenolic-derived metabolites and 3-indolepropionate, previously associated with improved metabolic health, and reduced inflammation. Correlations between molecular data and IBS symptoms were weak.
Conclusions:
FODMAPs, but not gluten, altered microbiota composition and correlated with phenolic-derived metabolites and 3-indolepropionate, with only weak associations with IBS symptoms. Thus, the minor effect of FODMAPs on IBS symptoms must be weighed against the effect on microbiota and metabolites related to positive health factors.
... In addition, indoleamine-2, 3-dioxygenase (IDO), an important enzyme in the Kyn metabolic pathway, and Quin, a downstream branch product of Kyn, are closely related to pain and the nervous system. Overexpressed IDO and Quin may lead to many mental disorders, such as depression and schizophrenia [12][13] , and aggravate pain responses [14] . These may account for the involvement of Trp metabolism in visceral pain, anxiety, and depression in IBS. ...
Objective
To observe the effect of moxibustion on behaviors and related products of tryptophan (Trp) metabolism in the colon of mice with irritable bowel syndrome (IBS), and to explore the mechanism of moxibustion in the IBS treatment.
Methods
Twenty-four mice were randomly divided into a normal group, a model group, a moxibustion group, and a probiotic group, with 6 mice in each group. The visceral pain model of IBS was established by enema with 2,4,6-trinitrobenzene sulfonic acid (TNBS) solution. Mice in the moxibustion group were treated with mild moxibustion at bilateral Zusanli (ST36), and those in the probiotic group were treated with probiotics such as Bifidobacterium by gavage. Abdominal withdrawal reflex (AWR) test, elevated plus-maze (EPM) test, and forced swimming test (FST) were performed after treatment. The expression levels of 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase 1 (TPH1) in the colon were detected by immunofluorescence, and the expression levels of Trp, kynurenine (Kyn), and indole-2,3-oxygenase (IDO) in the colon were detected by enzyme-linked immunosorbent assay.
Results
Compared with the normal group, the AWR scores were increased significantly in the model group under different pressure values ( P <0.01), the open-arm staying time and open-arm entries in the EPM test were decreased significantly ( P <0.01, P <0.05), the motionless time in the FST was increased significantly ( P <0.01), and the expression levels of colonic Trp, TPH1, IDO, 5-HT, and Kyn were increased significantly ( P <0.01) in the models. Compared with the model group, the AWR scores were differently decreased ( P <0.05 or P <0.01), the open-arm entries in the EPM test were increased ( P <0.05), the motionless times in the FST were decreased ( P <0.05), and the colonic expression levels of Trp, TPH1, IDO, and 5-HT were decreased ( P <0.01 or P <0.05) in the moxibustion and probiotic groups; the open-arm staying time was significantly increased in the moxibustion group ( P <0.01), and the colonic expression level of Kyn was significantly decreased in the probiotic group ( P <0.01).
Conclusion
Moxibustion at Zusanli (ST36) improves visceral pain and pain mood and down-regulates the expression levels of colonic TPH1, IDO, Trp, 5-HT, and Kyn in IBS mice.
... It was reported that KYN levels and the KYN/TRP ratio increased in IBS patients [41]. In addition, the KYN/TRP ratio was found to be positively correlated with the severity of abdominal complaints, as well as with anxiety and depressive symptoms [42]. These results have been imprecise as a consequence of the increase in activity of the kynurenine pathway. ...
(1) Background: A low-FODMAP diet is often recommended in the treatment of irritable bowel syndrome, but it does not improve abdominal symptoms in all patients, and an alternative diet is desirable. The purpose of this study was to evaluate the efficacy of a low-FODMAP diet with a concomitant reduction in tryptophan (TRP) intake in irritable bowel syndrome with diarrhea predominance (IBS-D) in relation to its metabolism via the serotonin and kynurenine pathways. (2) Methods: 40 healthy people (Group I, Controls) and 80 patients with IBS-D were included in the study. IBS-D patients were randomly divided into two groups of 40 each (Groups IIA and IIB). In Group IIA, the low-FODMAP diet was recommended, while in Group IIB, the same diet was recommended but with limited TRP intake for 8 weeks. The TRP intake was analyzed with the use of the nutritional calculator. Abdominal complaints were assessed using the Gastrointestinal Symptom Rating Scale (GSRS-IBS), and psychological status was simultaneously determined using two scales: the Hamilton Anxiety Scale (HAM-A) and the Hamilton Depression Scale (HAM-D). TRP and its metabolites: 5-hydoxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QA) were measured in urine using liquid chromatography tandem mass spectrometry (LC-MS/MS). (3) Results: The consumption of TRP per mg/kg/b.w./24 h has decreased in Group IIA from 20.9 ± 2.39 to 17.45 ± 2.41 (16.5%) and in Group IIB from 21.3 ± 2.33 to 14.32 (34.4%). Significantly greater improvement was found after nutritional treatment in patients in Group IIB as compared to Group IIA (GSRS score: 38.1% vs. 49.8%; HAM-A: 38.7% vs. 49.9%; HAM-D: 13.8% vs. 35.0%; p < 0.01). Reducing TRP intake showed a negative correlation with the degree of improvement in the GSRS score. (4) Conclusions: Lowering the TRP content in a low-FODMAP diet may be useful in treating IBS-D.
... Fitzgerald et al. indicated that IBS patients had an increased plasma KYN concentration and KYN/TRP ratio compared to healthy subjects. Furthermore, the KYN/TRP ratio was positively correlated with the severity of abdominal complaints, as well as with anxiety and depressive syndrome [39]. However, Christmas et al. [19] in patients with IBS-D showed significantly free serum tryptophan and significantly lower tryptophan dioxygenase. ...
(1) Background: L-tryptophan is a substrate for the synthesis of many biological compounds through the serotonin and kynurenine pathways. These compounds have a significant influence on gastrointestinal functions and mental processes. The aim of the study was to evaluate the urinary excretion of selected tryptophan metabolites in patients with constipation-predominant and diarrhoea-predominant irritable bowel syndrome (IBS-C and IBS-D, respectively), related to somatic and mental symptoms. (2) Methods: 120 people were included in the study and three groups were distinguished, with 40 individuals each, including healthy subjects (controls), patients with IBS-C and patients with IBS-D. The Gastrointestinal Symptoms Rating Scale (GSRS-IBS) was used to assess the severity of abdominal symptoms. The Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Depression Rating Scale (HAM-D) were used to evaluate the mental state of patients. Using liquid chromatography tandem mass spectrometry (LC-MS/MS), L-tryptophan and the following metabolites in urine, related to the creatinine level, were measured: 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA). (3) Results: In both groups of patients with IBS, changes in tryptophan metabolism were found as compared to the control group. We observed an increase in the activity of the serotonin pathway and a positive correlation between the 5-HIAA level and the GSRS score (p < 0.01) and HAM-A score (p < 0.001) in IBS-D patients. The IBS-C group was characterized by a higher concentration of kynurenines (KYN, QA) in urine. Moreover, the QA (p < 0.001) and KYNA (p < 0.05) levels were correlated with the HAM-D score among IBS-C patients. (4) Conclusions: Various changes in the tryptophan metabolism pathway can determine the differences in the clinical picture of irritable bowel syndrome. These results should be included in the nutritional and pharmacological treatment of this syndrome.
... In line with similar findings [6,30], there were no differences in plasma concentration of TRP and TRP neurotransmitter products between IBS subtypes, functional groups, or healthy controls. TRP is a precursor of 5-HT, KYN, 5-HIAA, and 5-HTP and is thought to play a critical role in IBS symptomology due to the effect of these neurotransmitters on disrupting motility, sensitivity, and secretion within the gastrointestinal tract [9]. ...
Amino acids are important in several biochemical pathways as precursors to neurotransmitters which impact biological processes previously linked to functional gastrointestinal disorders (FGIDs). Dietary protein consumption, metabolic host processes, and the gut microbiome can influence the plasma concentration of amino acids and neurotransmitters, and their uptake by tissues. The aim of this analysis was to quantify 19 proteogenic and 4 non-proteogenic amino acids and 19 neurotransmitters (including precursors and catabolites, herein referred to as neurotransmitters) to ascertain if their circulating concentrations differed between healthy participants and those with FGIDs. Plasma proteogenic and non-proteogenic amino acids and neurotransmitters were measured using ultra-performance liquid chromatography and liquid chromatography–mass spectrometry, respectively, from 165 participants (Rome IV: irritable bowel syndrome (IBS-constipation, IBS-diarrhea), functional constipation, functional diarrhea, and healthy controls). There were significant differences (p < 0.05) in pairwise comparisons between healthy controls and specific FGID groups for branched-chain amino acids (BCAAs), ornithine, and alpha-aminobutyric acid. No other significant differences were observed for the neurotransmitters or any other amino acids analyzed. Multivariate and bivariate correlation analyses between proteogenic and non-proteogenic amino acids and neurotransmitters for constipation (constipation (IBS-C and functional constipation) and phenotypes diarrhea (IBS-D and functional diarrhea)) and healthy controls suggested that associations between BCAAs, 5-hydroxytryptophan, and kynurenine in combination with tyrosine, 3,4-dihydroxyphenylalanine, and 3,4-dihydroxyphenylacetic acid and associations with gamma-aminobutyric acid, glutamate, asparagine, and serine are likely disrupted in FGID phenotypes. In conclusion, although correlations were evident between some proteogenic and non-proteogenic amino acids and neurotransmitters, the results showed minor concentration differences in plasma proteogenic and non-proteogenic amino acids, amino acid-derived metabolites, and neurotransmitters between FGID phenotypes and healthy controls.
... Additionally, Saji and co-workers [20] showed a correlation between specific enterotypes (I and III specifically) and dementia. Finally, studies showed that patients suffering from depression and/or anxiety frequently present changes in colonic motility, which can, in turn, alter intestinal physiology and the microbiome constitution [21,22]. ...
The literature on the crosstalk between the brain and the gut has increased considerably in recent years. It is widely accepted now that the microbiome plays a significant role in several brain disorders, neurodevelopment, neurocognitive stages, and physiological functions. However, the mechanisms that influence such crosstalk are still not well elucidated. In this sense, one of the possible mechanisms by which the microbiome could influence brain function is through gut hormones released by enteroendocrine cells: ghrelin, cholecystokinin (CCK), peptide YY (PYY), vasoactive intestinal polypeptide (VIP), glucagon-like peptide (GLP1-2), corticotropin-releasing factor (CRF), glucose-dependent insulinotropic polypeptide (GIP), secretin, serotonin (5-HT), and oxytocin. Especially when one considers that the brain expresses receptors for these hormones in areas important to the neurobiology of brain disorders (e.g., depression), such as the hippocampus, amygdala, hypothalamus, and suprachiasmatic nucleus. To strengthen this hypothesis, gastrointestinal dysfunction (such as altered motility or pain) is relatively common in depressive patients, and changes in diet (low-carbohydrate diets, for example) positively affect mood. Additionally, alterations in the gut microbiome are relatively common in depressive patients and are related to the levels of Akkermansia, Lactobacillus, Bifidobacteria, Faecalibacterium, Roseburia and Clostridium. Finally, concerning the gut-released hormones, the literature reports that ghrelin can be a peripheral marker for the antidepressant treatment success rate and has elevated levels during depression. GLP-1 is tightly correlated with HPA axis activity being decreased by high cortisol levels. CCK seems to be altered in depression due to increased inflammation and activation of Toll-like receptor 4. Such finds allow the postulation that hormones, the microbiome and mood are intertwined and co-dependent. VIP is correlated with circadian rhythms. There is a bidirectional connection of the circadian rhythms between the host and the microbiota. Circadian rhythm disruption is associated with both poor outcomes in mental health and alterations in the microbiota composition. In sum, in the past year, more and more research has been published showing the tight connection between gut and brain health and trying to decipher the feedback in play. Here, we focus on depression.
... Il existe des liens entre le SII et une altération du métabolisme du Trp (Figure 30) (Burr et al., 2019;Bosi et al., 2020). La kynurénine est augmentée dans le sérum de ces patients (Clarke et al., 2012) et l'activité périphérique d'IDO1 est positivement corrélée à la sévérité du SII (Fitzgerald et al., 2008). Les altérations de la motilité intestinale sont liées aux perturbations du métabolisme de la 5-HT, comme le suggère le contenu en 5-HT colique diminué et augmenté dans le SII-C et le SII-D respectivement (Manocha and Khan, 2012). ...
Les perturbations de l'axe cerveau-intestin-microbiote font l’objet de nombreuses études afin de mettre au point de nouveaux traitements pour les pathologies intestinales chroniques telles que le syndrome de l’intestin irritable (SII). Dans certains cas, à la suite d’une infection gastro-intestinale par des Entérobactéries et malgré l'élimination de l'agent pathogène, des troubles du transit et des douleurs abdominales chroniques persistent et peuvent favoriser le développement de symptômes anxio-dépressifs. Ceci est alors appelé SII post-infectieux (SII-PI). En développant un modèle préclinique d'infection à Citrobacter rodentium, mes travaux se sont focalisés sur (1) l’étude de l'impact de la cytokine IL-22 sur les symptômes associés au SII-PI, (2) l’étude du métabolisme du tryptophane (Trp), en particulier l'expression d’AhR induite par ses ligands dérivés du microbiote et, (3) l’étude du microbiote et du métabolome fécal sur les troubles de l'homéostasie suite à la résolution d’une infection gastro-intestinale. Ainsi, nous avons montré que le modèle murin d'infection à C. rodentium développe en période post-infectieuse, une hypersensibilité viscérale d’origine colique (HSVC) persistante, un comportement de type anxieux ainsi que des altérations cognitivo-émotionnelles, associés à une dysbiose, une inflammation à bas bruit et à une perméabilité intestinale augmentée montrant qu’il s’agit d’un modèle pertinent pour étudier les mécanismes physiopathologiques du SII-PI. Dans un premier temps, des analyses de métabolomique dirigée ont dévoilé des perturbations fonctionnelles au niveau fécal en phase post-infectieuse. Le métabolisme du Trp est altéré avec une diminution de la voie indole et de l'activité d’AhR ainsi qu’une diminution de la production du tryptophol. La production de la cytokine IL-22 peut être activée par la voie AhR et représente un acteur essentiel de l’homéostasie intestinale. Ainsi l’efficacité de la vectorisation d’IL-22 à l’aide d’une souche de Lactococcus lactis portant un plasmide d'expression eucaryote pour l’IL-22 murine (L. lactisIL-22) a été testée dans ce modèle animal de SII-PI. Le traitement avec L. lactisIL-22 permet d’améliorer les perturbations associées à l’infection par C. rodentium durant la phase post-infectieuse. Nos résultats suggèrent que le ciblage de la voie de signalisation AhR/IL-22 atténue les symptômes du SII-PI en agissant sur l'intégrité de la barrière épithéliale intestinale et les métabolites du Trp dérivés du microbiote. Les études de métabolomique ont été élargies afin d’identifier les perturbations fonctionnelles du microbiote fécal induite par l’infection. Ces travaux ont permis de préciser la physiopathologie du SII-PI et d’identifier de nouvelles cibles thérapeutiques potentielles telle que la voie AhR/IL-22. De plus, le rôle d’autres infections sur les comportements cognitivo-émotionnels de l’hôte a été étudié dans deux modèles animaux. Une infection chronique parasitaire à Blastocystis chez le rat a été utilisé afin de mimer un SII, ainsi qu’une infection chronique aux Escherichia coli producteurs de colibactine (CoPEC), Entérobactéries associées au cancer colorectal (CCR).
... Kaszthelyi et al. [37] showed that IBS patients had a higher blood concentration of SER and KYNA than healthy subjects. Fitzgerald et al. [38] showed positive correlation between the level of KYN/TRP and the intensity of IBS syndrome, as well as depressive syndromes. However, Christmas et al. [39] suggested that diarrhoea-predominant IBS would have elevated TRP in plasma due to changes in its metabolism, mainly enhanced the SER pathway, and inhibited the KYN pathway. ...
The causes of depression are diverse and are still not fully understood. Recently, an increasing role is attributed to nutritional and inflammatory factors. The aim of this study was to evaluate selected metabolites of the tryptophan kynurenine pathway in depressive patients with small intestinal bacterial overgrowth (SIBO). The study involved 40 healthy people (controls) and 40 patients with predominant small intestinal bacterial overgrowth (SIBO-D). The lactulose hydrogen breath test (LHBT) was performed to diagnose SIBO. The severity of symptoms was assessed using the Gastrointestinal Symptom Rating Scale (GSRS-IBS) and the Hamilton Depression Rating Scale (HAM-D). The concentration of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QA) in urine was determined using an LC-MS/MS method, before and after cyclic treatment with an antibiotic drug, rifaximin, for three months. The number of intraepithelial lymphocytes (IELs) in the duodenum and small intestinal mucosa, fecal calprotectin (FC) and serum level of C-reactive protein (CRP) were also determined. In patients with SIBO, a higher level of KYN and QA were found as compared to the control group. These two groups also differed in KYN/TRP (higher in SIBO) and KYNA/KYN ratios (lower in SIBO). A positive correlation was found between HAM-D and the number of IELs and the level of FC. Treatment with rifaximin improves the kynurenic pathway, as well as abdominal and mental complaints. Therefore, small intestinal bacterial overgrowth can be a cause of abdominal symptoms, but also mental disorders.
... Notably, half of ME/CFS patients had reported IBS [145]. In addition, Fitzgerald et al. reported high levels of plasma kynurenic/TRP ratio in severe IBS cases [146]. More importantly, through the manipulation of TRP metabolites and Indoleamine 2,3-dioxygenase (IDO) production, the microbiota can affect immune response by affecting cell differentiation and engaging AhR [147]. ...
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease with a substantial social and economic impact on individuals and their community. Despite its importance and deteriorating impact, progresses in diagnosis and treatment of ME/CFS is limited. This is due to the unclear pathophysiology of the disease and consequently lack of prognostic biomarkers. To investigate pathophysiology of ME/CFS, several potential pathologic hallmarks have been investigated; however, these studies have failed to report a consistent result. These failures in introducing the underlying reason for ME/CFS have stimulated considering other possible contributing mechanisms such as tryptophan (TRP) metabolism and in particular kynurenine pathway (KP). KP plays a central role in cellular energy production through the production of nicotinamide adenine dinucleotide (NADH). In addition, this pathway has been shown to mediate immune response and neuroinflammation through its metabolites. This review, we will discuss the pathology and management of ME/CFS and provide evidence pertaining KP abnormalities and symptoms that are classic characteristics of ME/CFS. Targeting the KP regulation may provide innovative approaches to the management of ME/CFS.
... Dysbiosis and a subsequent alteration in tryptophan metabolism is thought to contribute to the pathogenesis of several GI diseases, including IBD and IBS (Kennedy et al., 2017;Agus et al., 2018). Peripheral kynurenine activity was shown to be correlated with the severity of IBS symptoms (Fitzgerald et al., 2008). In an animal model of IBS, decreased activity of the indole pathway and AhR-dependent IL-22 production, was correlated with anxiety-like behaviors; visceral pain was not evaluated in this report (Maëva et al., 2022). ...
Inflammatory bowel disease (IBD), comprising Crohn’s disease and Ulcerative colitis, is a relapsing and remitting disease of the gastrointestinal tract, presenting with chronic inflammation, ulceration, gastrointestinal bleeding, and abdominal pain. Up to 80% of patients suffering from IBD experience acute pain, which dissipates when the underlying inflammation and tissue damage resolves. However, despite achieving endoscopic remission with no signs of ongoing intestinal inflammation or damage, 30–50% of IBD patients in remission experience chronic abdominal pain, suggesting altered sensory neuronal processing in this disorder. Furthermore, effective treatment for chronic pain is limited such that 5–25% of IBD outpatients are treated with narcotics, with associated morbidity and mortality. IBD patients commonly present with substantial alterations to the microbial community structure within the gastrointestinal tract, known as dysbiosis. The same is also true in irritable bowel syndrome (IBS), a chronic disorder characterized by altered bowel habits and abdominal pain, in the absence of inflammation. An emerging body of literature suggests that the gut microbiome plays an important role in visceral hypersensitivity. Specific microbial metabolites have an intimate relationship with host receptors that are highly expressed on host cell and neurons, suggesting that microbial metabolites play a key role in visceral hypersensitivity. In this review, we will discuss the techniques used to analysis the metabolome, current potential metabolite targets for visceral hypersensitivity, and discuss the current literature that evaluates the role of the post-inflammatory microbiota and metabolites in visceral hypersensitivity.
... Supplementation with Trp was sufficient to reduce the disease scores of endometritis but reversed in the context of gut microbiota abrogation. Impairment of microbial Trp metabolism in gut-dysbiotic mice reduced AhR ligand levels and promoted the KP pathway of Trp metabolism (24,43), which positively correlated with IBS (irritable bowel syndrome) severity (57). Treatment with IAld, indole, and IPA rescued the protective role of Trp to different degrees, which may depend on different capacities of AhR activation (43,52). ...
Infection-induced endometritis is a common and frequently occurring disease in humans and animals. Accumulating evidence suggests an important role of the gut microbiota in the development of infection-induced inflammation.
... 87,88 Monoamine oxidase A converts serotonin to 5-hydroxyindoleacetic acid in the brain and gut. 89 In the brain, serotonin is converted into melatonin, the primary hormone of the body's sleepwake cycle. 89 Indoleamine 2,3-dioxygenase might shunt Trp to kynurenine in the brain, leading to sleep disturbances. ...
Disorders of gut-brain interaction (DGBIs) are common conditions in community and clinical practice. As specialized enteroendocrine cells, enterochromaffin (EC) cells produce up to 95% of total body serotonin and coordinate luminal and basolateral communication in the gastrointestinal (GI) tract. EC cells affect a broad range of gut physiological processes, such as motility, absorption, secretion, chemo/mechanosensation, and pathologies, including visceral hypersensitivity, immune dysfunction, and impaired gastrointestinal barrier function. We aim to review EC cell and serotonin-mediated physiology and pathophysiology with particular emphasis on DGBIs. We explored the knowledge gap and attempted to suggest new perspectives of physiological and pathophysiological insights of DGBIs, such as (1) functional heterogeneity of regionally distributed EC cells throughout the entire GI tract; (2) potential pathophysiological mechanisms mediated by EC cell defect in DGBIs; (3) cellular and molecular mechanisms characterizing EC cells and gut microbiota bidirectional communication; (4) differential modulation of EC cells through GI segment-specific gut microbiota; (5) uncover whether crosstalk between EC cells and (i) luminal contents; (ii) enteric nervous system; and (iii) central nervous system are core mechanisms modulating gut-brain homeostasis; and (6) explore the therapeutic modalities for physiological and pathophysiological mechanisms mediated through EC cells. Insights discussed in this review will fuel the conception and realization of pathophysiological mechanisms and therapeutic clues to improve the management and clinical care of DGBIs.
... 95 The involvement of tryptophan metabolic pathways and IDO enzyme have been suggested in a number of gastrointestinal disorders including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). [96][97][98] From a microbial perspective, bacterial strain such as adhesiveinvasive Escherichia coli (AIEC) LF82 significantly upregulated the IDO-1 enzyme in an in vitro IBD model of dysbiosis. 99 Women with PCOS exhibit reduction in both the gut microbiome species richness (α diversity) and have changes in the composition of the microbial community (β diversity). ...
Polycystic ovary syndrome (PCOS) is a complex metabolic disorder commonly seen in females of reproductive age. The pathophysiology of PCOS is multifactorial and includes dysfunction in ovarian steroidogenesis and folliculogenesis, impaired gonadotropin levels, insulin resistance, gut microbiota imbalance, genetic predisposition, and lifestyle preferences. Low-grade inflammatory conditions such as obesity and impaired glucose tolerance are common metabolic disturbances in women with PCOS. A growing body of literature suggests strong evidence rendering PCOS in close proximity with chronic inflammation as documented by high levels of serum white blood cells, C-reactive protein, and various proinflammatory cytokines seen in this condition. Inflammation seems to be the most common metabolic denominator between the kynurenine pathway and PCOS. The association of tryptophan and kynurenine pathway has already been well documented in mood disorders, neurodegenerative diseases, chronic pain conditions, and different inflammatory states. In this manuscript, we describe the influence of sex steroid hormones on different enzymes of the KP; inflammatory nature of PCOS and CRP as a marker of IDO/TDO activity; and the effects of altered gut flora in women with PCOS. This review provides a novel view of the available evidence of tryptophan and downstream metabolites in PCOS in the context of underlying inflammation.
... These observations seem to suggest that the microbiota could both reduce tryptophan availability by expressing tryptophanase or alter host enzymes activity, like IDO or TDO. These alterations in enzymatic activity have already been associated with gastrointestinal disorders [81][82][83], suggesting again the importance of microbiota alterations in disease development. ...
Intriguing evidence is emerging in regard to the influence of gut microbiota composition and function on host health from the very early stages of life. The development of the saprophytic microflora is conditioned by several factors in infants, and peculiarities have been found for babies born prematurely. This population is particularly exposed to a high risk of infection, postnatal antibiotic treatment, feeding difficulties and neurodevelopmental disabilities. To date, there is still a wide gap in understanding all the determinants and the mechanism behind microbiota disruption and its influence in the development of the most common complications of premature infants. A large body of evidence has emerged during the last decades showing the existence of a bidirectional communication axis involving the gut microbiota, the gut and the brain, defined as the microbiota-gut-brain axis. In this context, given that very few data are available to demonstrate the correlation between microbiota dysbiosis and neurodevelopmental disorders in preterm infants, increasing interest has arisen to better understand the impact of the microbiota-gut-brain axis on the clinical outcomes of premature infants and to clarify how this may lead to alternative preventive, diagnostic and therapeutic strategies. In this review, we explored the current evidence regarding microbiota development in premature infants, focusing on the effects of delivery mode, type of feeding, environmental factors and possible influence of the microbiota-gut-brain axis on preterm clinical outcomes during their hospital stay and on their health status later in life.
... They showed a positive correlation between IBS and the intensity of its symptoms and levels of L-Trp and L-kyn in the cerebrospinal fluid of the subjects. However, the authors' observations did not confirm earlier studies showing a high L-kyn/L-Trp ratio due to enhanced L-Trp catabolism by the kynurenine pathway in IBS [115,126]. This difference points at an important aspect of studies on neurological diseases associated with functional GI disorders-the target tissue of determination of parameters of interest, including levels of L-Trp and products of its metabolism. ...
Migraine, the leading cause of disability in the population aged below 50, is associated with functional gastrointestinal (GI) disorders (FGIDs) such as functional nausea, cyclic vomiting syndrome, and irritable bowel syndrome (IBS). Conversely, changes in intestinal GI transit may cause diarrhea or constipation and are a component of the autonomic symptoms associated with pre- and post-dorsal phases of migraine attack. These mutual relationships provoke a question on a common trigger in migraine and FGIDs. The kynurenine (l-kyn) pathway (KP) is the major route for l-tryptophan (l-Trp) metabolism and transforms l-Trp into several neuroactive compounds. Changes in KP were reported in both migraine and FGIDs. Migraine was largely untreatable, but several drugs approved lately by the FDA, including monoclonal antibodies for calcitonin gene-related peptide (CGRP) and its receptor, create a hope for a breakthrough in migraine treatment. Derivatives of l-kyn were efficient in pain relief with a mechanism including CGRP inhibition. KP products are important ligands to the aryl hydrocarbon receptor (AhR), whose activation is implicated in the pathogenesis of GI and migraine. Toll-like receptors (TLRs) may play a role in migraine and IBS pathogeneses, and KP metabolites detected downstream of TLR activation may be an IBS marker. The TLR4 signaling was observed in initiating and maintaining migraine-like behavior through myeloid differentiation primary response gene 88 (MyD88) in the mouse. The aim of this review is to justify the view that KP modulation may provide common triggers for migraine and FGIDs with the involvement of TLR, AhR, and MyD88 activation.
... In another study feeding rats with Lactobacillus johnsonii, they found that level of serum kynurenine was significantly decreased in L. johnsonii fed rats compared to the controls (Valladares et al., 2013). Furthermore, plasma level of kynurenine was found to be increased in the patients with IBS relative to the controls and the IBS severity is correlated with kynurenine:tryptophan ratio (Fitzgerald et al., 2008;Gerard Clarke et al., 2009, 2012. These studies could indicate the possible link between the tryptophan metabolism and the gut-brain axis. ...
Although COVID-19 affects mainly lungs with a hyperactive and imbalanced immune response, gastrointestinal and neurological symptoms such as diarrhea and neuropathic pains have been described as well in patients with COVID-19. Studies indicate that gut–lung axis maintains host homeostasis and disease development with the association of immune system, and gut microbiota is involved in the COVID-19 severity in patients with extrapulmonary conditions. Gut microbiota dysbiosis impairs the gut permeability resulting in translocation of gut microbes and their metabolites into the circulatory system and induce systemic inflammation which, in turn, can affect distal organs such as the brain. Moreover, gut microbiota maintains the availability of tryptophan for kynurenine pathway, which is important for both central nervous and gastrointestinal system in regulating inflammation. SARS-CoV-2 infection disturbs the gut microbiota and leads to immune dysfunction with generalized inflammation. It has been known that cytokines and microbial products crossing the blood-brain barrier induce the neuroinflammation, which contributes to the pathophysiology of neurodegenerative diseases including neuropathies. Therefore, we believe that both gut–lung and gut–brain axes are involved in COVID-19 severity and extrapulmonary complications. Furthermore, gut microbial dysbiosis could be the reason of the neurologic complications seen in severe COVID-19 patients with the association of dysbiosis-related neuroinflammation. This review will provide valuable insights into the role of gut microbiota dysbiosis and dysbiosis-related inflammation on the neuropathy in COVID-19 patients and the disease severity.
... It was shown that the upregulation of the Indoleaminepyrrole 2,3-dioxygenase activates a metabolic pathway, which is also likely to be associated with the pathogenesis of IBS. Afterward, considerations have shown that both females [21] and males [22] with IBS have extended kynurenine concentrations compared to controls. Therefore, Fig. 1 Tryptophan Metabolism: Tryptophan is a substrate for the large neutral amino-acid transporter system and competes for transport with several other amino acids essential for brain function. ...
Serotonin or 5-hydroxytryptamine (5-HT)- a neurotransmitter of both the Enteric Nervous System and the Central Nervous System is synthesized by the hydroxylation of L- tryptophan to 5-hydroxytryptophan.
Serotonin has been associated with gut functions like assimilation and absorption, alongside the regulation of particle transport and fluid discharge in the gastrointestinal tract and its deficiency is found to be a prominent factor in the prevalence of gut disorders like Irritable Bowel Syndrome.
For this review, we assessed the conventional treatment methods of common drugs, with the recently accredited treatment options like dietary regulation, exercise, meditation, and acupuncture. Having found that the most commonly used drugs exhibited various side effects like nausea, fatigue, rash, and dizziness, an in-depth evaluation of different Indian dietary patterns and their respective effects on tryptophan levels has been highlighted to formulate an ideal diet for patients with Irritable Bowel Syndrome (IBS). This review seeks to explore the numerous studies conducted to link IBS with the lack of serotonin production in the body, alongside exploring the evidence associating certain foods with raised tryptophan levels to hypothesize a suitable Indian diet.
This review, in its essence, stresses the crucial need for further research on the dietary implications of common Indian foods and their FODMAP (Fermented Oligosaccharides, Disaccharides, Monosaccharides, And Polyols) contents, while underscoring the benefits of using unconventional and natural methods for the treatment of tryptophan-related gut disorders.
... Recently, inflammation was confirmed as a key in enhancing the TRP break-down along the TRP-KYN pathway in children and adolescents (Michels et al., 2018). IL-6, INF-γ, and TNFα were shown to accelerate TRP metabolism to produce KYN (Haverkamp et al., 2017;Michels et al., 2018;Fitzgerald et al., 2008;Wang et al., 2020). Present data revealed no relevant correlations between INF-γ and the indicators of TRP metabolism or the severity of depressive symptoms and TNF-α was not detectable in the whole study population. ...
The aim of the present study was to investigate possible associations between interleukin-6 (IL-6), interferon-gamma (INF-γ), tumor necrosis factor-alpha (TNF-α), lactoferrin and lipopolysaccharide binding protein (LBP) with TRP metabolism and signs of depression in a large cohort of outpatients referred for carbohydrate malab-sorption testing. Serum concentrations of IL-6, INF-γ, TNF-α, lactoferrin, LBP, tryptophan (TRP), kynurenine (KYN) and kynuric acid were determined in 250 adults referred for lactose and fructose malabsorption testing. All participants filled out the Beck Depression Inventory (BDI). Serum IL-6 levels were positively correlated with the BDI score (p = 0.001, ρ = 0.205) and indicators of TRP metabolism (KYN/TRP ratio, KYN) (P-values < 0.05, ρ = 0.176 and 0.136). Ninety-five individuals with a BDI score > 13 showed significantly higher IL-6 serum levels (1.7 [1.0-2.8] vs. 1.1 [0.8-1.7] pg/mL, p < 0.001) compared to 115 individuals with a BDI score ≤ 13. LBP showed a positive correlation with the KYN/TRP ratio (p = 0.005, ρ = 0.177). IL-6 and LBP were associated with indicators of TRP metabolism. IL-6 was found to be linked to signs of depression. Individuals with the presence of depressive symptoms showed higher serum IL-6 levels compared to individuals without depressive symptoms.
... One possible explanation for the pain felt in IBS resides within the gradual degradation of the kynurenine pathway and serotonin depletion. Having, as a result, a pro-inflammatory cascade, these modifications of the homeostasis could, in the future, be considered as a potential biological basis in order to certify the high comorbidity between IBS and the neuropsychiatric disorders [194,195]. ...
Background: Pain, a distinctive undesirable experience, encompasses several different and fluctuating presentations across varying mood disorders. Therefore, the present narrative review aimed to shed further light on the matter, accounting for both experimental animal models and clinical observations about major depressive disorder (MDD) pathology. Method: Major databases were inquired from inception until April 2016 for records about MDD and pain. Results: Pain and MDD are tightly associated with each other in a bi-directional fashion. Several cross-sectional and retrospective studies indicated a high presence of pain in the context of mood disorders, including MDD (up to 65%), but also increased prevalence rates in the case of mood disorders documented among people with a primary diagnosis of either psychological or somatic pain (prevalence rates exceeding 45%). The clinical implications of these observations suggest the need to account for mood and pain manifestations as a whole rather than distinct entities in order to deliver more effective interventions. Limitations: Narrative review, lack of systematic control groups (e.g., people with the primary diagnosis at review, but not the associated comorbidity as a study) to allow reliable comparisons. Prevalence rates and clinical features associated with pain varied across different studies as corresponding operational definitions did. Conclusions: Pain may have a detrimental effect on the course of mood disorders—the opposite holds. Promoting a timely recognition and management of such an often neglected comorbidity would therefore represent a primary goal toward the delivery of effective, multi-disciplinary care.
... Indeed, kynurenine levels increase in the serum of IBS patients 279 and the peripheral IDO1 activity positively correlates with IBS severity. 280 In the kynurenine pathway, kynurenic acid, as a modulator of glutamatergic NMDA receptor pathways, may have a role in development of IBS-associated visceral pain. Along the gastrointestinal tract, glutamate, via NMDA receptors, may act as an endogenous modulator of mechanosensitive pathways, transducing sensory stimuli deriving from pelvic and splanchnic afferents in response to neuroinflammation and hyperalgesia. ...
The ‘microbiota-gut-brain axis’ plays a fundamental role in maintaining host homeostasis, and different immune, hormonal, and neuronal signals participate to this interkingdom communication system between eukaryota and prokaryota. The essential aminoacid tryptophan, as a precursor of several molecules acting at the interface between the host and the microbiota, is fundamental in the modulation of this bidirectional communication axis. In the gut, tryptophan undergoes 3 major metabolic pathways, the 5-HT, kynurenine, and AhR ligand pathways, which may be directly or indirectly controlled by the saprophytic flora. The importance of tryptophan metabolites in the modulation of the gastrointestinal tract is suggested by several preclinical and clinical studies; however, a thorough revision of the available literature has not been accomplished yet. Thus, this review attempts to cover the major aspects on the role of tryptophan metabolites in host-microbiota cross-talk underlaying regulation of gut functions in health conditions and during disease states, with particular attention to 2 major gastrointestinal diseases, such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), both characterized by psychiatric disorders. Research in this area opens the possibility to target tryptophan metabolism to ameliorate the knowledge on the pathogenesis of both diseases, as well as to discover new therapeutic strategies based either on conventional pharmacological approaches or on the use of pre- and probiotics to manipulate the microbial flora.
... Because indoleamine 2,3-dioxygenase can shunt tryptophan in the brain to Kynurenine, it may lead to less serotonin production and its conversion to melatonin leading to sleep disorder. [57][58][59] Some microbes such as Clostridium sporogens, Lactobacolli, and Ruminococcus gnavus express tryptophanase and hence, help in serotonin biosynthesis. 60 As excess serotonergic function is associated with diarrhea and its reduction is associated with constipation, modulation of serotonin by its antagonists and agonists are useful in treatment of IBS-D and IBS-C ( Table 1). ...
Irritable bowel syndrome (IBS), a common functional gastrointestinal disorder (FGID), has often been considered rather inappropriately as psychogenic in the past. Though psychological issues are important co‐morbidities in a proportion of IBS patients, the evidences are far from enough to label this condition as psychogenic only. In the recent past, evidences are emerging that underscores the concept supporting pure psychogenic theory of IBS and suggest this disorder to be rather micro‐organic. Accordingly, a move of Rome IV Committee attempting to delete the term “functional” and designating these to be disorders of “gut‐brain interaction” rather than that of “brain‐gut interaction”; it emphasizes the importance of the gut over the brain in the pathogenesis. The introduction of the concept of multi‐dimensional clinical profile (MDCP) in Rome IV requires attention to diagnostic category of FGID, overlap, severity, psychological issues, and physiological dysfunction or biomarkers; this attempts to recognize clinical variability and multidimensionality of pathophysiology in management of these disorders. The recognition of the biological factors in the pathogenesis of IBS is a significant paradigm shift in the recent time. This is somewhat similar to the progress in the pathogenesis of peptic ulcer disease from psychological factor to acid to Helicobacter pylori infection. It is expected that in the near future, therapeutic modalities targeting the different of pathogenic mechanisms of different sub‐types of IBS may bring revolution in management of the disorder.
... These results differ from those of Fitzgerald who reported that IBS participants who rated their symptoms as severe as compared to HCs and IBS with less severe symptoms had higher morning levels of plasma kynurenine to Trp ratio. 40 Time of sample collection and the presence of a stressor in our study may explain these differences. ...
Background/aims:
Patients with irritable bowel syndrome (IBS) often report poor sleep quality. Whether poor sleep is associated with tryptophan (Trp) metabolites is unknown. We compared serum Trp metabolites in women with IBS and healthy controls (HCs) using targeted liquid chromatography mass spectrometry (LC-MS)-based profiling. In IBS only, we explored whether Trp metabolites are associated with IBS symptoms and subjective and objective sleep indices, serum cortisol, plasma adrenocorticotropic hormone (ACTH), and cortisol/ACTH levels.
Methods:
Blood samples were obtained every 80 minutes in 21 HCs and 38 IBS subjects following an anticipation-of-public-speaking stressor during a sleep laboratory protocol. Subjects completed symptom diaries for 28 days. Adjacent values of metabolites were averaged to represent 4 time-periods: awake, early sleep, mid-sleep, and mid-to-late sleep. Thirteen of 20 targeted Trp metabolites were identified.
Results:
Ten of 13 Trp metabolites decreased across the night, while nicotinamide increased in both groups. A MANOVA omnibus test performed after principal component analysis showed a significant difference in these 13 principal component (P = 0.014) between groups. Compared to HCs, nicotinamide levels were higher and indole-3-lactic acid levels lower in the IBS group. Melatonin and indole-3-acetic acid levels were associated with several subjective/objective sleep measures; decreased stool consistency/frequency and abdominal pain were positively associated with melatonin and serotonin in the IBS group. The kynurenine and kynurenic acid were associated with ACTH (positively) and cortisol/ACTH (negatively).
Conclusion:
Nighttime Trp metabolites may provide clues to poor sleep and stress with IBS. Further study of the mechanism of metabolite action is warranted.
This chapter introduces the current approaches to extract, separate, and detect tryptophan and its metabolites. Furthermore, high-throughput omics have also been included in this chapter to describe the large-scale study of tryptophan (Trp) metabolism. Among them, the detection of tryptophan and its metabolites can be achieved through high-performance liquid chromatography, capillary electrophoresis, near-infrared spectroscopy, amino acid analyzer, direct or indirect colorimetry, biosensors, or mass spectrometry. In addition, high-throughput metabolomics analysis is commonly used for rapid detection of Trp and its metabolites.
Mounting evidence points towards a crucial role of the kynurenine pathway (KP) in the altered gut-brain axis (GBA) balance in severe mental illness (SMI, namely depression, bipolar disorder, and schizophrenia) and cardiometabolic comorbidities. Preliminary evidence shows that serotonergic psychedelics and their analogues may hold therapeutic potential in addressing the altered KP in the dysregulated GBA in SMI and comorbidities. In fact, aside from their effects on mood, psychedelics elicit therapeutic improvement in preclinical models of obesity, metabolic syndrome, and vascular inflammation, which are highly comorbid with SMI.
Here, we review the literature on the therapeutic modulation of the KP in the dysregulated GBA in SMI and comorbidities, and the potential application of psychedelics to address the altered KP in the brain and systemic dysfunction underlying SMI and comorbidities. Psychedelics might therapeutically modulate the KP in the
altered GBA in SMI and comorbidities either directly, via altering the metabolic pathway by influencing the ratelimiting enzymes of the KP and affecting the levels of available tryptophan, or indirectly, by affecting the gut microbiome, gut metabolome, metabolism, and the immune system.
Despite promising preliminary evidence, the mechanisms and outcomes of the KP modulation with psychedelics
in SMI and systemic comorbidities remain largely unknown and require further investigation. Several concerns are discussed surrounding the potential side effects of this approach in specific cohorts of individuals with SMI and systemic comorbidities.
A growing appreciation for the role of the gut microbiome in health and disease, coupled with recent advances in microbiome-related research, has emphasized the importance of the gut microbiota in regulating brain function and behavior. Increasing clinical and preclinical studies are strengthening the concept that the microbiota-gut-brain axis plays a central role in maintaining cellular homeostasis and contributes to the pathophysiology of numerous brain diseases. The modes of communication between the gut microbiota and the brain are slowly being uncovered and include immune signaling pathways, host-microbe interactions in the enteric nervous system, tryptophan metabolism, the vagus nerve, gut hormone signaling, and signaling via microbial metabolites such as short chain fatty acids (SCFA). Indeed, animal models have been of paramount importance in unravelling the role of the gut microbiota in modulating brain function and behavior. Altered gut microbiota compositions have been implicated in a myriad of conditions including neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. Future studies aim to focus on understanding the mechanistic links between the gut microbiota and the brain, enabling the development of novel therapeutic strategies for multifaceted central nervous system (CNS) disorders.
In this systematic review and meta-analysis, a normative dataset is generated from the published literature on the kynurenine pathway in control participants extracted from case-control and methodological validation studies. Study characteristics were mapped, and studies were evaluated in terms of analytical rigour and methodological validation. Meta-analyses of variance between types of instruments, sample matrices and metabolites were conducted. Regression analyses were applied to determine the relationship between metabolite, sample matrix, biological sex, participant age and study age. The grand mean concentrations of tryptophan in the serum and plasma were 60.52 ± 15.38 μM and 51.45 ± 10.47 μM, respectively. The grand mean concentrations of kynurenine in the serum and plasma were 1.96 ± 0.51 μM and 1.82 ± 0.54 μM, respectively. Regional differences in metabolite concentrations were observed across America, Asia, Australia, Europe and the Middle East. Of the total variance within the data, mode of detection (MOD) accounted for up to 2.96%, sample matrix up to 3.23%, and their interaction explained up to 1.53%; the latter of which was determined to be negligible. This review was intended to inform future empirical research and method development studies and successfully synthesised pilot data. The pilot data reported in this study will inform future precision medicine initiatives aimed at targeting the kynurenine pathway by improving the availability and quality of normative data.
Introduction:
Diet is considered a culprit for symptoms in irritable bowel syndrome (IBS), although mechanistic understanding of underlying causes is lacking. Metabolomics, i.e. the analysis of metabolites in biological samples may offer a diet-responsive fingerprint for IBS. Our aim was to explore alterations in the plasma metabolome after interventions with fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) or gluten versus control in IBS, and to relate such alterations to symptoms.
Methods:
People with IBS (n=110) were included in a double-blind, randomized, crossover study with one-week provocations of FODMAPs, gluten or placebo. Symptoms were evaluated with the IBS severity scoring system (IBS-SSS). Untargeted metabolomics was performed on plasma samples using LC-qTOF-MS. Discovery of metabolite alterations by treatment was performed using random forest followed by linear mixed modelling. Associations were studied using Spearman correlation.
Results:
The metabolome was affected by FODMAP (classification rate (CR) 0.88, p<0.0001), but less by gluten intake CR 0.72, p=0.01). FODMAP lowered bile acids, whereas phenolic-derived metabolites and 3-indolepropionic acid (IPA) were higher compared to placebo. IPA and some unidentified metabolites correlated weakly to abdominal pain and quality of life. Gluten affected lipid metabolism weakly, but with no interpretable relationship to IBS.
Conclusions:
FODMAP affected gut microbial-derived metabolites relating to positive health outcomes. IPA and unknown metabolites correlated weakly to IBS severity. Minor symptom worsening by FODMAP intake must be weighed against general positive health aspects of FODMAP. The gluten intervention affected lipid metabolism weakly with no interpretable association to IBS severity.
Registration:
www.
Clinicaltrials:
gov as NCT03653689.
Irritable bowel syndrome (IBS) is the most commonly diagnosed illness by gastroenterologists. These symptoms occur widely in the general population at all ages and in both sexes. The condition is a considerable health-care burden, accounting for approximately half of all referrals to gastrointestinal clinics. The prevalence of IBS varies according on geographic region, demographic, and diagnostic criteria employed. IBS pathogenesis is complicated and poorly understood. Gut microbiota, small intestinal bacterial overgrowth (SIBO), visceral hypersensitivity, disruption of the gut-brain axis, psychosocial distress, and altered GI motility all are proposed as potential risk factors. Inflammatory bowel syndrome (IBS) is associated with considerable psychosocial comorbidities, which have an impact on patient quality of life, disease progression, and health-care expenditures. The present article reviews the latest evidence on the aetiology IBS, with a focus on psychiatric comorbidities and available management available.
Visceral hypersensitivity, a hallmark of disorders of the gut‐brain axis, is associated with exposure to early‐life stress (ELS). Activation of neuronal β3‐adrenoceptors (AR) has been shown to alter central and peripheral levels of tryptophan and reduce visceral hypersensitivity. In this study, we aimed to determine the potential of a β3‐AR agonist in reducing ELS‐induced visceral hypersensitivity and possible underlying mechanisms. Here, ELS was induced using the maternal separation (MS) model, where Sprague Dawley rat pups were separated from their mother in early life (postnatal day 2–12). Visceral hypersensitivity was confirmed in adult offspring using colorectal distension (CRD). CL‐316243, a β3‐AR agonist, was administered to determine anti‐nociceptive effects against CRD. Distension‐induced enteric neuronal activation as well as colonic secretomotor function were assessed. Tryptophan metabolism was determined both centrally and peripherally. For the first time, we showed that CL‐316243 significantly ameliorated MS‐induced visceral hypersensitivity. Furthermore, MS altered plasma tryptophan metabolism and colonic adrenergic tone, while CL‐316243 reduced both central and peripheral levels of tryptophan and affected secretomotor activity in the presence of tetrodotoxin. This study supports the beneficial role of CL‐316243 in reducing ELS‐induced visceral hypersensitivity, and suggests that targeting the β3‐AR can significantly influence gut‐brain axis activity through modulation of enteric neuronal activation, tryptophan metabolism, and colonic secretomotor activity which may synergistically contribute to offsetting the effects of ELS.
image
Background:
Optimal composition of intestinal bacteria is an essential condition for good health. Excessive growth of these bacteria can cause various ailments. The aim of this study was to assess the mental state and gastrointestinal complaints of patients with small intestinal bacterial overgrowth (SIBO) in relation to tryptophan metabolism and rifaximin treatment.
Methods:
120 subjects, aged 23-61 years, were enrolled in the study, and divided into 3 groups, 40 individuals each: healthy subjects (Controls), patients with SIBO and chronic diarrhea (SIBO-D), and with chronic constipation (SIBO-C). The lactulose hydrogen breath test (LHBT) was performed to diagnose SIBO. The mental state of patients was assessed using the Hamilton Anxiety Rating Scale (HAM-A), and the Hamilton Depression Rating Scale (HAM-D). L-tryptophan (TRP) and its metabolites: 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), xanthurenic acid (XA) and quinolinic acid (QA) were measured in urine by liquid-chromatography-tandem mass spectrometry and related to creatinine level. Patients with SIBO were recommended to take rifaximin for 10 days at daily dose 1200 mg, and this cycle was repeated in subsequent two months.
Results:
Mild and moderate anxiety, as well as mild depression were diagnosed in all SIBO patients. Changes in TRP metabolism were also observed in these patients. Specifically, an increase in the activity of the serotonin pathway of TRP metabolism in the group SIBO-D was observed. The SIBO-C patients showed an increase in the concentration of KYN, XA and QA. 5-HIAA/TRP and KYN/TRP ratios significantly decreased in group SIBO-D, and KYN and QA levels decreased in group SIBO-C after treatment with rifaximin. The levels of anxiety and depression decreased in both groups.
Conclusion:
Rifaximin treatment of SIBO patients ameliorated their mood disorders and gastrointestinal aliments underlined by changes in tryptophan metabolism. Trial registration Retrospectively registered (if applicable).
The essential amino acid tryptophan, under physiological conditions, self-assembles into amyloid-mimicking neurotoxic nanostructures, capable of driving amyloid cross-seeding of diverse proteins.
Major depressive disorder (MDD) is a common mental illness characterized by persistent low mood and anhedonia, normally accompanied with cognitive impairment. Due to its rising incidence and high rate of recurrence and disability, MDD poses a substantial threat to patients’ physical and mental health, as well as a significant economic cost to society. However, the etiology and pathogenesis of MDD are still unclear. Chronic inflammation may cause indoleamine-2,3-dioxygenase (IDO) to become overactive throughout the body and brain, resulting in excess quinolinic acid (QUIN) and less kynuric acid (KYNA) in the brain. QUIN’s neurotoxicity damages glial cells and neurons, accelerates neuronal apoptosis, hinders neuroplasticity, and causes depression due to inflammation. Therefore, abnormal TRP-KYN metabolic pathway and its metabolites have been closely related to MDD, suggesting changes in the TRP-KYN metabolic pathway might contribute to MDD. In addition, targeting TRP-KYN with traditional Chinese medicine showed promising treatment effects for MDD. This review summarizes the recent studies on the TRP-KYN metabolic pathway and its metabolites in depression, which would provide a theoretical basis for exploring the etiology and pathogenesis of depression.
The gut-brain axis is largely responsible for the health of the gut. Its dysfunction caused by peripheral or central mechanisms elicit digestive symptoms and mood disorders. The typical disorders caused by the dysfunction of the gut-brain axis are the functional gastrointestinal disorders. The progress in their knowledge lead to the conclusion that these are not idiopathic conditions but sufferance caused by the alteration of the gastrointestinal functions and of the communication between the gastrointestinal tract and the brain. The disorders of the gut-bran interaction largely known as functional gastrointestinal disorders are diagnosed and classified according to the outcomes of the working committees of the Rome Foundation. They are classified according to the topographic segment of the digestive tract to which the symptoms are attributed. The therapy of the functional gastrointestinal disorders is based on a comprehensive approach using the biopsychosocial model of disease. In this review we present the main functional gastrointestinal disorders and their management. Pharmacological therapy remains largely symptom-addressed but lifestyle and diet recommendations as well as psychotherapy are also important.
The human gut harbors more than 1014 microorganisms, with bacteria being the main population. Gut microbial composition and diversity participates in vital physiologic and immunologic processes maintaining host homeostasis. The disruption of the healthy microbial structure has been associated with various gastrointestinal disorders including inflammatory bowel disease, celiac disease, irritable bowel syndrome and others.KeywordsMicrobiotaInflammatory bowel diseaseCrohn’s diseaseUlcerative colitisIrritable bowel syndromeBrain–gut–microbiome axisCeliacFecal microbial transplantation
Lactobacillus casei (L. casei), a kind of probiotics, is known as a “healthy triple benefit bacterium” along with Lactobacillus acidophilus and Bifidobacterium. L. casei is associated with the alteration of the intestinal flora population, and the gut microbiota–brain axis has been demonstrated to play an important role in many central nervous system diseases. The aim of this study was to evaluate the effectiveness of L. casei intervention on ameliorating mental disorders and potential mechanisms using a depression-like rat model induced by chronic unpredictable mild stress (CUMS). L. casei intervention improved CUMS-induced depression-like behaviors of rats, including reduced body growth rate, decreased sucrose preference, increased immobility time, lowered moving distance and velocity. In addition, L. casei intervention amended gut microbiota structure changes induced by CUMS in rats. Furthermore, L. casei intervention reversed CUMS-induced protein expression changes of monoamines dopamine, noradrenaline and 5-hydroxytryptamine, brain-derived neurotrophic factor (BDNF) and its receptor of tyrosine kinase receptor B (TrkB), N-methyl-D-aspartic acid receptor 1, as well as CUMS-induced activations of ERK1/2 and p38 MAPK signal pathways. These findings suggested that L. casei could significantly protect against depression of rats, which was possibly associated with the alterations in the gut microbiota composition and mediations of BDNF-TrkB signaling.
Background
Understanding the mechanisms underpinning the response to acute stress is critical for determining how this can be modulated in both health and disease and across sexes. Stress can markedly alter the microbiome and gut‐brain axis signaling with the serotonergic system being particularly sensitive to acute stress. As the impact of acute stress on regional serotonergic dynamics in the gut‐brain axis and the contribution of the microbiome to this are poorly appreciated, we used microbiota‐deficient mice to assess whether the serotonergic response to acute stress exposure is microbiome dependent.
Methods
Adult male and female conventional, germ‐free, and colonized germ‐free mice underwent a single acute stressor and samples were harvested immediately or 45 minutes following stress. Serotonin and related metabolites and serotonergic gene expression were determined.
Key Results
Our data clearly show the microbiota influenced gastrointestinal serotonergic response to acute stress in a sex‐ and region‐dependent manner. Male‐specific poststress increases in colonic serotonin were absent in germ‐free mice but normalized following colonization. mRNA serotonergic gene expression was differentially expressed in colon and ileum of germ‐free mice on a sex‐dependent basis. Within the frontal cortex, absence of the microbiome altered basal serotonin, its main metabolite 5‐hydroxyindoleacetic acid, and prevented stress‐induced increases in serotonin turnover.
Conclusions and Inferences
The gut microbiome influences the set points of the brain and gastrointestinal serotonergic systems and affected their response to acute stress in a sex‐ and region‐dependent manner.
Tryptophan (TRP), an essential amino acid in mammals, is involved in several physiological processes including neuronal function, immunity, and gut homeostasis. In humans, TRP is metabolized via the kynurenine and serotonin pathways, leading to the generation of biologically active compounds, such as serotonin, melatonin and niacin. In addition to endogenous TRP metabolism, resident gut microbiota also contributes to the production of specific TRP metabolites and indirectly influences host physiology.
The variety of physiologic functions regulated by TRP reflects the complex pattern of diseases associated with altered homeostasis. Indeed, an imbalance in the synthesis of TRP metabolites has been associated with pathophysiologic mechanisms occurring in neurologic and psychiatric disorders, in chronic immune activation and in the immune escape of cancer. In this chapter, the role of TRP metabolism in health and disease is presented. Disorders involving the central nervous system, malignancy, inflammatory bowel and cardiovascular disease are discussed.
Anxiety disorders are a complex set of illnesses in which genetic factors, particularly stress, play a role in the etiopathogenesis. In recent years, inflammation and intestinal microbiota have also been included in this complex network of relationships. The functions associated with tryptophan catabolism and serotonin biosynthesis have long been associated with anxiety disorders. Tryptophan catabolism progresses toward the path of the kynurenine in the presence of stress and inflammation. The catabolism of kynurenine is a pathway in which many enzymes play a role and a large number of catabolites with neuroactive properties occur. The body’s serotonin biosynthesis is primarily performed by enterochromaffin cells located in the intestines. A change in the intestinal microbiota composition (dysbiosis) directly affects the serotonin biosynthesis. Stress, unhealthy nutrition, and the use of antibiotics cause dysbiosis. In the light of this new perspective, the role of dysbiosis-induced inflammation and kynurenine pathway catabolites activated sequentially come into prominence in the etiopathogenesis of anxiety disorders.
Depresi merupakan suatu keadaan yang mempengaruhi seseorang secara afektif, fisiologis, kognitif dan perilaku sehingga mengubah pola dan respon yang biasa dilakukan. Psikoneuroimunologi adalah bidang yang mempelajari interaksi antara sistem saraf dan imunitas, dan hubungan antara perilaku dan kesehatan. Fokus utama adalah respon imunologi dan psikologis terhadap stres. Kajian psikoneuroimunologi, menunjukkan adanya jalur komunikasi timbal balik antara sistem saraf, endokrin dan sistem munitas. Adanya keterlibatan dari sistem imunitas dalam gangguan kejiwaan. Beberapa penelitian menunjukkan adanya kelainan neuroimmune berhubungan dengan kejadian depresi. Interaksi dan gangguan sistem neuroimmune dan neuroendokrin diperantarai sel dan humoral, berhubungan dengan patofisiologi atau patogenesis penyakit depresi. Penyebab depresi dalam sistem imunitas menyatakan bahwa sitokin dapat menyebabkan efek sentral dan perifer yang mempengaruhi perubahan psikologis dan fisiologis. Induksi sitokin pada pasien yang rentan dapat berkembang menjadi gangguan depresi. Trauma pada masa kecil sebagai faktor kerentanan penyebab depresi. Adanya kelainan pada regulasi respon neuroendokrin pada pasien depresi, dengan hiperaktivitas sumbu HPA yang didorong oleh hipersekresi hormon hipotalamus peptida corticotropine (CRH), Daerah tertentu dari otak, termasuk hippocampus, lebih mudah terjadi kerusakan jika terjadi peningkatan glukokortikoid. Peradangan dan sitokin berperan penting dalam mengatur hubungan antara stres dan perkembangan depresi, menunjukkan hubungan yang kompleks antara stres, sistem imun dan neuroendokrin. Stres psikologis meningkatkan sitokin pro-inflamasi, yang merespon reaksi stres dan kecemasan pada pasien. Peningkatan aktivitas makrofag dan produksi sitokin pro-inflamasi dan beberapa protein fase akut telah dilaporkan secara konsisten.
Serotonin (5-HT) is a critical signaling molecule in the gut. 5-HT released from enterochromaffin cells initiates peristaltic, secretory, vasodilatory, vagal, and nociceptive reflexes. Despite being pathophysiologically divergent, ulcerative colitis (UC) and irritable bowel syndrome (IBS) are both associated with clinical symptoms that include alterations in the normal patterns of motility, secretion, and sensation. Our aim was to test whether enteric 5-HT signaling is defective in these disorders.
Rectal biopsy specimens were obtained from healthy controls and patients with UC, IBS with diarrhea (IBS-D), and IBS with constipation (IBS-C). Key elements of 5-HT signaling, including measures of 5-HT content, release, and reuptake, were analyzed with these samples.
Mucosal 5-HT, tryptophan hydroxylase 1 messenger RNA, serotonin transporter messenger RNA, and serotonin transporter immunoreactivity were all significantly reduced in UC, IBS-C, and IBS-D. The enterochromaffin cell population was decreased in severe UC samples but was unchanged in IBS-C and IBS-D. When 5-HT release was investigated under basal and mechanical stimulation conditions, no changes were detected in any of the groups relative to controls.
These data show that UC and IBS are associated with similar molecular changes in serotonergic signaling mechanisms. While UC and IBS have distinct pathophysiologic properties, these data suggest that shared defects in 5-HT signaling may underlie the altered motility, secretion, and sensation. These findings represent the first demonstration of significant molecular alterations specific to the gut in patients with IBS and support the assertion that disordered gastrointestinal function in IBS involves changes intrinsic to the bowel.
Context
The Primary Care Evaluation of Mental Disorders (PRIME-MD) was developed
as a screening instrument but its administration time has limited its clinical
usefulness.Objective
To determine if the self-administered PRIME-MD Patient Health Questionnaire
(PHQ) has validity and utility for diagnosing mental disorders in primary
care comparable to the original clinician-administered PRIME-MD.Design
Criterion standard study undertaken between May 1997 and November 1998.Setting
Eight primary care clinics in the United States.Participants
Of a total of 3000 adult patients (selected by site-specific methods
to avoid sampling bias) assessed by 62 primary care physicians (21 general
internal medicine, 41 family practice), 585 patients had an interview with
a mental health professional within 48 hours of completing the PHQ.Main Outcome Measures
Patient Health Questionnaire diagnoses compared with independent diagnoses
made by mental health professionals; functional status measures; disability
days; health care use; and treatment/referral decisions.Results
A total of 825 (28%) of the 3000 individuals and 170 (29%) of the 585
had a PHQ diagnosis. There was good agreement between PHQ diagnoses and those
of independent mental health professionals (for the diagnosis of any 1 or
more PHQ disorder, κ = 0.65; overall accuracy, 85%; sensitivity, 75%;
specificity, 90%), similar to the original PRIME-MD. Patients with PHQ diagnoses
had more functional impairment, disability days, and health care use than
did patients without PHQ diagnoses (for all group main effects, P<.001). The average time required of the physician to review the
PHQ was far less than to administer the original PRIME-MD (<3 minutes for
85% vs 16% of the cases). Although 80% of the physicians reported that routine
use of the PHQ would be useful, new management actions were initiated or planned
for only 117 (32%) of the 363 patients with 1 or more PHQ diagnoses not previously
recognized.Conclusion
Our study suggests that the PHQ has diagnostic validity comparable to
the original clinician-administered PRIME-MD, and is more efficient to use.
Figures in this Article
Mental disorders in primary care are common, disabling, costly, and
treatable.1- 5
However, they are frequently unrecognized and therefore not treated.2- 6
Although there have been many screening instruments developed,7- 8
PRIME-MD (Primary Care Evaluation of Mental Disorders)5
was the first instrument designed for use in primary care that actually diagnoses
specific disorders using diagnostic criteria from the Diagnostic
and Statistical Manual of Mental Disorders, Revised Third Edition9(DSM-III-R) and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition10(DSM-IV).
PRIME-MD is a 2-stage system in which the patient first completes a
26-item self-administered questionnaire that screens for 5 of the most common
groups of disorders in primary care: depressive, anxiety, alcohol, somatoform,
and eating disorders. In the original study,5
the average amount of time spent by the physician to administer the clinician
evaluation guide to patients who scored positively on the patient questionnaire
was 8.4 minutes. However, this is still a considerable amount of time in the
primary care setting, where most visits are 15 minutes or less.11
Therefore, although PRIME-MD has been widely used in clinical research,12- 28
its use in clinical settings has apparently been limited. This article describes
the development, validation, and utility of a fully self-administered version
of the original PRIME-MD, called the PRIME-MD Patient Health Questionnaire
(henceforth referred to as the PHQ).
DESCRIPTION OF PRIME-MD PHQ
ABSTRACT
|
DESCRIPTION OF PRIME-MD PHQ
|
STUDY PURPOSE
|
METHODS
|
RESULTS
|
COMMENT
|
REFERENCES
The 2 components of the original PRIME-MD, the patient questionnaire
and the clinician evaluation guide, were combined into a single, 3-page questionnaire
that can be entirely self-administered by the patient (it can also be read
to the patient, if necessary). The clinician scans the completed questionnaire,
verifies positive responses, and applies diagnostic algorithms that are abbreviated
at the bottom of each page. In this study, the data from the questionnaire
were entered into a computer program that applied the diagnostic algorithms
(written in SPSS 8.0 for Windows [SPSS Inc, Chicago, Ill]). The computer program
does not include the diagnosis of somatoform disorder, because this diagnosis
requires a clinical judgment regarding the adequacy of a biological explanation
for physical symptoms that the patient has noted.
A fourth page has been added to the PHQ that includes questions about
menstruation, pregnancy and childbirth, and recent psychosocial stressors.
This report covers only data from the diagnostic portion (first 3 pages) of
the PHQ. Users of the PHQ have the choice of using the entire 4-page instrument,
just the 3-page diagnostic portion, a 2-page version (Brief PHQ) that covers
mood and panic disorders and the nondiagnostic information described above,
or only the first page of the 2-page version (covering only mood and panic
disorders) (Figure 1).
Figure 1. First Page of Primary Care Evaluation
of Mental Disorders Brief Patient Health QuestionnaireGrahic Jump Location+View Large |
Save Figure |
Download Slide (.ppt)
|
View in Article ContextCopyright held by Pfizer Inc, but may be photocopied ad libitum.
For office coding, see the end of the article.
The original PRIME-MD assessed 18 current mental disorders. By grouping
several specific mood, anxiety, and somatoform categories into larger rubrics,
the PHQ greatly simplifies the differential diagnosis by assessing only 8
disorders. Like the original PRIME-MD, these disorders are divided into threshold
disorders (corresponding to specific DSM-IV diagnoses,
such as major depressive disorder, panic disorder, other anxiety disorder,
and bulimia nervosa) and subthreshold disorders (in which the criteria for
disorders encompass fewer symptoms than are required for any specific DSM-IV diagnoses: other depressive disorder, probable alcohol
abuse or dependence, and somatoform and binge eating disorders).
One important modification was made in the response categories for depressive
and somatoform symptoms that, in the original PRIME-MD, were dichotomous (yes/no).
In the PHQ, response categories are expanded. Patients indicate for each of
the 9 depressive symptoms whether, during the previous 2 weeks, the symptom
has bothered them "not at all," "several days," "more than half the days,"
or "nearly every day." This change allows the PHQ to be not only a diagnostic
instrument but also to yield a measure of depression severity that can be
of aid in initial treatment decisions as well as in monitoring outcomes over
time. Patients indicate for each of the 13 physical symptoms whether, during
the previous month, they have been "not bothered," "bothered a little," or
"bothered a lot" by the symptom. Because physical symptoms are so common in
primary care, the original PRIME-MD dichotomous-response categories often
led patients to endorse physical symptoms that were not clinically significant.
An item was added to the end of the diagnostic portion of the PHQ asking
the patient if he or she had checked off any problems on the questionnaire:
"How difficult have these problems made it for you to do your work, take care
of things at home, or get along with other people?" As with the original PRIME-MD,
before making a final diagnosis, the clinician is expected to rule out physical
causes of depression, anxiety and physical symptoms, and, in the case of depression,
normal bereavement and history of a manic episode.
STUDY PURPOSE
ABSTRACT
|
DESCRIPTION OF PRIME-MD PHQ
|
STUDY PURPOSE
|
METHODS
|
RESULTS
|
COMMENT
|
REFERENCES
Our major purpose was to test the validity and utility of the PHQ in
a multisite sample of family practice and general internal medicine patients
by answering the following questions:
Are diagnoses made by the PHQ as accurate as diagnoses
made by the original PRIME-MD, using independent diagnoses made by mental
health professionals (MHPs) as the criterion standard?Are the frequencies of mental disorders found by
the PHQ comparable to those obtained in other primary care studies?Is the construct validity of the PHQ comparable
to the original PRIME-MD in terms of functional impairment and health care
use?Is the PHQ as effective as the original PRIME-MD
in increasing the recognition of mental disorders in primary care patients?How valuable do primary care physicians find the
diagnostic information in the PHQ?How comfortable are patients in answering the questions
on the PHQ, and how often do they believe that their answers will be helpful
to their physicians in understanding and treating their problems?
Psychological and anamnestic data from 308 patients were collected to investigate whether patients with abdominal complaints from organic causes could be distinguished psychologically or by their case histories from patients with functional abdominal complaints. Two years later the same patients took part in a follow up study. Only 9% of the patients with functional abdominal complaints became symptom free. Most variables showed no significant difference between the organic and the functional group. The most important variables with predictive value were psychological factors, factors associated with the severity and factors associated with the duration of the complaints.
Little is known about the comparability of outpatients with irritable bowel syndrome (IBS) and patients with IBS in primary care with regard to severity of complaints, perceived limitations, other aspects of the complaints, and sex differences.
To compare outpatients with IBS with primary care patients with IBS.
One hundred and nine patients with IBS were recruited from general practices in Amsterdam and 86 patients with IBS were recruited from the outpatient clinic of the Department of Internal Medicine of the University Hospital in Nijmegen.
Each patient completed a questionnaire on demographic variables, abdominal complaints, related complaints, and attributed causes of their abdominal complaints. The scores of the two groups were compared by univariate and multivariate analysis.
The outpatient group contained significantly more men, reported more severe abdominal pain, more frequent complaints, more interference with daily activities, and a higher degree of avoidance of activities (p < 0.01) than the primary care group. When each sex was analysed separately, these differences remained for female (p < 0.01) but not for male patients. Outpatients were more likely to attribute their complaints to somatic causes (p < 0.01), whereas primary care patients were more likely to attribute their complaints to stress (p < 0.01) or their agitated way of life (p < 0.05). Multivariate analysis showed that a high severity score, a large number of additional complaints, and a low score on the stress attribution were important determinants for being in the outpatient group.
Female outpatients consider their complaints to be more serious and interfering than do patients with IBS in primary care. Male outpatients were comparable to primary care patients with IBS. More research needs to be done into sex specific differences in IBS and into the factors that influence the decision to refer a patient with IBS.
Over the past 10 years the technique of tryptophan depletion has been used increasingly as a tool for studying brain serotonergic systems.
To review the technique of tryptophan depletion and its current status as a tool for investigating psychiatric disorders.
Systematic review of preclinical and clinical studies.
Tryptophan depletion produces a marked reduction in plasma tryptophan and consequently brain serotonin (5-HT) synthesis and release. In healthy volunteers the effects of tryptophan depletion are influenced by the characteristics of the subjects and include some mood lowering, some memory impairment and an increase in aggression. In patients with depression tryptophan depletion tends to result in no worsening of depression in untreated subjects but a relapse in those who have responded to antidepressants (particularly serotonergic agents). In panic disorder the results are similar.
The findings that tryptophan depletion produces a relapse of symptoms in patients with depression and panic disorder who have responded to treatment with antidepressants suggests that enhanced 5-HT function is important in maintaining response in these conditions.
Interferon-gamma (IFN-gamma)-induced indoleamine 2,3-dioxygenase (IDO) activity inhibits the growth of susceptible intracellular pathogens by catalyzing the oxidative cleavage of the indole ring of L-tryptophan and depleting pools of the essential amino acid. Tumor necrosis factor-alpha (TNF-alpha) synergistically enhances the IDO activity induced by IFN-gamma at the level of transcription in human epithelial cells. The purpose of this study was to characterize the molecular mechanisms responsible for synergistic gene expression in response to IFN-gamma and TNF-alpha. It was found that IFN-gamma-induced mechanisms, such as the binding of Stat1 to gamma activation sequences (GAS) and IFN regulatory factor-1 (IRF-1) to IFN-stimulated response elements (ISREs), are more highly activated following treatment with IFN and TNF-alpha. This enhanced signal transduction may be due to the increase in IFN-gamma receptor (IFNGR) expression following combined cytokine stimulation and is a likely contributor to the synergy. Additionally, the contribution of a third previously uncharacterized GAS element that forms a complex with Stat1 was investigated using a plasmid reporter system that controls for copy number. When the GAS-3 sequence was included in the regulatory region, gene expression was significantly increased relative to a region containing the mutated GAS-3. This suggests that GAS-3 is transcriptionally active and contributes to IFN-gamma-induced regulation of the IDO gene.
Serotonin, a key denominator of the brain-gut axis, is involved in the regulation of gastrointestinal motility, secretion, and perception as well as cognition and mood.
To assess the effects of an acutely lowered serotonin synthesis, using the acute tryptophan depletion (ATD) method, on visceral perception, affective memory performance, and mood in diarrhoea predominant irritable bowel syndrome patients (d-IBS) and controls.
In a randomised, double blind, crossover design, 14 d-IBS patients and fourteen matched controls were studied under ATD and placebo conditions, respectively. Perception of urge and pain was scored during rectal distensions. Affective memory performance, mood, and biochemical parameters of serotonergic metabolism were simultaneously assessed.
ATD significantly decreased plasma tryptophan (67.0 (2.0) v 24.9 (2.0) mumol/l) and 5-hydroxyindole acetic acid concentrations (29.9 (1.0) v 15.8 (0.6) nmol/l). ATD was associated with significantly increased urge scores specifically in the lower pressure range and overall increased pain scores. ATD significantly lowered the perceptual threshold for first perception compared with placebo (patients 10.6 (1.2) v 13.6 (0.8) mm Hg, controls 12.6 (1.3) v 15.7 (1.2) mm Hg) but not for maximal tolerable discomfort (patients 50.5 (3.6) v 51.6 (3.3) mm Hg, controls 50.9 (3.3) v 48.8 (2.9) mm Hg). ATD induced a significant shift in affective memory bias towards preferential loss of positive material but no significant changes in mood. ATD did not differentially affect the patient or control group.
We have provided evidence that serotonergic modulation by ATD affects both visceral perception as well as cognition in d-IBS and controls. Simultaneous measurement of brain and gut function and the application of ATD contribute to the elucidation of the complex pathophysiology of IBS.
Interferon-gamma (IFN-gamma) induces the enzyme indoleamine dioxygenase (IDO) in a variety of human cell types. Furthermore, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) synergistically increase IFN-induced IDO activity. Inasmuch as cytokines can upregulate cytokine receptor expression, one mechanism of cytokine synergy may be at the level of receptor expression. To test the hypothesis that this mechanism of IDO regulation is active in epithelial cells, HeLa cells were treated with IFN-gamma, TNF-alpha, or IL-1beta to determine optimal cytokine concentrations and time for maximal cytokine receptor expression. Flow cytometric analysis with antibodies to receptors for IFN-gamma, TNF-alpha, or IL-1beta indicated that each cytokine upregulated expression of the other cytokine receptors by 4 h, with maximal expression observed between 16 and 20 h after cytokine treatment. Furthermore, increases in IFN-gamma receptors (IFNGR) induced by IL-1beta were found to be dependent on NF-kappaB transactivation. To determine if increases in IFNGR expression alone contributes to synergistic IDO induction, cells were stimulated with IL-1beta to upregulate receptor expression, and the NF-kappaB concentration was allowed to return to basal levels. When treated with IFN-gamma, enhanced Stat1 signaling and IDO induction were still observed, indicating that increased cytokine receptor expression contributes to synergistic increases in IDO activity.
Introduction: It has been demonstrated that glutamate, the major N-methyl-D-asparate (NMDA) receptor agonist in the central nervous system, could play a role in the mechanism of pain in the enteric nervous system. Recently, other NMDA receptor agonists and antagonists, the tryptophan metabolites of kynurenic pathway, were also found in the periphery, where they might be responsible for visceral pain. Objectives: Our aim was to evaluate the level of kynurenine metabolites in the serum of irritable bowel syndrome (IBS) patients. Materials and methods: 37 IBS patients (M/F = 11/26, mean age - 49 year), qualified according to Rome II Criteria, and 20 healthy volunteers (M/F = 9/11 mean age - 45 year) were included into the study. Tryptofan, serotonin, kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, kynurenic acid, anthranilic acid were assayed using the HPLC method in the samples of blood taken from all subjects. Acute phase parameters were measured in both IBS patients and controls to exclude other inflammatory sources of kynurenine metabolites. Results: We have observed a significantly decreased concentration of kynurenic acid (NMDA receptor antagonist) and a marked increase in anthranilic and 3-hydroxyanthranilic acid (precursors of endogenous NMDA receptor agonist) in IBS patients (p=0.013), compared to controls. Acute phase parameters were not changed in both studied groups. We demonstrated, for the first time, a marked decrease in the concentration of endogenous NMDA receptor antagonist in IBS patients. Moreover, the concentrations of the precursors of endogenous NMDA receptor agonist were higher, as compared to controls. Conclusions: Our results may have some clinical implications in the view of understanding the mechanisms of visceral pain in IBS subjects and/or in looking for some biochemical markers of visceral hypersensitivity.
Objective:
To investigate the effects of tryptophan depletion in untreated depressed patients. Rapid dietary depletion of the precursor of serotonin synthesis, tryptophan, causes a transient return of depression in 67% of patients who have had a therapeutic antidepressant response.
Method:
Forty-three untreated depressed patients underwent tryptophan depletion in a double-blind, placebocontrolled cross-over study. After testing, they received open sequential antidepressant treatment.
Results:
Mood did not change when tryptophan was depleted but did change on the day after the depletion test. Relative to the control test, 37% of the patients had 10-point or greater decrease in Hamilton Depression Rating Scale (Ham-D) score, while 23% had a 10-point or greater increase in Ham-D score on the day after the tryptophan depletion test. Change in mood was correlated to treatment response after testing. Patients whose condition worsened proved to be highly refractory to treatment while those who showed improvment were more likely to respond.
Conclusions:
That tryptophan depletion did not rapidly worsen depression argues that serotonin function is not linearly related to the level of depression and if reduced serotonin function does cause depression, then it is either as predisposing factor or due to a postsynaptic deficit in the utilization of serotonin.
Objective:
While considerable attention has focused on improving the detection of depression, assessment of severity is also important in guiding treatment decisions. Therefore, we examined the validity of a brief, new measure of depression severity.
Measurements:
The Patient Health Questionnaire (PHQ) is a self-administered version of the PRIME-MD diagnostic instrument for common mental disorders. The PHQ-9 is the depression module, which scores each of the 9 DSM-IV criteria as "0" (not at all) to "3" (nearly every day). The PHQ-9 was completed by 6,000 patients in 8 primary care clinics and 7 obstetrics-gynecology clinics. Construct validity was assessed using the 20-item Short-Form General Health Survey, self-reported sick days and clinic visits, and symptom-related difficulty. Criterion validity was assessed against an independent structured mental health professional (MHP) interview in a sample of 580 patients.
Results:
As PHQ-9 depression severity increased, there was a substantial decrease in functional status on all 6 SF-20 subscales. Also, symptom-related difficulty, sick days, and health care utilization increased. Using the MHP reinterview as the criterion standard, a PHQ-9 score > or =10 had a sensitivity of 88% and a specificity of 88% for major depression. PHQ-9 scores of 5, 10, 15, and 20 represented mild, moderate, moderately severe, and severe depression, respectively. Results were similar in the primary care and obstetrics-gynecology samples.
Conclusion:
In addition to making criteria-based diagnoses of depressive disorders, the PHQ-9 is also a reliable and valid measure of depression severity. These characteristics plus its brevity make the PHQ-9 a useful clinical and research tool.
OBJECTIVE: While considerable attention has focused on improving the detection of depression, assessment of severity is also important in guiding treatment decisions. Therefore, we examined the validity of a brief, new measure of depression severity.
MEASUREMENTS: The Patient Health Questionnaire (PHQ) is a self-administered version of the PRIME-MD diagnostic instrument for common mental disorders. The PHQ-9 is the depression module, which scores each of the 9 DSM-IV criteria as “0” (not at all) to “3” (nearly every day). The PHQ-9 was completed by 6,000 patients in 8 primary care clinics and 7 obstetrics-gynecology clinics. Construct validity was assessed using the 20-item Short-Form General Health Survey, self-reported sick days and clinic visits, and symptom-related difficulty. Criterion validity was assessed against an independent structured mental health professional (MHP) interview in a sample of 580 patients.
RESULTS: As PHQ-9 depression severity increased, there was a substantial decrease in functional status on all 6 SF-20 subscales. Also, symptom-related difficulty, sick days, and health care utilization increased. Using the MHP reinterview as the criterion standard, a PHQ-9 score ≥10 had a sensitivity of 88% and a specificity of 88% for major depression. PHQ-9 scores of 5, 10, 15, and 20 represented mild, moderate, moderately severe, and severe depression, respectively. Results were similar in the primary care and obstetrics-gynecology samples.
CONCLUSION: In addition to making criteria-based diagnoses of depressive disorders, the PHQ-9 is also a reliable and valid measure of depression severity. These characteristics plus its brevity make the PHQ-9 a useful clinical and research tool.
On the basis of preclinical studies, we hypothesized that deficient serotonin neurotransmission may be associated with the respiratory hyperactivity and carbon dioxide sensitivity seen in panic disorder. We used the tryptophan depletion method to investigate the effects of transient reductions in serotonin on respiration in five patients with panic disorder and seven normal control subjects. During room air breathing, the patients showed significantly increased ventilation when tryptophan-depleted, while the normal subjects showed no significant changes in respiration. These preliminary data suggest that serotonergic manipulation may affect ventilatory indices, with panic disorder patients being particularly sensitive to the effect of tryptophan depletion.
There is now some evidence that major depression may be accompanied by an immune response. The latter condition is suggested by elevated secretion of neopterin and interferon-γ (IFNγ) and by lower L-tryptophan (L-TRP) plasma levels. This study investigated the plasma levels of neopterin, L-TRP, and the L-TRP/competing amino acids (CAA) ratio in 30 normal control subjects and 47 depressed subjects (16 minor depressed, 13 simple major depressed, and 18 melancholic subjects), and IFNγ secretion by mitogen-stimulated peripheral blood mononuclear cells in 7 normal control subjects and 13 major depressed subjects. Plasma neopterin levels were significantly higher in depressed subjects than in normal controls; 61% of melancholic patients had increased neopterin levels (⩾ 7 nmol/1) with a specificity of 90%. Patients with major depression had significantly lower L-TRP and L-TRP/CAA values compared with normal control subjects. The amino acid values were significantly and negatively correlated with plasma neopterin levels. Major depressed subjects exhibited significantly higher IFNγ secretion than did normal control subjects. The results further support the hypothesis that major depression is accompanied by an immune response and that the lower L-TRP availability in that illness may be an epiphenomenon of immune activation.
Details of physical symptoms, psychological and social dysfunction of 42 outpatients diagnosed as having irritable bowel syndrome (IBS) were collected by interview and questionnaire. Social stresses and problems were also elicited as well as the impact of symptoms on their subjects' daily lives. High proportions of subjects were handicapped in their social, sexual and working lives by IBS symptoms and social stresses and problems were common. Forty-eight per cent were classified as having a 'minor psychiatric illness' using the Clinical Psychiatric Interview. Women were more severely affected by physical symptoms (with the exception of diarrhoea) and were more likely to be in pain longer and for more days in the month. They were also more likely than men to be diagnosed as having a psychiatric illness.
Using a reliable and valid structured diagnostic interview scale (ADIS-R), and patients with careful medical characterization, we found significantly more diagnosable psychopathology, particularly anxiety disorders, among treatment seeking patients with irritable bowel syndrome than among comparable age and sex samples of treatment seeking patients with Inflammatory Bowel Disease. Significant differences were also found on the Hamilton Anxiety Rating Scale and Hamilton Rating Scale for Depression between IBS patients and the IBD patients and controls, who did not differ. Comparable levels of psychiatric disorder among parents of probands were found in all three groups. The results are consistent with Latimer's (1983) notion of IBS patients being a subclass of 'neurotics'.
Functional abdominal complaints are frequently a reason to refer a patient to an outpatients' clinic for internal medicine. According to general views, certain psychologic and anamnestic data can constitute an indication for the diagnosis 'functional'. However, in our experience patients with functional complaints cannot be distinguished from patients with organic disease on such data. These same anamnestic and psychologic data, however, do have value in predicting the outcome of the complaints. Apparently, psychologic factors play a role in the course of functional abdominal complaints. Therefore, we tested the hypothesis that prognosis of functional abdominal complaints can be improved by psychologic intervention, and we offered our patients such a psychologic intervention in the form of a cognitive-behavioural group treatment. The first, encouraging, results are presented.
The excitatory amino acids L-glutamate and N-methyl-D-aspartate (NMDA) produced contractions of the myenteric plexus-longitudinal muscle preparation of the guinea pig ileum over the concentration range of 3 X 10(-6) to 10(-3) M. The contractile response to L-glutamate and NMDA, but not carbamyl choline, was blocked noncompetitively by 0.6 mM Mg++. In the absence of Mg++, concentration-dependent increases in contractile force also were produced by, in order of potency, L-aspartate, L-homocysteate and D-glutamate, but not by quisqualate, kainate or quinolinate. L-Glutamate was competitively antagonized by the selective NMDA receptor antagonists D-2-amino-5-phosphonovalerate and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (3 X 10(-6)-3 X 10(-5) M), as well as by the nonselective excitatory amino acid antagonist gamma-D-glutamylglycine (3 X 10(-4) M). Glutamic acid diethyl ester (3 X 10(-4) M) noncompetitively antagonized L-glutamate. L-Glutamate was not blocked by gamma-D-glutamylaminomethyl sulphonate (3 X 10(-4) M), an antagonist which preferentially antagonizes kainate and quisqualate. In addition, the phencyclidine-like drugs etoxadrol (10(-7)-10(-5) M), dextromethorphan (10(-6)-10(-5) M) and 5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine (10(-9)-10(-7) M) noncompetitively antagonized L-glutamate. The (+) isomer of 5-methyl-10, 11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine was approximately 10-fold more potent than the (-) isomer in antagonizing L-glutamate. The present results demonstrate that receptors for the excitatory amino acid L-glutamate are present in the guinea pig myenteric plexus and are of the NMDA subtype.(ABSTRACT TRUNCATED AT 250 WORDS)
The receptors for glutamic acid (L‐Glu) present in the guinea‐pig myenteric plexus‐ileal longitudinal muscle preparation have been studied by measuring the muscle contraction induced by numerous putative endogenous agonists acting at these receptors. Furthermore, the actions of different concentrations of antagonists, glycine, Mg ²⁺ and Ca ²⁺ on the ileal contractions induced by l‐G1u have been evaluated.
The EC 50 values of the most common putative endogenous agonists of these receptors were: L‐Glu 1.9 × 10 ⁻⁵ m; L‐aspartate 8 × 10 ⁻⁵ m ; quinolinate 5 × 10 ⁻⁴ M; L‐homocysteate 1.4 × 10 ⁻⁴ M; the dipeptide aspartyl‐glutamate 8 × 10 ⁻⁵ m, while N‐acetyl‐aspartyl‐glutamate was inactive. Among the molecules used to classify excitatory amino acid receptors, N‐methyl‐D‐aspartate (NMDA) was the most potent (EC 50 5 × 10 ⁻⁴ m). Kainic and quisqualic acids were almost completely inactive.
The responses to L‐Glu were competitively antagonized by 2‐amino‐5‐phosphonovaleric acid. They were, also, prevented by hyoscine (10 ⁻⁷ m) and by tetrodotoxin (3 × 10 ⁻⁷ m ), suggesting that the L‐Glu‐induced ileal contraction was in some way dependent upon an action on the myenteric cholinergic neurones. Kynurenic acid was a non‐competitive antagonist, γ‐D‐glutamyl‐taurine (10 ⁻⁴ m ) and aminophosphonobutyric acid (10 ⁻⁴ m ) did not modify the L‐Glu‐induced contractions.
Glycine (10 ⁻⁵ m ) significantly potentiated the effects of glutamate especially when the ionic composition of the superfusion medium contained concentrations of Ca ²⁺ in the range of 0.6–1.2 mM. Strychnine 3 × 10 ⁻⁵ m did not modify the actions of glycine.
The data presented here confirm the presence of NMDA receptors in the guinea‐pig myenteric plexus, and show that these receptors, similar to those present in primary neuronal cultures may be modulated by glycine.
Life events and difficulties were recorded for the year preceding onset of abdominal pain in 135 consecutive referrals to three gastrointestinal clinics, and for the equivalent time period in a matched, healthy community comparison series. Fifty-six patients were found to have an organic gastrointestinal disorder. Severely threatening events and major difficulties known to play a critical aetiological role in clinical depression, occurred with much the same frequency during the 38 weeks before onset of non-organic ('functional') gastrointestinal disorder. There was no such relationship between the severity of threat and organic disorder. A measure of 'goal frustration' reflecting the degree to which the subjects aims and ambitions were insurmountably obstructed by the occurrence of the event, was significantly associated with organic disorder. This finding may explain the often reported association between life stress and organic gastrointestinal disorder.
One hundred consecutive referrals to a general medical out-patient clinic were evaluated psychiatrically under blind conditions in order to investigate the nature and occurrence of non-organic disease presenting as gastrointestinal illness. Twenty-eight patients had marked psychiatric illness with or without physical illness, and there was an association between psychiatric illness and the absence of organic disease, as determined by outcome at follow-up of 4-11 months. Patients with obsessional traits were more at risk of non-organic illness. Historical items indicating a likelihood of non-organic gastrointestinal illness included "nerves", "depression", unhappy childhood, early parental loss and early separations from parents during childhood. Psychiatric illness often persisted after treatment for physical symptoms. Some of the techniques used in this study to identify psychiatric illness could be usefully employed in everyday practice.
Considerable evidence has accrued in the last two decades to support the hypothesis that alterations in serotonergic neuronal function in the central nervous system occur in patients with major depression. These findings include the following: (a) reduced cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (5-HT) in drug-free depressed patients; (b) reduced concentrations of 5-HT and 5-HIAA in postmortem brain tissue of depressed and (or) suicidal patients; (c) decreased plasma tryptophan concentrations in depressed patients and a profound relapse in remitted depressed patients who have responded to a serotonergic antidepressant when brain tryptophan availability is reduced; (d) in general, all clinically efficacious antidepressants augment 5-HT neurotransmission following chronic treatment; (e) clinically efficacious antidepressant action by all inhibitors of 5-HT uptake; (f) increases in the density of 5-HT2 binding sites in postmortem brain tissue of depressed patients and suicide victims, as well as in platelets of drug-free depressed patients; (g) decreased number of 5-HT transporter (determined with [3H]imipramine or [3H]paroxetine) binding sites in postmortem brain tissue of suicide victims and depressed patients and in platelets of drug-free depressed patients. In our studies, this reduction in platelet 5-HT transporter binding is not due to prior antidepressant treatment of hypercortisolemia and is not observed in mania, Alzheimer disease, schizophrenia, panic disorder, fibromyalgia, or atypical depression. In a pilot study, this deficit predicted treatment response to an experimental antidepressant. These findings support the hypothesis that alterations in 5-HT neurons play a role in the pathophysiology of depression.
To investigate the effects of tryptophan depletion in untreated depressed patients. Rapid dietary depletion of the precursor of serotonin synthesis, tryptophan, causes a transient return of depression in 67% of patients who have had a therapeutic antidepressant response.
Forty-three untreated depressed patients underwent tryptophan depletion in a double-blind, placebo-controlled cross-over study. After testing, they received open sequential antidepressant treatment.
Mood did not change when tryptophan was depleted but did change on the day after the depletion test. Relative to the control test, 37% of the patients had 10-point or greater decrease in Hamilton Depression Rating Scale (Ham-D) score, while 23% had a 10-point or greater increase in Ham-D score on the day after the tryptophan depletion test. Change in mood was correlated to treatment response after testing. Patients whose condition worsened proved to be highly refractory to treatment while those who showed improvement were more likely to respond.
That tryptophan depletion did not rapidly worsen depression argues that serotonin function is not linearly related to the level of depression and if reduced serotonin function does cause depression, then it is either as predisposing factor or due to a postsynaptic deficit in the utilization of serotonin.
Although physiological stimuli in the healthy gastrointestinal tract are generally not associated with conscious perception, chronic abdominal discomfort and pain are the most common symptoms resulting in patient visits with gastroenterologists. Symptoms may be associated with inflammatory conditions of the gut or occur in the form of so-called functional disorders. The majority of patients with functional disorders appear to primarily have inappropriate perception of physiological events and altered reflex responses in different gut regions. Recent breakthroughs in the neurophysiology of somatic and visceral sensation are providing a series of plausible mechanisms to explain the development of chronic hyperalgesia within the human gastrointestinal tract. A central concept to all these mechanisms is the development of hyperexcitability of neurons in the dorsal horn, which can develop either in response to peripheral tissue irritation or in response to descending influences originating in the brainstem. Taking clinical characteristics and the concept of central hyperexcitability into account, a model is proposed by which abdominal pain from chronic inflammatory conditions of the gut and functional bowel disorders such as noncardiac chest pain, nonulcer dyspepsia, and irritable bowel syndrome could develop by multiple mechanisms either alone or in combination.
An isocratic reversed-phase high-performance liquid chromatographic method for the simultaneous determination of tryptophan and four metabolites of the kynurenine pathway (kynurenine, 3-hydroxykynurenine, kynurenic acid and 3-hydroxyanthranilic acid) in human serum is described. This new method, which uses both isocratic elution and two on-line connected programmable ultraviolet and spectrofluorimetric detectors, allows the determination of these metabolites, in the physiological ranges, with satisfying specificity and sensitivity within 30 min.
Irritable bowel syndrome (IBS) is a chronic disorder that has been found to be associated with psychiatric disorders and a history of physical and/or sexual abuse. To date, the relationship of posttraumatic stress disorder (PTSD) and IBS has not been investigated. The primary purpose of this study was to examine the relationship of IBS and PTSD.
Fifty consecutive IBS patients admitted to a clinical treatment study were assessed for IBS, trauma history, and psychiatric disorders.
Twenty-seven IBS patients (54%) met criteria for a psychiatric diagnosis at some time in their lives. Twenty-two patients (44%) reported a trauma history. Eighteen (36%) were diagnosed with PTSD. Those IBS patients with a trauma history were more likely to have other comorbid psychiatric diagnoses.
These results suggest that IBS is often associated with psychiatric disorders, indicating that assessment and treatment of these comorbid conditions may be important in the treatment of IBS. PTSD, which had not been previously investigated in relation to IBS, had a high prevalence, indicating the need for careful trauma and PTSD assessment in patients with IBS. Patients with IBS who have a trauma history may be more at risk for other comorbid psychiatric disorders than IBS patients without a trauma history.
Evidence that the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays a role in the pathophysiology of mood disorders has been accumulating over the past three decades. Recent studies on this neurotransmitter have extended across the spectrum of psychiatric disorder, suggesting a role for 5-HT in psychosis, aggression, eating disorders and addiction. However, much of the evidence has come from post-mortem examination of the brain or measures of peripheral rather than central 5-HT function. The technique of tryptophan depletion allows investigation of brain 5-HT function in living subjects by examining the behavioural responses to this pharmacological challenge. This review considers the current status of tryptophan depletion as an experimental technique and discusses the implications of findings both in affective disorders and in a range of other psychiatric syndromes. MEDLINE and PSYCHLIT searches were completed for the years 1966 to November 1996 using the key words 'serotonin', '5-hydroxytryptamine', 'tryptophan' and 'depletion'. In addition relevant journals were hand-searched for the period from 1980 to December 1996. Forty-four double-blind studies in humans and three clinical case reports were identified; these cover a range of psychiatric disorders including mood disorders and psychoses, anxiety and eating disorders and specific behaviours such as appetite, aggression and craving. The studies reviewed utilized a variety of differing methodologies reducing the extent to which results can be generalized. A series of studies in depressed patients (before and after treatment with antidepressants) and their first-degree relatives have shown the importance of an intact 5-HT system in the action of antidepressants and offer new insights into the biology of affective disorder. The mood change induced by tryptophan depletion may predict those patients likely to respond to 5-HT-specific drugs. Rapid tryptophan depletion has also been reported to exacerbate both panic and aggression in vulnerable individuals. Effects in other disorders are conflicting and further research is needed to clarify these findings.
Alterations in noradrenergic and serotonergic function in the central nervous system (CNS) have been implicated in the pathophysiology of depression and the mechanism of action of antidepressant drugs. Based on changes in norepinephrine and serotonin metabolism in the CNS, it has been postulated that subgroups of patients with differential responses to norepinephrine and serotonin reuptake inhibitors may exist. Alpha-methylparatyrosine (AMPT), which causes rapid depletion of brain catecholamines, has been used as a noradrenergic probe to test the hypothesis that changes in neurotransmission through the catecholamine system may underlie the therapeutic response to norepinephrine reuptake inhibitors. Brain serotonin is dependent on plasma levels of the essential amino acid tryptophan. Rapid tryptophan depletion, in the form of a tryptophan-free amino acid drink, has been used as a serotonergic probe to identify therapeutically responsive subsets of patients. Using these probes, we have recently examined the behavioral effects of reduced concentrations of brain monoamines on depressed patients treated with a variety of serotonin selective reuptake inhibitors (SSRIs) or the relatively norepinephrine-selective antidepressant desipramine, during 3 different states: drug-free and depressed; in remission on antidepressant drugs; and drug-free in remission. The results of a series of investigations confirm the importance of monoamines in the mediation of depressed mood, but also suggest that other brain neural systems may have more of a primary role than previously thought in the pathophysiology of depression. Noradrenergic and serotonergic probes may be used in time to identify subsets of depressed patients to determine which patients might respond differentially to the new selective norepinephrine reuptake inhibitors or SSRIs.
Serotonin (5-HT) may play an important role in the regulation of colonic motility in humans. However, it is not known whether alterations in the colonic 5-HT system are involved in the pathophysiology of irritable bowel syndrome (IBS).
Colonic mucosal specimens ranging from the ascending colon to the rectum were obtained from patients with diarrhea- or constipation-predominant IBS (n = 7 and n = 8, respectively) and from subjects with normal bowel habits (n = 7) by endoscopic biopsy in order to determine whether patients with different clinical manifestations of IBS have different mucosal disposition of 5-HT. The tissue concentrations of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid, were determined by reversed-phase high-performance liquid chromatography with fluorescence detection.
In all study groups, the mean mucosal 5-HT concentrations obtained from the rectum were significantly (p < 0.05) higher than those obtained from more cephalic regions of the colon. In addition, the overall mean mucosal 5-HT concentrations obtained from patients with constipation-predominant IBS were significantly (p < 0.05) higher than those obtained from the control subjects and patients with diarrhea-predominant IBS. No significant differences were observed in 5-hydroxyindoleacetic acid concentrations among the three groups.
The mucosal 5-HT concentrations in the colon showed an ascending cephalocaudal gradient in all study groups. Although the mucosal 5-HT concentrations were elevated in patients with constipation-predominant IBS as compared with those with diarrhea-predominant IBS and the control subjects, further studies are necessary to determine whether the elevated mucosal 5-HT is a cause or a result of abnormal colonic motility.
N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that have an important role in long-term potentiation and memory processing in the central nervous system. The aims in this study were to determine whether NMDA receptors are expressed in the peripheral nervous system and identify their role in mediating behavioral pain responses to colonic distention in the normal gut.
Immunohistochemical localization of the NR1 subunit showed that NMDA receptors are expressed on the cell bodies and peripheral terminals of primary afferent nerves innervating the colon. Dorsal root ganglia neurons retrogradely labeled from the colon in short-term culture responded to addition of NMDA with increased intracellular [Ca2+]. Activation of peripheral NMDA receptors in colonic tissue sections caused Ca2+-dependent release of the proinflammatory neuropeptides, calcitonin gene-related peptide and substance P. Behavioral pain responses to noxious mechanical stimulation were inhibited in a reversible, dose-dependent manner by intravenous administration of memantine, a noncompetitive antagonist of the NMDA receptor. Single fiber recordings of decentralized pelvic nerves showed that colorectal distention responsive afferent nerve activity was inhibited by memantine.
Peripheral NMDA receptors are important in normal visceral pain transmission, and may provide a novel mechanism for development of peripheral sensitization and visceral hyperalgesia.
The cytokine interferon-gamma stimulates human monocytes/macrophages to release large amounts of neopterin. Increased neopterin concentrations in body fluids of patients are observed during diseases with activated cellular (=TH1-type) immune response such as allograft rejection, virus infections, autoimmune disorders, or malignant tumors but also in neurodegenerative diseases or during pregnancy. In various cells interferon-gamma induces indoleamine 2,3-dioxygenase (IDO) which degrades tryptophan via the kynurenine pathway. Therefore like increased neopterin formation, enhanced tryptophan degradation is observed in diseases concomitant with cellular immune activation. Disturbed metabolism of tryptophan affects biosynthesis of neurotransmitter 5-hydroxytryptamine (serotonin), and it appears to be associated with an increased susceptibility for depression. In fact, enhanced neopterin concentrations together with increased degradation of tryptophan and low serum levels of tryptophan correlate with neuropsychiatric abnormalities like cognitive decline and depressive symptoms especially in long-lasting and chronic diseases. Activation of IDO could represent an important link between the immunological network and the pathogenesis of depression.
The irritable bowel syndrome (IBS) is part of the larger group of functional gastrointestinal (GI) disorders that, despite differences in location and symptom patterns, share common features with regard to their motor and sensory physiology, central nervous system (CNS) relationships, and the approach to patient care.¹ IBS is a functional bowel disorder characterized by symptoms of abdominal pain or discomfort that is associated with disturbed defecation.² This disorder is highly prevalent and can be associated with significant emotional distress, impaired health-related quality of life (HRQL), disability, and high health care costs. Psychosocial factors, although not part of IBS per se, have an important role in modulating the illness experience and its clinical outcome.³
GASTROENTEROLOGY 2002;123:2108-2131
Tryptophan is an essential amino acid and the least abundant constituent of proteins. In parallel it represents a source for two important biochemical pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by the tetrahydrobiopterin-dependent tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides initiated by the enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). Whereas TDO is located in the liver cells, IDO is expressed in a large variety of cells and is inducible by the cytokine interferon-gamma. Therefore, accelerated tryptophan degradation is observed in diseases and disorders concomitant with cellular immune activation, e. g. infectious, autoimmune, and malignant diseases, as well as during pregnancy. According to the cytostatic and antiproliferative properties of tryptophan-depletion on T lymphocytes, activated T-helper type 1 (Th-1) cells may down-regulate immune response via degradation of tryptophan. Especially in states of persistent immune activation availability of free serum tryptophan is diminished and as a consequence of reduced serotonin production, serotonergic functions may as well be affected. Accumulation of neuroactive kynurenine metabolites such as quinolinic acid may contribute to the development of neurologic/psychiatric disorders. Thus, IDO seems to represent a link between the immunological network and neuroendocrine functions with far reaching consequences in regard to the psychological status of patients. These observations provide a basis for the better understanding of mood disorder and related symptoms in chronic diseases.
The factors affecting gut activity in inflammatory bowel disease are unclear, but purines and kynurenines may be involved in the regulation of neuronal activity and therefore gut motility and secretion. We have measured the serum levels of these compounds in patients and in sex- and age-matched controls. Purines and kynurenines were analysed using HPLC. The levels of tryptophan and its metabolites 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid were unchanged in all patients. However, the levels of kynurenine and kynurenic acid were significantly elevated in patients with inflammatory bowel disease when compared to control subjects. There were no significant differences between patients and controls for any of the purines analysed or for neopterin. In the inflammatory bowel disease patients serum lipid peroxidation products were significantly elevated when compared to control subjects, suggesting the presence of increased oxidative stress consistent with inflammatory activity. The elevated level of kynurenic acid may represent either a compensatory response to elevated activation of enteric neurones, or a primary abnormality, which induces a compensatory increase in gut activity, but may indicate a role for kynurenine modulation of glutamate receptors in the symptoms of inflammatory bowel disease.
The aim of this study was to compare the response of symptoms and cytokine ratios in irritable bowel syndrome (IBS) with ingestion of probiotic preparations containing a lactobacillus or bifidobacterium strain.
Seventy-seven subjects with IBS were randomized to receive either Lactobacillus salivarius UCC4331 or Bifidobacterium infantis 35624, each in a dose of 1 x 10 10 live bacterial cells in a malted milk drink, or the malted milk drink alone as placebo for 8 weeks. The cardinal symptoms of IBS were recorded on a daily basis and assessed each week. Quality of life assessment, stool microbiologic studies, and blood sampling for estimation of peripheral blood mononuclear cell release of the cytokines interleukin (IL)-10 and IL-12 were performed at the beginning and at the end of the treatment phase.
For all symptoms, with the exception of bowel movement frequency and consistency, those randomized to B infantis 35624 experienced a greater reduction in symptom scores; composite and individual scores for abdominal pain/discomfort, bloating/distention, and bowel movement difficulty were significantly lower than for placebo for those randomized to B infantis 35624 for most weeks of the treatment phase. At baseline, patients with IBS demonstrated an abnormal IL-10/IL-12 ratio, indicative of a proinflammatory, Th-1 state. This ratio was normalized by B infantis 35624 feeding alone.
B infantis 35624 alleviates symptoms in IBS; this symptomatic response was associated with normalization of the ratio of an anti-inflammatory to a proinflammatory cytokine, suggesting an immune-modulating role for this organism, in this disorder.
Prostaglandins, a family of lipidic molecules released during inflammation, display immunomodulatory properties in several models. One use includes exposure of monocyte-derived dendritic cells (DCs) to a cocktail of cytokines that contains prostaglandin E2 (PGE2) for purposes of maturation; such cells are currently being used for cancer immunotherapy trials. Our analysis of the transcription profile of DCs matured in the presence of tumor necrosis factor alpha (TNFalpha) and PGE2 revealed a strong up-regulation of indoleamine 2-3 dioxygenase (IDO), an enzyme involved in tryptophan catabolism and implicated in both maternal and T-cell tolerance. Using quantitative assays to monitor levels of IDO mRNA, protein expression, and enzyme activity, we report that PGE2 induces mRNA expression of IDO; however, a second signal through TNF receptor (TNF-R) or a Toll-like receptor (TLR) is necessary to activate the enzyme. Interestingly, use of TNFalpha, lipopolysaccharide, or Staphylococcus aureus Cowan I strain (SAC) alone does not induce IDO. The effect of PGE2 is mediated by activation of adenylate cyclase via the Gs-protein-coupled receptor E prostanoid-2 (EP2). A better understanding of these regulatory mechanisms and the crosstalk between TNF-R/TLR and EP2 signaling pathways will provide insight into the regulation of T-cell activation by DCs and may help to improve existing immunotherapy protocols.
The essential amino acid tryptophan is a constituent of proteins and is also a substrate for two important biosynthetic pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides. The latter pathway is initiated by the enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). TDO is located in liver cells, whereas IDO is expressed in a variety of cells including monocyte-derived macrophages and dendritic cells and is preferentially induced by Th1-type cytokine interferon-gamma. Tryptophan depletion via IDO is part of the cytostatic and antiproliferative activity mediated by interferon-gamma in cells. In vivo tryptophan concentration can be measured by HPLC by monitoring its natural fluorescence (285 nm excitation and 365 nm emission wavelength). IDO activity is characterized best by the kynurenine to tryptophan ratio which correlates with concentrations of immune activation markers such as neopterin. Low serum/plasma tryptophan concentration is observed in infectious, autoimmune, and malignant diseases and disorders that involve cellular (Th1-type) immune activation as well as during pregnancy due to accelerated tryptophan conversion. Thus, in states of persistent immune activation, low tryptophan concentration may contribute to immunodeficiency. Decreased serum tryptophan can also effect serotonin biosynthesis and thus contribute to impaired quality of life and depressive mood. As such, monitoring tryptophan metabolism in chronic immunopathology provides a better understanding of the association between immune activation and IDO and its role in the development of immunodeficiency, anemia and mood disorders.
Irritable bowel syndrome (IBS) is a functional disorder with an etiology that has been linked to both psychological stress and infection. The primary aim of this study was to examine the hypothalamic-pituitary-adrenal axis in patients with IBS and to relate such response to plasma cytokine profiles.
A total of 151 subjects, 76 patients and 75 controls, were recruited. The patients with IBS were diagnosed according to Rome II criteria. Forty-nine patients and 48 matched controls had cytokine levels measured, and a subset of 21 patients and 21 controls also underwent a corticotropin-releasing hormone (CRH) stimulation test with plasma levels of adrenocorticotropic hormone (ACTH) and cortisol measured. The remaining 27 patients and 27 controls underwent a dexamethasone (1 mg) challenge.
Cortisol and the proinflammatory cytokines interleukin (IL)-6 (together with its soluble receptor) and IL-8 were elevated in all IBS subgroups (diarrhea predominant, constipated, and alternators), although the elevation was most marked in the constipated subgroup. There was no alteration in the anti-inflammatory cytokine IL-10. Following CRH infusion, an exaggerated release of both ACTH and cortisol was observed in patients with IBS. There was a significant correlation between the ACTH response (deltaACTH) and the IL-6 levels. A similar relationship existed between the deltaACTH/deltacortisol ratio and the IL-6 levels. Dexamethasone suppression of cortisol was similar in patients and controls.
IBS is characterized by an overactivation of the hypothalamic-pituitary-adrenal axis and a proinflammatory cytokine increase.
Irritable bowel syndrome affects approximately 10-15% of the European population, although prevalence rates vary depending on the classification used and the country surveyed. This may be due to differences in patterns of medical care and diagnosis of the condition. Up to 70% of individuals with irritable bowel syndrome may not have been formally diagnosed. The disorder affects 1.5-3 times as many women as men and poses a significant economic burden in Europe, estimated at euro 700-euro 1600 per person per year. It also reduces quality of life and is associated with psychological distress, disturbed work and sleep, and sexual dysfunction. It is a chronic disorder, which affects many individuals for more than 10 years. Most patients are managed in primary care, although some are referred to gastroenterologists and other specialists. Patients with irritable bowel syndrome undergo more abdomino-pelvic surgery than the general population. We propose that a positive diagnosis of the condition may avoid the delay in diagnosis many patients experience. We conclude that, in Europe, there are significant unmet needs including lack of familiarity with irritable bowel syndrome, difficulties in diagnosis and lack of effective treatments for the multiple symptoms of the disorder. The development of pan-European guidelines for irritable bowel syndrome will benefit patients with this condition in Europe.
The neurodegeneration hypothesis proposed major depression as a consequence of the imbalance between neuroprotective and neurodegenerative metabolites in the kynurenine pathway. To test the hypothesis, plasma tryptophan and kynurenine pathway metabolites were studied in 58 patients with major depression and 189 normal controls. The mean tryptophan breakdown index was higher (p=0.036), and mean kynurenic acid concentration and mean neuroprotective ratios were lower, in depressed patients (p=0.003 and 0.003, respectively). In receiver operating characteristic analysis, the kynurenic acid concentrations and the neuroprotective ratio showed clear discrimination between depressed patients and controls with area under the curve 79% and 76.3% respectively. The neuroprotective ratio did not change after treatment in those with repeated episodes of depression but it increased significantly (p=0.044) in those with first episodes. The results suggested that the reduction in neuroprotective markers, which indicated an impaired neuroprotection, might play an important role in pathophysiology of major depression.
To assess the effect of acute changes in serotonin (5-HT) synthesis using the acute tryptophan depletion (ATD) paradigm on gastrointestinal (GI) and mood symptoms in irritable bowel syndrome (IBS).
In a randomized double-blind crossover study, 29 subjects (18 patients with ROME II defined IBS and 11 age-matched controls) were studied under ATD and acute tryptophan increase (ATI) conditions. GI symptoms, mood and anxiety ratings, as well as plasma tryptophan concentrations were measured.
Total (and free) plasma tryptophan concentrations decreased on the ATD day in patients (73%[82%]) and controls (73%[80%]), and increased on the ATI day in patients (59%[143%]) and controls (61%[381%]). Compared with the ATD day, IBS patients reported more GI symptoms on the ATI day at +210 (p < 0.001) and at +270 (p < 0.05) min post drink. IBS patients also reported less anxiety on the ATI day compared with the ATD day at +270 min (p < 0.001). ATD and ATI did not affect these ratings in control participants. IBS patients had a lower mood compared with controls (p < 0.05), but this did not differ between the ATI and ATD days in either group.
IBS patients' GI and anxiety responses to changes in tryptophan load differ from controls. This suggests a difference in serotonergic functioning between these two groups and provides evidence to support the hypothesis that 5-HT dysfunction is involved in IBS.
In recent times, the perception of functional gastrointestinal disorders such as irritable bowel syndrome (IBS) has shifted fundamentally. Such disorders are now thought of as serious diseases characterized by perturbations in the neuronal regulation of gastrointestinal function. The concept of visceral hypersensitivity, the characterization of neuronal networks in the 'brain-gut axis' and the identification of several novel 5-HT-mediated mechanisms have contributed to this shift. Here, we review how some of the more promising of these new mechanisms (e.g. those involving 5-HT transporters and the 5-HT(2B), 5-HT(7) and putative 5-HT(1p) receptors) might lead to a range of second-generation therapies that could revolutionize the treatment of functional gastrointestinal disorders, particularly IBS.
We set out to test the hypothesis that irritable bowel syndrome (IBS) is characterized by an augmented cellular immune response with enhanced production of proinflammatory cytokines. We further aimed to explore whether symptoms and psychiatric comorbidity in IBS are linked to the release of proinflammatory cytokines.
We characterized basal and Escherichia coli lipopolysaccharide (LPS)-induced cytokine production in peripheral blood mononuclear cells (PBMCs) from 55 IBS patients (18 mixed-, 17 constipation-, 20 diarrhea-predominant) and 36 healthy controls (HCs). PBMCs were isolated by density gradient centrifugation and cultured for 24 hours with or without (1 ng/mL) LPS. Cytokine production (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, and IL-6) was measured by enzyme-linked immunosorbent assay. Abdominal symptoms and psychiatric comorbidities were assessed by using the validated Bowel Disease Questionnaire and the Hospital Anxiety and Depression Scale.
IBS patients showed significantly (P < .017) higher baseline TNF-alpha, IL-1beta, IL-6, and LPS-induced IL-6 levels compared with HCs. Analyzing IBS subgroups, all cytokine levels were significantly (P < .05) higher in diarrhea-predominant IBS (D-IBS) patients, whereas constipation-predominant IBS patients showed increased LPS-induced IL-1beta levels compared with HCs. Baseline TNF-alpha and LPS-induced TNF-alpha and IL-6 levels were significantly higher in patients reporting more than 3 bowel movements per day, urgency, watery stools, and pain associated with diarrhea compared with patients without these symptoms (all P < .05). LPS-induced TNF-alpha production was associated significantly (r = 0.59, P < .001) with anxiety in patients with IBS.
Patients with D-IBS display enhanced proinflammatory cytokine release, and this may be associated with symptoms and anxiety.
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