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The role of inflammation and the gut microbiome in depression and anxiety

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Abstract

The study of the gut microbiome has increasingly revealed an important role in modulating brain function and mental health. In this review, we underscore specific pathways and mechanisms by which the gut microbiome can promote the development of mental disorders such as depression and anxiety. First, we review the involvement of the stress response and immune system activation in the development of depression and anxiety. Then, we examine germ‐free murine models used to uncover the role of the gut microbiome in developing and modulating pertinent activity in the brain and the immune system. We also document multiple pathways by which stress‐induced inflammation harms brain function and ultimately affects mental health, and review how probiotic and prebiotic treatments have shown to be beneficial. Lastly, we provide an overview of gut microbiome‐derived compounds (short‐chain fatty acids, tryptophan catabolites, microbial pattern recognition) and related mechanisms (vagal nerve activity and fecal microbiota transplants) involved in mediating the influence of the gut microbiome to mental health. Overall, a picture of the gut microbiome playing a facilitating role between stress response, inflammation, and depression, and anxiety is emerging. Future research is needed to firmly establish the microbiome's causal role, to further elucidate the mechanisms by which gut microbes influence brain function and mental health, and to possibly develop treatments that improve mental health through microbiotic targets.

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... From studies in mammals such as rodents and humans, intestinal bacteria are known to improve host health via their probiotic functions such as the activation of immunity (Shi et al., 2017) and anti-obesity action (Barathikannan et al., 2019), and by supplying nutrients (Yadav et al., 2018)., as well as via prebiotic functions that regulate the balance of intestinal bacteria (Gibson et al., 2017;Hill et al., 2014). In addition to these various biological functions, studies in rodent models have shown that intestinal bacteria can affect higher-order brain functions, such as anxiety (Peirce and Alviñ a, 2019), depression (Peirce and Alviñ a, 2019), and cognitive functions (Chu et al., 2019), via communication with the brain-gut axis (Grenham et al., 2011;Mayer et al., 2014;Peirce and Alviñ a, 2019). In the past decade, the probiotic and prebiotic functions of these intestinal bacteria have attracted considerable attention, and the causative factors and mechanisms have been elucidated (Erny et al., 2015;Lyte, 2014;Strandwitz, 2018;van de Wouw et al., 2018). ...
... From studies in mammals such as rodents and humans, intestinal bacteria are known to improve host health via their probiotic functions such as the activation of immunity (Shi et al., 2017) and anti-obesity action (Barathikannan et al., 2019), and by supplying nutrients (Yadav et al., 2018)., as well as via prebiotic functions that regulate the balance of intestinal bacteria (Gibson et al., 2017;Hill et al., 2014). In addition to these various biological functions, studies in rodent models have shown that intestinal bacteria can affect higher-order brain functions, such as anxiety (Peirce and Alviñ a, 2019), depression (Peirce and Alviñ a, 2019), and cognitive functions (Chu et al., 2019), via communication with the brain-gut axis (Grenham et al., 2011;Mayer et al., 2014;Peirce and Alviñ a, 2019). In the past decade, the probiotic and prebiotic functions of these intestinal bacteria have attracted considerable attention, and the causative factors and mechanisms have been elucidated (Erny et al., 2015;Lyte, 2014;Strandwitz, 2018;van de Wouw et al., 2018). ...
... From studies in mammals such as rodents and humans, intestinal bacteria are known to improve host health via their probiotic functions such as the activation of immunity (Shi et al., 2017) and anti-obesity action (Barathikannan et al., 2019), and by supplying nutrients (Yadav et al., 2018)., as well as via prebiotic functions that regulate the balance of intestinal bacteria (Gibson et al., 2017;Hill et al., 2014). In addition to these various biological functions, studies in rodent models have shown that intestinal bacteria can affect higher-order brain functions, such as anxiety (Peirce and Alviñ a, 2019), depression (Peirce and Alviñ a, 2019), and cognitive functions (Chu et al., 2019), via communication with the brain-gut axis (Grenham et al., 2011;Mayer et al., 2014;Peirce and Alviñ a, 2019). In the past decade, the probiotic and prebiotic functions of these intestinal bacteria have attracted considerable attention, and the causative factors and mechanisms have been elucidated (Erny et al., 2015;Lyte, 2014;Strandwitz, 2018;van de Wouw et al., 2018). ...
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Lactic acid bacteria (LAB) influence multiple aspects of host brain function via the production of active metabolites in the gut, which is known as the pre/pro-biotic action. However, little is known about the biogenic effects of LAB on host brain function. Here, we reported that the Lactobacillus plantarum SBT2227 promoted sleep in Drosophila melanogaster. Administration of SBT2227 primarily increased the amount of sleep and decreased sleep latency at the beginning of night-time. The sleep-promoting effects of SBT2227 were independent of the existing gut flora. Furthermore, heat treatment or mechanical crushing of SBT2227 did not suppress the sleep-promoting effects, indicative of biogenic action. Transcriptome analysis, and RNAi mini-screening for gut-derived peptide hormones revealed the requirement of neuropeptide F, a homologue of the mammalian neuropeptide Y, for the action of SBT2227. These biogenic effects of SBT2227 on the host sleep provide new insights into the interaction between the brain and gut bacteria.
... The intestinal microbiota plays a key role in health and wellness through its protective, and metabolic actions (Cani, 2018). "Gut dysbiosis" or alterations of gut microbiota have been shown to be associated with various diseases and disorders like inflammatory bowel disease (IBD; Khan et al., 2019), type 2 diabetes (Gurung et al., 2020), cardiovascular disease (Tang et al., 2017), and even mental disorders like depression and anxiety (Zalar et al., 2018;Peirce and Alviña, 2019). Incidentally, preliminary report also suggests a differential microbial profile in COVID-19 patients as compared to healthy individuals (Gu et al., 2020;Zuo et al., 2020). ...
... This may lead to endotoxins and other harmful bacteria to seep into the circulation causing an immune reaction and inflammation. Many animal studies have shown that administration of endotoxins peripherally causes global expression of pro-inflammatory cytokines in the brain (Peirce and Alviña, 2019). The other mechanisms through which peripheral inflammation spread to the brain and cause neuro-inflammation can be by sending inflammatory signals to the brain by afferent nerves, activated immune cells migrating to the brain and cytokines crossing the blood brain barrier (Peirce and Alviña, 2019). ...
... L. farciminis administration to mice suppressed stress-induced neuroinflammation during partial restraint stress . Lot of probiotics such as Bifidobacterium breve, Lactobacillus helveticus NS8, L. rhamnosus, and B. longum have shown anxiolytic effects in preclinical models (Peirce and Alviña, 2019). Similar benefit of probiotics has been observed in many human studies. ...
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Coronavirus disease 2019 (COVID-19) is a major pandemic facing the world today caused by SARS-CoV-2 which has implications on our mental health as well. The uncertain future, fear of job loss, lockdown and negative news all around have taken a heavy toll on the mental health of individuals from across the world. Stress and anxiety can affect the COVID-19 patients even more. Recent study suggests COVID-19 infection may lead to post-traumatic stress disorder (PTSD). Certain prebiotics and probiotics have been shown to have anxiolytic effect through gut microbiota modulation. Incidentally, preliminary report also suggests a differential microbial profile in COVID-19 patients as compared to healthy individuals. Gut microbiota’s role in anxiety and depression is well studied. The importance of the “gut-brain” axis has been implicated in overall mental health. It is known that diet, environmental factors and genetics play an important role in shaping gut microbiota. Trials may be initiated to study if personalized diet and supplementation based on individual’s gut microbiome profile may improve the general mental well-being of people prone to anxiety during this pandemic. Also, COVID-19 patients may be provided personalized nutritional therapy based on their gut microbiota profile to see if PTSD and anxiety symptoms can be alleviated.
... In turn, this may lead to modifications of the composition of IM, which may affect the inflammatory response as well as anxiety and depressive symptoms (Butler et al., 2019;Lange et al., 2020;Manigault et al., 2019;Tao et al., 2020;Wang et al., 2018 ; see Figure 1). Due mainly to these reasons, the study of inflammation in ADs has gained special interest (Michopoulos et al., 2017;Peirce & Alviña, 2019). Although trials examining links between inflammation and anxiety are less frequent in the literature, clinical research has reported elevated levels of pro-inflammatory cytokines with increased severity of anxiety symptoms, compared to healthy individuals (Alessi & Bennett, 2020;Niles et al., 2018;Peirce & Alviña, 2019). ...
... Due mainly to these reasons, the study of inflammation in ADs has gained special interest (Michopoulos et al., 2017;Peirce & Alviña, 2019). Although trials examining links between inflammation and anxiety are less frequent in the literature, clinical research has reported elevated levels of pro-inflammatory cytokines with increased severity of anxiety symptoms, compared to healthy individuals (Alessi & Bennett, 2020;Niles et al., 2018;Peirce & Alviña, 2019). In particular, patients with panic disorder (PD) present an inflammatory response due to elevated levels of pro-inflammatory cytokines, such as interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL) 6, and IL-1β (Alessi & Bennett, 2020;Petrowski et al., 2018;Quagliato & Nardi, 2018). ...
... As presented above, not all studies report results of direct associations between the severity of anxiety symptoms and inflammation, which means that there are multiple confounding variables that make it difficult to obtain consistent results (Jeon et al., 2019). For these reasons, and given that in humans this link is not yet well-defined (Peirce & Alviña, 2019;Salim et al., 2012), the importance of examining the possible mechanisms involved in AD from a multifactorial approach leads to a unifying conceptualization of health and disease. This would provide a better understanding of these phenomena associated with these highly prevalent disorders: providing new insights into possible causes-effects and for the creation of new study models in the development of innovative and multidisciplinary psychotherapies (Allen et al., 2017;Black et al., 2020;Ganci et al., 2019). ...
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Introduction Chronic exposure to stress is a major risk factor in anxiety disorders (ADs) and can be accompanied by an altered microbiome–gut–brain axis and a compromised immune system. In recent years, the study of inflammatory processes in AD has gained special attention. Continued stress causes the reactivity of the hypothalamic–pituitary–adrenal (HPA) axis, the alteration of the intestinal microbiota and the consequent release of pro‐inflammatory cytokines, affecting the sensitivity to stress and the similar behavior of anxiety. Method The aim of the present study was to evaluate the interrelationships between measures of proinflammatory cytokines and cortisol in patients with panic disorder (PD). Results The main results of the correlation analysis revealed that the levels of pro‐inflammatory cytokines interleukin (IL)‐1β, IL‐12, and tumor necrosis factor gamma were negatively correlated with cortisol scores (area under the curve with respect to the ground). Conclusions These results suggest that the inflammatory response is associated with the reactivity of the HPA axis in patients with PD and may influence the maintenance of anxiety behavior.
... Advances in the field have been showing how gut microbiota could influence the development of mood disorders such as anxiety and depression (Peirce and Alviña, 2019;Huang and Wu, 2021). In a recent study, pregnant women had their microbiota sequenced through stool samples during the third trimester of pregnancy, and children's behaviour was analyzed at 2 years of age. ...
... As already mentioned, dysbiosis may be related to the genesis of chronic inflammation in obesity and, through the gut-brain axis, trigger neuroinflammation and the development of psychiatric manifestations (Peirce and Alviña, 2019;Milano et al., 2020;Shi et al., 2020). Maternal diet influences offspring's brain development, e.g., affecting microglial maturation and gene expression (Thion et al., 2018) and also gut microbiota composition (Buffington et al., 2016). ...
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Since the first evidence suggesting that maternal nutrition can impact the development of diseases in the offspring, much has been elucidated about its effects on the offspring’s nervous system. Animal studies demonstrated that maternal obesity can predispose the offspring to greater chances of metabolic and neurodevelopmental diseases. However, the mechanisms underlying these responses are not well established. In recent years, the role of the gut-brain axis in the development of anxiety and depression in people with obesity has emerged. Studies investigating changes in the maternal microbiota during pregnancy and also in the offspring demonstrate that conditions such as maternal obesity can modulate the microbiota, leading to long-term outcomes in the offspring. Considering that maternal obesity has also been linked to the development of psychiatric conditions (anxiety and depression), the gut-brain axis is a promising target to be further explored in these neuropsychiatric contexts. In the present study, we review the relationship between maternal obesity and anxious and depressive features, exploring the gut-brain axis as a potential mechanism underlying this relationship.
... In this sense, there is evidence that suggests the close relationship between the immune system and the intestinal microbiota, an example of which is the production of immunocytokines in response to the metabolism of intestinal bacteria [53]. The overstimulation of the HPA axis will lead to an increase in the permeability of the intestinal barrier; subsequently, a phenomenon known as endotoxemia occurs, in which the bacterial endotoxins pass into the blood circulation, triggering the onset of peripheral inflammation; the signals will Nutrients 2022, 14, 1107 5 of 39 arrive at the CNS via the vagus nerve, again promoting the neuroinflammatory response of glial cells [54]. This fact will lead to a greater systemic deterioration of the subjects with depression [55]. ...
... Nutrients 2022, 14, 1107 5 of 40 munocytokines in response to the metabolism of intestinal bacteria [53]. The overstimulation of the HPA axis will lead to an increase in the permeability of the intestinal barrier; subsequently, a phenomenon known as endotoxemia occurs, in which the bacterial endotoxins pass into the blood circulation, triggering the onset of peripheral inflammation; the signals will arrive at the CNS via the vagus nerve, again promoting the neuroinflammatory response of glial cells [54]. This fact will lead to a greater systemic deterioration of the subjects with depression [55]. ...
Article
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Major depressive disorder (MDD) is an incapacitating condition characterized by loss of interest, anhedonia and low mood, which affects almost 4% of people worldwide. With rising prevalence, it is considered a public health issue that affects economic productivity and heavily increases health costs alone or as a comorbidity for other pandemic non-communicable diseases (such as obesity, cardiovascular disease, diabetes, inflammatory bowel diseases, etc.). What is even more noteworthy is the double number of women suffering from MDD compared to men. In fact, this sex-related ratio has been contemplated since men and women have different sexual hormone oscillations, where women meet significant changes depending on the age range and moment of life (menstruation, premenstruation, pregnancy, postpartum, menopause…), which seem to be associated with susceptibility to depressive symptoms. For instance, a decreased estrogen level promotes decreased activation of serotonin transporters. Nevertheless, sexual hormones are not the only triggers that alter neurotransmission of monoamines and other neuropeptides. Actually, different dietary habits and/or nutritional requirements for specific moments of life severely affect MDD pathophysiology in women. In this context, the present review aims to descriptively collect information regarding the role of malnutrition in MDD onset and course, focusing on female patient and especially macro- and micronutrient deficiencies (amino acids, ω3 polyunsaturated fatty acids (ω3 PUFAs), folate, vitamin B12, vitamin D, minerals…), besides providing evidence for future nutritional intervention programs with a sex-gender perspective that hopefully improves mental health and quality of life in women.
... About every third patient with liver disease develops depression at one point in his or her life [4] and every third patient with depressive disorder develops an alcohol disorder [1]. In liver disease, inflammatory processes, cytokines, and an altered intestinal microbiome presumably contribute to the development of depression [5][6][7]. Recently, in a rat model of chronic stress, it has been shown that, after fecal microbiota transplant, the gut barrier integrity was broken, subsequently leading to liver disease and an increased inflammatory cytokine expression, with higher astrocyte activation, indicating an inflammatory process in the brain [8]. Several studies point towards a microbiota-brain-dysfunction as a potential contributor to mental disorders [9,10]. ...
... Analyses of genetic risk factors by use of genome wide studies [46] and inflammatory pathways [47] underline the complexity of the disease. Of note, as outlined before, more and more studies shed light on the connection between mental health and the gut microbiome [6], the latter being an important potential link between liver disease and depression. In summary, our study suggests that the FIB-4 score is not only relevant for hepatic diseases but also for extrahepatic endpoints, such as depression and other psychiatric diseases. ...
Article
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Background: Liver disease and depression are known to be closely associated. Non-invasive tests (NIT), such as the FIB-4 score, have been recommended by different guidelines to rule out advanced fibrosis and to stratify the risk of liver-related outcomes in patients with chronic liver diseases. However, the predictive value of an elevated FIB-4 score regarding the development of depression and/or anxiety disorders among the general population is unknown. Methods: By using the Disease Analyzer database (IQVIA), which compiles diagnoses and laboratory values as well as basic medical and demographic data of patients followed in general practices in Germany, we identified 370,756 patients with available lab values for FIB-4 score calculation between 2005 and 2019. Patients with an FIB-4 score < 2 were matched 1:1 to patients with an FIB-4 index ≥ 2 by age, sex and yearly consultation frequency. Results: In regression analysis, the incidence rate ratio (IRR) of depression was significantly higher among patients with an FIB-4 score ≥ 2.0 compared to patients with a lower FIB-4 score <2.0 (IRR: 1.12, p < 0.001). This association was significant for both female (IRR: 1.10, p = 0.004) and male (IRR: 1.15, p < 0.001) patients and strongest in the age groups ≤50 years (IRR: 1.42, p < 0.001) and 51-60 years (IRR: 1.34, p < 0.001). There was no significant association between an elevated FIB-4 score ≥ 2.0 and the incidence of depression among patients aged 60 years and older. There was no significant increase in the IRR of anxiety disorders for patients with high or low FIB-4 scores. Conclusion: Our study suggests a previously unknown association between an elevated FIB-4 score and an increased incidence of depression. This finding suggests that the FIB-4 score is not only a valuable tool for the prediction of liver-specific endpoints but also may be of relevance for the prediction of extrahepatic comorbidities, which in turn may argue for clinical screening programs in patients with an elevated FIB-4.
... 256 This peripheral inflammation can also influence mental health by promoting the entry of neurotoxins into the brain and also by obstructing neurotransmitter systems. 257 Although the direct mechanism of gut bacteria influencing neuropsychiatric disorders was clearly not studied, many studies believe that gut-induced stress has a vital role along with disrupted gut microbiome and various other factors in causing depression, anxiety, and other psychological disorders. Recently, Jiang et al. has demonstrated that fecal samples from patients with major depressive disorder have shown increased Bacteroidetes, Protobacteria and Actinobacteria along with less Firmicutes when compared with fecal samples from healthy controls. ...
... 259 Both major brain disorders, depression and anxiety are indicated to be influenced by stress-regulated HPA axis pathway, which is believed to be strongly modulated by gut microbiota composition. 257,260 An epigenetic study using GF mouse models had demonstrated that GF mice showed significant difference in gene expression in the brain systems when compared with control mice, notably in the areas of cortex, cerebellum, striatum, and hippocampus. 261 It is suggested that the gut-brain axis may be affected by regulation of stress hormones and the establishment of neuronal circuits. ...
Article
The role of microbiota in health and diseases is being highlighted by numerous studies since its discovery. Depending on the localized regions, microbiota can be classified into gut, oral, respiratory, and skin microbiota. The microbial communities are in symbiosis with the host, contributing to homeostasis and regulating immune function. However, microbiota dysbiosis can lead to dysregulation of bodily functions and diseases including cardiovascular diseases (CVDs), cancers, respiratory diseases, etc. In this review, we discuss the current knowledge of how microbiota links to host health or pathogenesis. We first summarize the research of microbiota in healthy conditions, including the gut-brain axis, colonization resistance and immune modulation. Then, we highlight the pathogenesis of microbiota dysbiosis in disease development and progression, primarily associated with dysregulation of community composition, modulation of host immune response, and induction of chronic inflammation. Finally, we introduce the clinical approaches that utilize microbiota for disease treatment, such as microbiota modulation and fecal microbial transplantation.
... Changes in the diversity and composition of the gut microbiota have been reported for a wide range of brain disorders and different potential mechanisms of action have been reviewed. For long, the gut microbiota has been linked to the hypothalamic-pituitary-adrenal axis and mood disorders such as bipolar disorders and major depression disorders (MDD) (Cheung et al., 2019;Kelly et al., 2019;Peirce and Alviña, 2019). Also, Autism Spectrum Disease (ASD) is one the diseases that have been studied in depth (Saurman et al., 2020) and there is increasing interest in the gut-brain axis in schizophrenia research (Golofast and Vales, 2020). ...
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There is a growing body of evidence highlighting the significant role of gut microbiota in various pathologies. We performed a systematic review to review the different microbiota involved in neuropsychiatric diseases. 50 studies (23 studies for autism spectrum disorders, 18 for major depression, and 9 for schizophrenia), representing 2,137 patients and 2,844 controls. Concerning the microbiota, the genera Prevotella, Clostridium, Bacteroides, Bifidobacterium, Ruminococcus, Megamonas, and Faecalbacterium were the ones detected with the most frequent variation of their relatives abundance. We also assess the overlap between the different pathologies. This study provides new insights into the complex relationship between the brain and the gut and the implications in neuropsychiatric pathologies. The identification of unique signatures in neuropsychiatric diseases suggests new possibilities in targeted anti or probiotic treatment.
... The vagus nerve directly mediates intestinal permeability, immune-inflammatory response, endocrine signal transmission and intestinal reflex activities (Bonaz et al., 2018). Intestinal flora alters vagal nerve signals and causes behavioral abnormalities (Peirce and Alviña, 2019). It has been reported that specific bacterial strains utilize vagus nerve signals to communicate with brain and changes the behavior (Yu et al., 2020). ...
Article
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Alcohol use disorders (AUD) is characterized by persistent or intermittent alcohol cravings and compulsive drinking. The functional changes in the central nervous system (CNS) after alcohol consumption are alcohol-associated cognitive impairment and mood disorders, which are major health issues reported in AUDs. Studies have shown that transferring the intestinal microbiota from AUDs patients to germ-free animals causes learning and memory dysfunction, depression and anxiety-like behavior, indicating the vital role of intestinal microbiota in development of neuropsychiatric disorders in AUD. Intestinal flora composition of AUD patients are significantly different from normal people, suggesting that intestinal flora imbalance orchestrate the development of neuropsychiatric disorders in AUD. Studies suggests that gut microbiome links bidirectional signaling network of the enteric nervous system (ENS) to central nervous system (CNS), forming gut-microbe-brain axis (brain-gut axis). In this review, we discussed pathogenesis and possible treatment of AUD-induced cognitive deficits, anxiety, and depression disorders. Further, we described the mechanism of intestinal flora imbalance and dysfunction of hippocampus-amygdala-frontal cortex (gut-limbic circuit system dysfunction). Therefore, we postulate therapeutic interventions of gut-brain axis as novel strategies for treatment of AUD-induced neuropsychiatric disorders.
... [11][12][13] As the link between body and soul in IBD is thought to be bidirectional, these mental conditions may be the result of active IBD, but may also play a role in triggering or intensifying physical symptoms in patients with IBD. 14,15 This points to the need of mental health screening as part of a holistic treatment approach. To the best of our knowledge, there are no generally accepted guidelines for the matter. ...
Article
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Background Depression and anxiety are common among inflammatory bowel disease (IBD) patients. Not only do they worsen quality of life, but also worsen the prognosis of the IBD. Yet, there are no widely accepted guidelines for screening for depression or anxiety in this population. The Hospital Anxiety and Depression Scale (HADS) is a self-administered questionnaire designed to measure anxiety and depression in the physically ill. The purpose of this study was to establish the utility of the HADS as a screening tool in IBD patients. Methods Seventy-nine IBD patients (age 29.86 ± 8.36, 51.9% female, 77.2% Crohn’s disease) were recruited consecutively at the day treatment unit, Gastroenterology Department, Sheba Medical Center. They were asked to complete the HADS, the Beck Depression Inventory (BDI), and the State-Trait Anxiety Inventory (STAI). The scores of the HADS depression and anxiety subscales were correlated with the BDI and STAI scores, and the rates of above-threshold scores were calculated and compared between the three questionnaires and findings from previous studies. Results The two HADS subscales significantly correlated with and the BDI ( r s = .69, p < 0.001) and STAI state and trait anxiety ( r s = .853, p < 0.001; r s = .744, p < 0.001, respectively). The usual HADS cut-off scores yielded adequate rate of anxiety but lower than expected depression rates. Conclusions Our findings suggest the HADS as a valid screening tool for anxiety and depression in IBD patients. We recommend administering it routinely in gastrointestinal (GI) follow-ups using a lower cut-off score for depression than anxiety (greater than 7 vs greater than 11, respectively).
... Нейроны ЭНС являются первой точкой контакта эффекторов нервной системы с кишечной микробиотой. Восходящая афферентация из кишечника передаются в различные отделы ЦНС и ВНС через волокна блуждающего нерва -nervus vagus, который имеет эфферентные и афферентные пути и играет фундаментальную роль в обеспечении сигналов от мозга к кишечнику и наоборот [29][30][31][32]. ...
Article
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The review presents modern ideas about changes in the quantitative and qualitative composition of the human intestinal microbiome and their role in the development of stress-induced mental and neurological disorders, eating disorders, autism, etc. The dualism of the role of the commensal representatives of the microbiome, which have the ability to modulate metabolic and signaling reactions in conditionally healthy people and patients suffering from various neurological, psychoemotional and cognitive disorders associated with the development of neuroinflammation, is shown. The favorable and negative effects established by foreign researchers are associated with the presence of specific surface membrane proteins in the intestinal microbiota, the production of certain short-chain fatty acids, mucin degradation, changes in the intestinal barrier function, endotoxin production, as well as the synthesis of certain neurotransmitters. The prospects and difficulties of searching for new microbial biomarkers for predicting the development of stress-induced diseases, as well as for creating new microbial nutraceuticals and new-generation medicines based on living bacteria are considered.
... SCFAs, mainly butyrate, propionate and acetate produced as by-products of microbial fermentation, are also involved in reducing inflammatory processes [Ohira et al. 2017] and they are the arbitrators for the colonic inflammatory response (CIR) [Maslowski andMackay 2011, Sommer andDantas 2011]. Inflammation due to stress contributes to the process of depression and anxiety [Barnes et al. 2017, Peirce andAlviña 2019]. The influence of diet on the microbiota population was demonstrated in a study where ten healthy participants received treatment based on the animal and plant diet to monitor variations in the gut microbiota profile. ...
Article
The human gut microbiome has received considerable attention since it has been demonstrated that it changes with obesity, diabetes, liver illnesses, cancer and neurological diseases and has been pointed out to be of key importance for the treatment of obesity-related and neurological diseases. Focusing on the neurodegenerative diseases, gut resident microbiota seems to interfere in normal brain functioning. Recent advancements in research shed light on the detailed physiology of the microbiome, its active role in disease and health, its relationship with stress and how modifications in the gut microbiota tend to influence behavioral changes. The dynamic nature of the microbiome stimulates the CNS signaling mechanism, which contributes to its active role in healthy homeostasis. This review aimed to highlight the role of microorganisms in the maintenance of normal homeostasis, their influence on mood disorders such as depression and anxiety, their potential implications in the management and treatment of depressive disorders.
... Des études ont montré des liens entre l'inflammation causée par le stress et l'anxiété et l'augmentation de la perméabilité intestinale due à la déstabilisation du microbiome. La prise de prébiotiques et probiotiques a démontré une amélioration à la fois de la perméabilisation mais aussi du niveau d'anxiété chez le rongeur (Peirce and Alviña, 2019). Il a également été rapporté que l'administration à long terme de formulation comme l'aspirine peut diminuer l'inflammation et augmenter la longévité chez les souris et le vieillissement sain chez l'Homme (Rothwell et al., 2011;Strong et al., 2008). ...
Thesis
Le vieillissement est un processus complexe modulé par des facteurs génétiques et épigénétiques. Il est caractérisé par une apparition progressive de pathologies associées à l’âge associées à un déclin progressif des capacités régénératrices cellulaires et tissulaires. Notre objectif est de retarder ces effets en induisant un rajeunissement global ou en améliorant les capacités régénératrices de l’organisme. En 2007, le Dr. Yamanaka a montré que des fibroblastes humains pouvaient être convertis en cellules pluripotentes en induisant l’expression de 4 facteurs de transcription. Notre équipe a montré en 2011 que les cellules sénescentes, qui s’accumulent au cours du vieillissement, pouvaient également être reprogrammées et retrouver une physiologie et un métabolisme rajeuni. Notre hypothèse est qu’une reprogrammation transitoire in vivo pourrait effacer les marques du vieillissement cellulaire et améliorer la régénération tissulaire afin de restaurer la physiologie cellulaire, retarder le vieillissement tissulaire et leurs conséquences délétères. Pour ce faire, nous avons utilisé un modèle murin transgénique pour contrôler l’induction de l’expression des facteurs de reprogrammation. Ces animaux récapitulent également le phénotype humain du syndrome d’Hutchinson-Gilford aussi appelé Progéria, mimant un vieillissement physiologique accéléré. Nos résultats montrent une augmentation significative de l’espérance de vie et une amélioration de l’intégrité tissulaire liée à une activation de la régénération tissulaire. L’impact d’une reprogrammation transitoire contrôlée sur les pathologies liées à l’âge a aussi été étudié et un rôle protecteur dans l’ostéoarthrite et l’ostéoporose est observé chez des animaux âgés de 8 mois. De plus, une induction à faible dose pendant 2 semaines à un âge précoce, permet un allongement de l’espérance de vie sur les âges tardifs associé à une diminution des marqueurs phénotypiques associés à l’âge. Ceci suggère un effet mémoire de la reprogrammation transitoire tout au long de la vie. Ce travail démontre comment la reprogrammation cellulaire transitoire réduit l’impact négatif du vieillissement au niveau de l’organisme.
... Since the invention of the microscope in 1681 by A. Leeuwenhoek and the first detection of microorganisms in fecal masses and to this day, the problem of the coexistence of a macroorganism with a microbiota has been surrounded by many mysteries and riddles [13][14][15]. The biological balance between the host organism and its microbiota developed during evolution, is a sensitive indicator of homeostasis, which reacts to any pathological abnormalities both in the body and in the external environment [16][17][18][19][20]. ...
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In the distal part of the gastrointestinal tract of animals and its lumen bacteria and parietal microorganisms of the mucous membrane contribute to primary and secondary metabolism and actively interact with populations of host immune cells and influence them in their own way. Mentioned parts of the organism represent the largest, and still insufficiently studied, reservoir of microbiota. Therefore, the analysis of the specific weight of dysbacteriosis in cats, the study of the etiology and features of the course, as well as an attempt to classify this syndrome in cats, will allow us to develop more effective approaches to their correction. The aim of this article was to analyze the dysbacteriosis distribution in cats according to the veterinary reporting of three clinics in the Moscow region over the past five years (2016-2020). The influence of age, sex, and season on the manifestations of dysbacteriosis was revealed.
... Hyperactivation of the HPA axis is commonly seen under multiple stress conditions, and corticosterone, as the final compound, is released from the adrenal glands within a short time following stimulation (Peirce and Alviña, 2019). However, the HPA axis is less developed in newly hatched chicks (Frankiensztajn et al., 2020). ...
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Recent studies have revealed that fecal microbiota transplantation exerts beneficial effects on modulating stress-related inflammation and gastrointestinal health of the host. The aim of this study was to examine if cecal microbiota transplantation (CMT) presents similar efficiency in improving the health status of egg-laying strain chickens. Chicken lines 63 and 72 divergently selected for resistance or susceptibility to Marek's disease were used as CMT donors. Eighty-four d-old male recipient chicks (a commercial DeKalb XL layer strain) were randomly assigned into 3 treatments with 7 replicates per treatment and 4 birds per replicate (n=7): saline (control, CTRL), cecal solution of line 63 (63-CMT), and cecal solution of line 72 (72-CMT) for a 16-wk trial. Cecal transplant gavage was conducted once daily from d 1 to d 10, then boosted once weekly from wk 3 to wk 5. The results indicated that 72-CMT birds had the highest body weight and ileal villus/crypt ratio among the treatments at wk 5 (P ≤ 0.05); and higher heterophil/lymphocyte ratios than that of 63-CMT birds at wk 16 (P < 0.05). 72-CMT birds also had higher levels of plasma natural IgG and Interleukin (IL)-6 at wk 16, while 63-CMT birds had higher concentrations of ileal mucosal secretory IgA at wk 5 and plasma IL-10 at wk 16 (P < 0.05), with a tendency for lower mRNA abundance of splenic IL-6 and tumor necrosis factor (TNF)-α at wk 16 (P = 0.08 and 0.07, respectively). In addition, 72-CMT birds tended to have the lowest serotonin concentrations (P = 0.07) with the highest serotonin turnover in the ileum at wk 5 (P < 0.05). There were no treatment effects on the levels of plasma corticosterone and testosterone at wk 16 (P > 0.05). In conclusion, early postnatal CMT from different donors led to different patterns of growth and health status through the regulation of ileal morphological structures, gut-derived serotonergic activities, peripheral cytokines, and antibody production in recipient chickens.
... Therefore, it is suggested that current psychobiotics may have limited potential to disrupt a depression-associated gut microbial ecosystem unless more complex communities are used (28). Manipulating the gut-brain axis of depression via fecal microbiota transplantation (FMT) has been explored by using the fecal matter of depressed donors in germ-free mice (29,30), but whether FMT from a 'healthy' donor can influence recipient depressive symptoms has yet to be explored. ...
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Depression is a recurrent, heterogeneous mood disorder occurring in more than 260 million people worldwide. Gut microbiome dysbiosis is associated with the development of depressive-like behaviors by modulating neuro-biochemical metabolism through the microbiome-gut-brain (MGB) axis. Fecal microbiota transplantation (FMT) has been proposed as a potential therapeutic solution for depression, but the therapeutic efficiency and mechanism are unknown. Here, we performed an FMT from Sprague-Dawley (SD) rats ('healthy' controls) to Fawn-hooded (FH) rats (depression model). Pre-FMT, the FH rats exhibited significantly elevated depressive-like behaviors and distinct neurotransmitter and cytokine levels compared with SD rats. Post-FMT, FH recipients receiving FH fecal microbiota (FH-FH rats) showed aggravated depressive-like behaviors, while the ones receiving SD microbiota (FH-SD rats) had significantly alleviated depressive symptoms, a significant increase in hippocampal neurotransmitters, and a significant decrease of some hippocampal cytokines than FH-FH rats. SD-FMT resulted in the FH-SD rats' gut microbiome resembling the SD donors, and a significant shift in the serum metabolome but not the hippocampal metabolome. Co-occurrence analysis suggests that SD-FMT prevented recipients' depression development via the significant decrease of gut microbial species such as Dialister sp., which led to the recipients' metabolic modulation in serum and hippocampus through the enteric nervous system, the intestinal barrier, and the blood-brain barrier. Our results provided new data pointing to multiple mechanisms of interaction for the impact of gut microbiome modulation on depression therapy. IMPORTANCE Depression is a chronic, recurrent mental disease, which could make the patients commit suicide in severe cases. Considering that gut microbiome dysbiosis could cause depressive symptoms in animals through the MGB axis, the modification of gut microbiota is expected to be a potential therapy for depression, but the daily administration of probiotics is invalid or transient. In this study, we demonstrated that the gut microbiome transferred from a healthy rat model to a depressive rat model could regulate the recipient's neurobiology and behavior via the systematic alternation of the depressive gut microbiota followed by the serum and hippocampal metabolism. These results underline the significance of understanding the impact of gut microbiota on mental disorders and suggest that 'healthy' microbiota transplantation with the function to solve the host's cerebral inflammation may serve as a novel therapeutic strategy for depression.
... Obesity, T2D, and depression, the intertwined trio metabolic syndromes are considered as the manifestation of chronic multisystem inflammation (Peirce and Alviña, 2019;Scheithauer et al., 2020). Diet-induced dysbiosis of intestinal microbiota (currently known as microbiota insufficiency syndrome) is changing the intestinal permeability (leaky gut) that is allowing the translocation of endotoxins (LPS) into systematics. ...
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The present study has been aimed at evaluating the antiobesity, antihyperglycemic, and antidepressive potentials of Asparagus racemosus starter-based rice fermented foods. High-throughput NGS technology has revealed a number of bacterial genera in the prepared fermented rice, such as Lactobacillus (29.44%), Brevundimonas (16.21%), Stenotrophomonas (6.18%), Pseudomonas (3.11%), Bacillus (2.88%), and others (<2%). Eight-week administration of rice fermented food has increased food intake, whole-body weight, organ weight, different fat masses, serum lipid profiles, and histology of liver and adipose tissues in HFD-induced obese mice. In addition, upregulation of fatty acid oxidation and downregulation of adipocytogenesis- and lypogenesis-related genes along with the expression of their regulatory nuclear factors such as PPARα, PPARγ, PPARδ, and SREBP-1c have also been noted. Moreover, fermented food decreases fasting blood glucose level and improves glucose and insulin tolerance as well as the expression of GLUT4 receptor. Antiobesity and antihyperglycemic effects are also supported by the changes in insulin, leptin, and adiponectin hormone levels. The real-time polymerase chain reaction (RT-PCR) and denaturing gradient gel electrophoresis (DGGE) analyses have clearly demonstrated the intense colonization of Bacteroides, Lactobacillus , and Bifidobacterium , as well as the suppressed growth rate of γ- and δ-Proteobacteria and Firmicutes in the gut after fermented food intake. In the intestine, the latter group of microorganisms possibly modulate short-chain fatty acid (SCFA) levels such as acetate, butyrate, and propionate more than twofold. The impairment of memory-learning and anxiety-like obesity-associated cognitive phenotypes is mitigated significantly ( p < 0.01) by fermented food as well. Thus, the formulated fermented food could be used as a natural therapeutic to alleviate obesity and its associated psychological and pathophysiological ailments.
... The gut microbiome also interacts significantly with inflammation and immunometabolism to influence depression incidence A. Mudra Rakshasa-Loots et al. and severity [152]. Manipulation of the gut microbiome has shown some promise in the treatment of depression, although the mechanisms underlying this "microbiota-gut-brain axis" remain unclear [153]. ...
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People living with HIV face a high risk of mental illness, especially depression. We do not yet know the precise neurobiological mechanisms underlying HIV-associated depression. Depression severity in the general population has been linked to acute and chronic markers of systemic inflammation. Given the associations between depression and peripheral inflammation, and since HIV infection in the brain elicits a neuroinflammatory response, it is possible that neuroinflammation contributes to the high prevalence of depression amongst people living with HIV. The purpose of this review was to synthesise existing evidence for associations between inflammation, depression, and HIV. While there is strong evidence for independent associations between these three conditions, few preclinical or clinical studies have attempted to characterise their interrelationship, representing a major gap in the literature. This review identifies key areas of debate in the field and offers perspectives for future investigations of the pathophysiology of HIV-associated depression. Reproducing findings across diverse populations will be crucial in obtaining robust and generalisable results to elucidate the precise role of neuroinflammation in this pathophysiology. Molecular Psychiatry; https://doi.
... Traditional models of stress indicate that hosts experiencing stress-related conditions, such as anxiety or depression triggered by psychosocial stressful stimuli, frequently suffer gut microbial dysbiosis (Pierce and Alviña, 2019;Meyyappan et al., 2020). For example, in rodents in which dominance-subordination relationships are tested, socially stressed individuals show lower gut bacterial diversity and alterations in microbial metabolism related to short-chain fatty acids (SCFAs) compared to controls (Bharwani et al., 2016). ...
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Animals living in anthropogenically disturbed habitats are exposed to environmental stressors which can trigger physiological reactions, such as chronic elevations of glucocorticoid hormones. Physiological responses to stressors may induce changes in the gut microbiome, most likely, facilitated by the gut-brain communication. Although these effects have been observed in humans and animal models, elucidating gut bacterial changes in wild animals under natural stressful conditions is still an ongoing task. Here we analyzed the association between physiological stress related to anthropogenic forest disturbance and changes in gut bacterial communities of black howler monkeys (Alouatta pigra) living in forest fragments in Mexico. We measured individuals' fecal glucocorticoid metabolites (fGCMs) as an index of physiological stress and created inventories of fecal bacterial communities sequencing the 16S rRNA gene to assess gut microbiome change. We evaluated environmental stress by estimating differences in food availability-feeding tree diversity and biomass-in each group's habitat. We found that both fGCMs and food availability indices were related to gut bacterial community shifts in black howler monkeys. Furthermore, using structural equation modeling, we found that a decrease in food availability, estimated through reductions in feeding tree basal area, increased fGCMs, which in turn induced increases in bacterial richness. Our findings show that the activation of the hypothalamic-pituitary-adrenal (HPA)-axis, which is a physiological response sensitive to environmental stressors such as the ecological disturbance of a habitat, contributes to structure the gut microbiome of arboreal primates in disturbed forests.
... Around 15% of the population suffers from anxiety, which is now a growing public health problem [3]. This disorder is associated with irritable bowel syndrome, inflammatory bowel disease, and other pathologies [4,5]. Among the novel methods developed for the treatment of anxiety disorders is the modulation of the intestinal microbiota by intestinal microbiota transplantation (IMT) [6]. ...
... As mentioned earlier, gut microbial structural stability plays an important role in metabolism, immunity, and homeostasis. Disturbances in the microbial structure are associated with a variety of neurological diseases, such as autism (Saurman et al., 2020), PD (Elfil et al., 2020), AD (Sochocka et al., 2019), and even affect mental behavior (Lach et al., 2018;Peirce and Alvi na, 2019). More and more studies have linked epilepsy susceptibility to changes in gut microbiota structure. ...
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Epilepsy is a common chronic brain disease. There are many clinical methods to control epileptic seizures, such as anti-seizure medications (ASMs) or surgical removal of epileptogenic lesions. However, the pathophysiology of epilepsy is still unknown, making it difficult to control or prevent it. The host’s immune system monitors gut microbes, interacts with microbes through pattern recognition receptors such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) expressed by innate immune cells, and activates immune responses in the body to kill pathogens and balance the relationship between microbes and host. In addition, inflammatory responses induced by the innate immune system are seen in animal models of epilepsy and temporal lobe epilepsy brain tissue to combat pathogens or injuries. This review summarizes the potential relationship between gut microbes, innate immunity, and epilepsy based on recent research to provide more hints for researchers to explore this field further.
... The gut microbiome living in our body has recently been considered to act as one of our organs [1,2]. As well as being involved in the maintenance of homeostatic processes in the body, disturbances in the gut microbiome are closely linked to inflammatory diseases [3][4][5]. Furthermore, the gut microbiome can manage our health and even our behavior [6,7]. ...
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To investigate the effect of the maternal gut microbiome on fetal endochondral bone formation, fetuses at embryonic day 18 were obtained from germ-free (GF) and specific-pathogen-free (SPF) pregnant mothers. Skeletal preparation of the fetuses’ whole bodies did not show significant morphological alterations; however, micro-CT analysis of the tibiae showed a lower bone volume fraction in the SPF tibia. Primary cultured chondrocytes from fetal SPF rib cages showed a lower cell proliferation and lower accumulation of the extracellular matrix. RNA-sequencing analysis showed the induction of inflammation-associated genes such as the interleukin (IL) 17 receptor, IL 6, and immune-response genes in SPF chondrocytes. These data indicate that the maternal gut microbiome in SPF mice affects fetal embryonic endochondral ossification, possibly by changing the expression of genes related to inflammation and the immune response in fetal cartilage. The gut microbiome may modify endochondral ossification in the fetal chondrocytes passing through the placenta.
... EVs released by the human microbiota -here called Outer Membrane Vesicles (OMVs) -may play a significant role in health and disease, acting locally and systemically as intercellular communicators to facilitate the aforementioned processes (Nagakubo et al., 2019). The largest part of the human microbiota inhabits the gastrointestinal system, where they modulate aspects as diverse as insulin signalling, behaviour and allergy (Bunyavanich et al., 2016;Caricilli et al., 2011;Peirce & Alviña, 2019). Recent work has demonstrated that components of the microbiota release OMVs that appear to impact tissue homeostasis and physiological alterations during disease, for example in promoting immune tolerance or activation, and in trafficking of bacterial toxins (Ñahui Palomino et al., 2021). ...
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Previously thought to be nothing more than cellular debris, extracellular vesicles (EVs) are now known to mediate physiological and pathological functions throughout the body. We now understand more about their capacity to transfer nucleic acids and proteins between distant organs, the interaction of their surface proteins with target cells, and the role of vesicle-bound lipids in health and disease. To date, most observations have been made in reductionist cell culture systems, or as snapshots from patient cohorts. The heterogenous population of vesicles produced in vivo likely act in concert to mediate both beneficial and detrimental effects. EVs play crucial roles in both the pathogenesis of diseases, from cancer to neurodegenerative disease, as well as in the maintenance of system and organ homeostasis. This two-part review draws on the expertise of researchers working in the field of EV biology and aims to cover the functional role of EVs in physiology and pathology. Part I will outline the role of EVs in normal physiology.
... The gut microbiome living in our body has recently been considered to act as one of our organs [1,2]. As well as being involved in the maintenance of homeostatic processes in the body, disturbances in the gut microbiome are closely linked to inflammatory diseases [3][4][5]. Furthermore, the gut microbiome can manage our health and even our behavior [6,7]. ...
Article
Full-text available
To investigate the effect of the maternal gut microbiome on fetal endochondral bone formation, fetuses at embryonic day 18 were obtained from germ-free (GF) and specific-pathogen-free (SPF) pregnant mothers. Skeletal preparation of the fetuses’ whole bodies did not show significant morphological alterations; however, micro-CT analysis of the tibiae showed a lower bone volume fraction in the SPF tibia. Primary cultured chondrocytes from fetal SPF rib cages showed a lower cell proliferation and lower accumulation of the extracellular matrix. RNA-sequencing analysis showed the induction of inflammation-associated genes such as the interleukin (IL) 17 receptor, IL 6, and immune-response genes in SPF chondrocytes. These data indicate that the maternal gut microbiome in SPF mice affects fetal embryonic endochondral ossification, possibly by changing the expression of genes related to inflammation and the immune response in fetal cartilage. The gut microbiome may modify endochondral ossification in the fetal chondrocytes passing through the placenta.
Article
There is a bi-directional connection between the gut microbiome and the brain. Changes in the composition of the microbiome affect emotions, behavior, and the stress response involved in the pathogenesis of depression. Depression and anxiety are often associated with dysbiosis and inflammatory bowel disease. Dysbiosis enhances stress response and low-grade systemic inflammation, and vice versa. This vicious circle may be responsible for the formation of depression. Antidepressants therapy should be accompanied by the elimination of dysbiosis. For these purposes diet, prebiotics, probiotics and faecal microbiota transplantation can be used. The advantages and disadvantages of each method are considered. The manipulation of microbiome composition has been shown to have great therapeutic potential in the treatment of depression and anxiety.
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The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates, and infants, is limited by a paucity of good quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts, by complementary information about targeted and non-targeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis-generating allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a sub-division into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as well as type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, non-invasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (e.g. liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, like artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to identify complex phenotypes and subpopulations of patients to improve development of medicines for children with potential economic advantages.
Article
Background Vulnerability theories propose that suboptimal levels of lipid markers and proinflammatory proteins predict future heightened depression. Scar models posit the reverse association. However, most studies that tested relationships between non-specific immune/endocrine markers and depression did not separate temporal inferences between people and within-person and how different immunometabolism markers related to unique depression symptoms. We thus used cross-lagged prospective network analyses (CLPN) to investigate this topic. Methods Community midlife women ( n = 2224) completed the Center for Epidemiologic Studies-Depression scale and provided biomarker samples across five time-points spanning 9 years. CLPN identified significant relations ( edges ) among components ( nodes ) of depression (depressed mood, somatic symptoms, interpersonal issues), lipid markers [insulin, fasting glucose, triglycerides, low-density lipoprotein-cholesterol (LDL), high-density lipoprotein-cholesterol (HDL)], and proinflammatory proteins [C-reactive protein (CRP), fibrinogen], within and across time-points. All models adjusted for age, estradiol, follicle-stimulating hormone, and menopausal status. Results In within-person temporal networks, higher CRP and HDL predicted all three depression components ( d = 0.131–2.112). Increased LDL preceded higher depressed mood and interpersonal issues ( v. somatic symptoms) ( d = 0.251–0.327). Elevated triglycerides predicted more somatic symptoms ( v. depressed mood and interpersonal problems) ( d = 0.131). More interpersonal problems forecasted elevated fibrinogen and LDL levels ( d = 0.129–0.331), and stronger somatic symptoms preceded higher fibrinogen levels ( d = 0.188). Conclusions Results supported both vulnerability and scar models. Long-term dysregulated immunometabolism systems, social disengagement, and related patterns are possible mechanistic accounts. Cognitive-behavioral therapies that optimize nutrition and physical activity may effectively target depression.
Article
Background Gut microbiome and dietary patterns have been suggested to be associated with depression/anxiety. However, limited effort has been made to explore the effects of possible interactions between diet and microbiome on the risks of depression and anxiety. Methods Using the latest genome-wide association studies findings in gut microbiome and dietary habits, polygenic risk scores (PRSs) analysis of gut microbiome and dietary habits was conducted in the UK Biobank cohort. Logistic/linear regression models were applied for evaluating the associations for gut microbiome-PRS, dietary habits-PRS, and their interactions with depression/anxiety status and Patient Health Questionnaire (PHQ-9)/Generalized Anxiety Disorder-7 (GAD-7) score by R software. Results We observed 51 common diet–gut microbiome interactions shared by both PHQ score and depression status, such as overall beef intake × genus Sporobacter [hurdle binary (HB)] ( P PHQ = 7.88 × 10 ⁻⁴ , P depression status = 5.86 × 10 ⁻⁴ ); carbohydrate × genus Lactococcus (HB) ( P PHQ = 0.0295, P depression status = 0.0150). We detected 41 common diet–gut microbiome interactions shared by GAD score and anxiety status, such as sugar × genus Parasutterella (rank normal transformed) ( P GAD = 5.15 × 10 ⁻³ , P anxiety status = 0.0347); tablespoons of raw vegetables per day × family Coriobacteriaceae (HB) ( P GAD = 6.02 × 10 ⁻⁴ , P anxiety status = 0.0345). Some common significant interactions shared by depression and anxiety were identified, such as overall beef intake × genus Sporobacter (HB). Conclusions Our study results expanded our understanding of how to comprehensively consider the relationships for dietary habits–gut microbiome interactions with depression and anxiety.
Article
Motor vehicle exhaust emissions have become the main source of urban air pollution in China, but few studies have explored the association of short-term exposure to traffic-related air pollutants (TRAPs) with anxiety disorders. Thus, we used an overdispersed, generalized additive model (GAM) to investigate the association between TRAPs and hospital admissions (HAs) for anxiety in Qingdao, a coastal Chinese city with high vehicle ownership. In addition, stratified analyses were performed by gender, age, season and hospitalization frequency (first admission and readmission). A positive association between TRAPs and HAs for anxiety was observed. Both inhalable particulate matter (PM10) and nitrogen dioxide (NO2) showed significant effects at lag 3 in the single-day lag structure, and each 10 μg/m³ increase in the concentrations was significantly associated with increases of 0.88% [95% confidence interval (CI): 0.04%, 1.72%] for PM10 and 2.74% (0.45%, 5.08%) for NO2 on anxiety hospitalizations. For fine particulate matter (PM2.5) and carbon monoxide (CO), the strongest effects were found at lag05 and lag04 [2.67% (0.77%, 4.62%) and 0.19% (0.04%, 0.34%), respectively] in the multiday lag structure. The estimates of PM2.5 were relatively robust after adjusting for other pollutants in the two-pollutant model. Stratified analyses indicated that the associations were stronger in females and younger individuals (<45 in age) than in males and elderly individuals (≥45 in age). Furthermore, the effects of PM2.5 and CO were most obvious during the cold season. Regarding hospitalization frequency, only PM2.5 was found to have a significant effect in the first-admission group. The results showed that short-term exposure to TRAPs, especially to PM2.5, was significantly associated with the increased risk of daily HAs for anxiety, which can help clinicians and policymakers better understand the effects of TRAPs to implement targeted interventions.
Article
Background Associations between depression and non-communicable disease have been well-described. However, the evidence for its role in the development of infectious disease is less understood. We aimed to examine prospective associations between depression and risk of hospitalisation for infection in middle-aged adults from the UK Biobank (linked with Hospital Episode Statistics) and assessed the role of several depression-related factors. Methods We assessed prospective associations between depression status at the baseline assessment (2006-2010) and hospitalisations for infection up to the end of March 2016 in 460,418 middle-aged adults enrolled in the UK Biobank (mean age=56.23±8.11 years, 53.5% female). Cox regression was used to assess associations between depression and subsequent hospitalisations for any infections, as well as infection subtypes, viral infections, and bacterial infections. Amongst those with depression, we also examined the role of depression duration, the age of onset, and the use of antidepressants in hospitalisation risk. Results Depression at baseline was prospectively associated with an increased risk of hospitalisation for infection (adjusted hazard ration (aHR)=1.20, 95% confidence interval (CI)=1.16 to 1.25). This association was found for all infection subtypes apart from infections of the central nervous system (p=0.911) and the skin (p=0.313). Receipt of a depression diagnosis in late adulthood and use of antidepressants (but only in those with none/mild depressive symptoms at baseline) increased the risk of hospitalisation for infection amongst those with depression. Conclusions These findings suggest that depression might be a risk factor which could be used to identify those at risk of hospitalisation for infection. Future research is required to understand the underlying factors that might result in this increased risk, so that targeted interventions can be developed. Funding: AR is supported by Guy’s Charity grant number EIC180702; AD is funded by Guy’s Charity grant number EIC180702 and MRC grant number MR/SO28188/1. The views expressed are those of the author[s] and not necessarily those of the ESRC, NIHR, the Department of Health and Social Care or King’s College London.
Article
Relevance . Despite the constant improvement of methods for correcting the intestinal microbiota, the occurrence of dysbacteriosis in various pathological processes not only does not decrease, but, on the contrary, increases. Therefore, the choice of the optimal therapeutic regimen for the correction of the lightest compensated degree of intestinal dysbiosis in cats, in our opinion, is an urgent direction of scientific research in veterinary medicine. Methods . Evaluation of the effectiveness of pharmacotherapy in cats with compensated intestinal dysbiosis (n = 15) is given. The animals were divided by the envelope method into two experimental groups: A 1 (n = 6) and A 2 (n = 9). The dynamics of individual hematological and immunological blood parameters of cats with grade 1 dysbiosis in the course of their therapy (before treatment, on days 7 and 14) is shown. Results . With compensated intestinal dysbiosis in cats, the appointment of the Purina Pro Plan dietary food shows a therapeutic effect, which leads to an overall clinical improvement as early as after 6.16±0.60 days. However, the use of the probiotic «Lactobifadol» against the background of diet therapy normalizes appetite after 2.39 days, an unpleasant odor from the oral cavity after 0.84 days, feces after 0.89 days, accelerates the overall clinical improvement of animals with intestinal dysbiosis of the 1st degree by 2.16 days earlier, when compared with the indicators of cats of the A 1 group.
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The volume and breadth of research on the role of the microbiome in neurodevelopmental and neuropsychiatric disorders has expanded greatly over the last decade, opening doors to new models of mechanisms of the gut-brain axis and therapeutic interventions to reduce the burden of these outcomes. Studies have highlighted the window of birth to 3 years as an especially sensitive window when interventions may be the most effective. Harnessing the powerful gut-brain axis during this critical developmental window clarifies important investigations into the microbe-human connection and the developing brain, affording opportunities to prevent rather than treat neurodevelopmental disorders and neuropsychiatric illness. In this review, we present an overview of the developing intestinal microbiome in the critical window of birth to age 3; and its prospective relationship with neurodevelopment, with particular emphasis on immunological mechanisms. Next, the role of the microbiome in neurobehavioral outcomes (such as autism, anxiety, and attention-deficit hyperactivity disorder) as well as cognitive development are described. In these sections, we highlight the importance of pairing mechanistic studies in murine models with large scale epidemiological studies that aim to clarify the typical health promoting microbiome in early life across varied populations in comparison to dysbiosis. The microbiome is an important focus in human studies because it is so readily alterable with simple interventions, and we briefly outline what is known about microbiome targeted interventions in neurodevelopmental outcomes. More novel examinations of known environmental chemicals that adversely impact neurodevelopmental outcomes and the potential role of the microbiome as a mediator or modifier are discussed. Finally, we look to the future and emphasize the need for additional research to identify populations that are sensitive to alterations in their gut microbiome and clarify how interventions might correct and optimize neurodevelopmental outcomes.
Article
Background Inflammation has been linked to a variety of mental and physical health outcomes that disproportionately impact women, and which can impair sexual function; thus, there is reason to expect a link between inflammation and women's sexual functioning. Aim To test the hypothesis that higher concentrations of C-reactive protein (CRP), a general biomarker of inflammation, would predict women's lower sexual desire. Method As 2 independent research teams, we conducted 3 separate studies (total n = 405) that assessed salivary CRP and various measurements of sexual desire in different women populations. Outcomes Female Sexual Function Index, Sexual Desire Inventory-2, Decreased Sexual Desire Screener, and Sexual Interest and Desire Inventory. Results Regardless of the way sexual desire was measured (e.g., state vs trait; general desire vs. desire functioning) and the population sampled (i.e., healthy vs. clinically diagnosed with sexual dysfunction), all the studies revealed null results. Clinical Implications While exploratory, the convergence of these null results across studies and researchers suggests that if there is an association between inflammation and women's sexual desire, it is likely very subtle. Strengths & Limitations Across 2 independent research teams, 3 unrelated studies, and various measurements of sexual desire, results were consistent. These points lend to the generalizability of the results. However, study designs were cross-sectional. Conclusions Future research may reveal (i) a non-linear threshold effect, such that inflammation does not begin to impact women's sexual desire until it is at a high level, (ii) inflammatory biomarkers other than CRP might be more sensitive in detecting associations between inflammation and desire, should they exist, or (iii) the mechanisms underlying sexual dysfunction may differ between sexes. Clephane K, et al. Lack of Evidence for a Relationship Between Salivary CRP and Women's Sexual Desire: An Investigation Across Clinical and Healthy Samples. J Sex Med 2021;XX:XXX–XXX.
Article
Background Major depressive disorder (MDD) is underscored by daytime dysfunction-associated features, including mood disturbances, impaired cognition, fatigue, and daytime sleepiness. Importantly, the gut-brain axis may represent a potential mechanistic link between MDD and daytime dysfunction. Therefore, this study aimed to explore the gut microbiome composition and daytime dysfunction in Chinese patients with MDD. Methods We enrolled 36 patients with MDD and 45 healthy controls (HCs) matched by age, sex, and body mass index (BMI). Daytime function including emotion, fatigue, and sleepiness were assessed using the Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD). 16S rRNA sequencing was employed to characterize the gut microbiota in stool samples. Results The operational taxonomic units (OTUs) OTU255, OUT363 were positively correlated with HAMD and HAMA. OTU244, OTU542 and OTU221 were positively correlated with ESS, HAMD and HAMA. OTU725 and OTU80 were positively correlated with FSS, ESS, HAMD and HAMA, while OTU423 and OTU502 were negatively correlated with all above. Flavonifractor positively correlated with fatigue in patients with MDD and all individuals simultaneously. The correlation between gut microbiome and daytime function was different in MDD and HCs. Conclusions We identified several OTUs associated with the severity of fatigue, depression, daytime sleepiness and anxiety in all individuals. Our results revealed the differences in microbiome found between patients with MDD and HCs. These findings provide insights into the potential microbiota changes that occur in MDD, and will enable the development of specific therapeutic strategies for targeting the various symptoms of depression.
Chapter
The microbiome is the indigenous microbial population (microbiota) and the host environment in which it lives, and it is revolutionising how doctors think about germs in human health and illness. The understanding that most microbes in human bodies perform vital ecosystem functions that benefit the whole microbial host system is perhaps the most basic development. The microbiome is a collection of varied and numerous bacteria that live in the gastrointestinal system. Generally, this ecosystem comprises billions of microbial cells that play a vital role in human health control. Immunity, nutrition absorption, digestion, and metabolism have all been linked to the microbiome. Researchers have discovered that changes in the microbiome are linked to the development of diseases including obesity, inflammatory lung disease, and CVS diseases, carcinoma in recent times. A change in the microbial population of the intestine has a big impact on human health and disease aetiology. These changes are caused by a combination of factors, including lifestyle and the existence of an underlying illness. Dysbiosis makes the host more susceptible to infection, the type of which varies depending on the anatomical location. The distinct metabolic processes and roles of these bacteria inside each bodily location are accounted for by the inherent variety of the human microbiota. As a result, it is critical to comprehend the human microbiome’s microbial makeup and behaviours as they relate to health and illness.
Article
Chronic low back pain (CLBP) is one of the leading causes of pain and disability in adults in the United States and disproportionately burdens non-Hispanic Black (NHB) individuals and females. Approximately 90% of CLBP cases are of unknown cause, and it is imperative that potential causes be explored. It has been reported that diet quality can influence pain state via diet-induced inflammation. The present study assessed the relationship between Dietary Inflammatory Index (DII) and movement evoked-pain severity in people with CLBP and investigated whether race/sex moderated the relationship between DII and movement-evoked pain. Results revealed no significant differences in DII scores between males and females, or between NHB and non-Hispanic White (NHW) participants. Participant sex significantly modified the relationship between DII and movement-evoked pain severity (p=0.0155), such that movement-evoked pain severity was significantly impacted by DII scores in females, but not males. Participant race did not significantly moderate the DII – movement-evoked pain severity relationship. These results suggest that diet-induced inflammation may impact the CLBP experiences of females to a greater degree than males. Further research is needed to determine whether dietary interventions that reduce inflammation improve CLBP outcomes and whether these interventions may be differentially-beneficial based on sex. Perspective: This article highlights the impact of diet-induced inflammation in a community-based sample as a whole, as well as stratified in various sociodemographic groups. This work expands our understanding of the influence of diet on pain experience and suggests that modifications to diet may be efficacious treatments for reducing chronic pain.
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The human gut microbiome modulates health and disease and can be manipulated by lifestyle and diet. This article presents a summary of what we know to date, and what the future might hold for this rapidly evolving field of science and technology, including its role in personalised health.
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BACKGROUND: Vulnerability theories propose that suboptimal levels of lipid markers and proinflammatory proteins predict future heightened depression. Scar models posit the reverse association. However, most studies that tested relationships between non-specific immune/endocrine markers and depression did not separate temporal inferences between people and within-person and how different immunometabolism markers related to unique depression symptoms. We thus used cross-lagged prospective network analyses (CLPN) to investigate this topic. METHODS: Community midlife women (n = 2,224) completed the Center for Epidemiologic Studies-Depression scale and provided biomarker samples across five time-points spanning nine years. CLPN identified significant relations (edges) among components (nodes) of depression (depressed mood, somatic symptoms, interpersonal issues), lipid markers (insulin, fasting glucose, triglycerides, low-density lipoprotein-cholesterol (LDL), high-density lipoprotein-cholesterol (HDL)), and proinflammatory proteins (C-reactive protein (CRP), fibrinogen), within and across time-points. All models adjusted for age, estradiol, follicle-stimulating hormone, and menopausal status. RESULTS: In within-person temporal networks, higher CRP and HDL predicted all three depression components (d = 0.131 to 2.112). Increased LDL preceded higher depressed mood and interpersonal issues (vs. somatic symptoms) (d = 0.251 to 0.327). Elevated triglycerides predicted more somatic symptoms (vs. depressed mood and interpersonal problems) (d = 0.131). More interpersonal problems forecasted elevated fibrinogen and LDL levels (d = 0.129 to 0.331), and stronger somatic symptoms preceded higher fibrinogen levels (d = 0.188). CONCLUSIONS: Results supported both vulnerability and scar models. Long-term dysregulated immunometabolism systems, social disengagement, and related patterns are possible mechanistic accounts. Cognitive-behavioral therapies that optimize nutrition and physical activity may effectively target depression.
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Background Inflammation is a risk factor for chronic physical illnesses. Evidence is building that inflammation is also a risk factor for mental illnesses making inflammation a common mechanism which could explain the high comorbidity between mental and physical illnesses. Method Based on a systematic search, a review on factors associated with inflammation in the depressed chronically ill has been conducted. Relevant articles have been selected according to the methodological considerations (scope, sample size, type of analysis and bias). Results Five categories of factors mediate the association between chronic physical and mental illnesses: (1) social–demographic factors, (2) social–economic background, (3) adverse health behaviours, (4) psychological stress and (5) genetics. Psychological therapies and medication also moderate this association. A theoretical model of the interplay between inflammation, depression and chronic physical illness is then presented. Discussion Inflammation contribute to both chronic physical and mental illnesses. These conclusions support future advances in clinical and research practice, as well as training and education.
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Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161+ regulatory T (Treg) cells as a distinct, highly suppressive population of Treg cells that mediate wound healing. These Treg cells were enriched in intestinal lamina propria, particularly in Crohn’s disease. CD161+ Treg cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on Treg cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORγt, FOSL2, AP-1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161+ Treg cell signature in Crohn’s disease mucosa associated with reduced inflammation. These findings identify CD161+ Treg cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut.
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Background: Interleukin-6 (IL-6) is elevated in circulation with chronic stress and may contribute to neurobehavioral complications. We have reported that repeated social defeat stress in mice caused recruitment of proinflammatory monocytes to the brain and triggered the onset of anxiety-like behavior. Therefore, the purpose of this study was to determine the role of IL-6 signaling in the peripheral immune response, neuroinflammation, and anxiety following stress. Methods: Wild-type and IL-6 knockout mice were subjected to repeated social defeat, and immune and behavioral parameters were determined 14 hours later. Results: Although monocyte release and recruitment to the brain during stress were maintained in the IL-6 knockout mice, anxiety and social avoidance were prevented. NanoString analysis of fluorescence-activated cell-sorted blood monocytes (CD11b+/Ly6Chi) and brain monocytes (CD11b+/CD45hi) revealed a unique pattern of immune-related gene expression that was dependent on stress and IL-6. For instance, blood monocytes after stress had a transcriptional signature and immune profile consistent with priming, which was attenuated in monocytes from IL-6 knockout stress mice. Moreover, the monocytes recruited to the brain and associated with the development of anxiety had a transcriptional signature (enhanced IL-1β, CD14, Mmp9, Myd88, Ager, and Stat3) that was dependent on IL-6. Conclusions: Here, we show the effects of IL-6 on the transcriptional signature of monocytes in circulation and brain after stress. Overall, robust increases in IL-6 after stress induced a primed profile in monocytes that were recruited to the brain and propagated IL-1-mediated inflammation and anxiety.
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Key points: Chronic (psychosocial) stress changes gut microbiota composition, as well as inducing behavioural and physiological deficits. The microbial metabolites short-chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, (neuro)immune regulation and host metabolism, but their role in stress-induced behavioural and physiological alterations is poorly understood. Administration of SCFAs to mice undergoing psychosocial stress alleviates enduring alterations in anhedonia and heightened stress-responsiveness, as well as stress-induced increases in intestinal permeability. In contrast, chronic stress-induced alterations in body weight gain, faecal SCFAs and the gene expression of the SCFA receptors FFAR2 and FFAR3 remained unaffected by SCFA supplementation. These results present novel insights into mechanisms underpinning the influence of the gut microbiota on brain homeostasis, behaviour and host metabolism, informing the development of microbiota-targeted therapies for stress-related disorders. Abstract: There is a growing recognition of the involvement of the gastrointestinal microbiota in the regulation of physiology and behaviour. Microbiota-derived metabolites play a central role in the communication between microbes and their host, with short-chain fatty acids (SCFAs) being perhaps the most studied. SCFAs are primarily derived from fermentation of dietary fibres and play a pivotal role in host gut, metabolic and immune function. All these factors have previously been demonstrated to be adversely affected by stress. Therefore, we sought to assess whether SCFA supplementation could counteract the enduring effects of chronic psychosocial stress. C57BL/6J male mice received oral supplementation of a mixture of the three principle SCFAs (acetate, propionate and butyrate). One week later, mice underwent 3 weeks of repeated psychosocial stress, followed by a comprehensive behavioural analysis. Finally, plasma corticosterone, faecal SCFAs and caecal microbiota composition were assessed. SCFA treatment alleviated psychosocial stress-induced alterations in reward-seeking behaviour, and increased responsiveness to an acute stressor and in vivo intestinal permeability. In addition, SCFAs exhibited behavioural test-specific antidepressant and anxiolytic effects, which were not present when mice had also undergone psychosocial stress. Stress-induced increases in body weight gain, faecal SCFAs and the colonic gene expression of the SCFA receptors free fatty acid receptors 2 and 3 remained unaffected by SCFA supplementation. Moreover, there were no collateral effects on caecal microbiota composition. Taken together, these data show that SCFA supplementation alleviates selective and enduring alterations induced by repeated psychosocial stress and these data may inform future research into microbiota-targeted therapies for stress-related disorders.
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The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan (Trp) plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance. Recent discoveries have underscored that changes in the microbiota modulate the host immune system by modulating Trp metabolism. Moreover, Trp, endogenous Trp metabolites (kynurenines, serotonin, and melatonin), and bacterial Trp metabolites (indole, indolic acid, skatole, and tryptamine) have profound effects on gut microbial composition, microbial metabolism, the host's immune system, the host-microbiome interface, and host immune system–intestinal microbiota interactions. The aryl hydrocarbon receptor (AhR) mediates the regulation of intestinal immunity by Trp metabolites (as ligands of AhR), which is beneficial for immune homeostasis. Among Trp metabolites, AhR ligands consist of endogenous metabolites, including kynurenine, kynurenic acid, xanthurenic acid, and cinnabarinic acid, and bacterial metabolites, including indole, indole propionic acid, indole acetic acid, skatole, and tryptamine. Additional factors, such as aging, stress, probiotics, and diseases (spondyloarthritis, irritable bowel syndrome, inflammatory bowel disease, colorectal cancer), which are associated with variability in Trp metabolism, can influence Trp–microbiome–immune system interactions in the gut and also play roles in regulating gut immunity. This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions. Increased mechanistic insight into how the microbiota modulates the intestinal immune system through Trp metabolism may allow for the identification of innovative microbiota-based diagnostics, as well as appropriate nutritional supplementation of Trp to prevent or alleviate intestinal inflammation. Moreover, this review provides new insight regarding the influence of the gut microbiota on Trp metabolism. Additional comprehensive analyses of targeted Trp metabolites (including endogenous and bacterial metabolites) are essential for experimental preciseness, as the influence of the gut microbiota cannot be neglected, and may explain contradictory results in the literature.
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Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.
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Objective: The Treatment-Resistant Depression Registry investigated whether adjunctive vagus nerve stimulation (VNS) with treatment as usual in depression has superior long-term outcomes compared with treatment as usual only. Method: This 5-year, prospective, open-label, nonrandomized, observational registry study was conducted at 61 U.S. sites and included 795 patients who were experiencing a major depressive episode (unipolar or bipolar depression) of at least 2 years' duration or had three or more depressive episodes (including the current episode), and who had failed four or more depression treatments (including ECT). Patients with a history of psychosis or rapid-cycling bipolar disorder were excluded. The primary efficacy measure was response rate, defined as a decrease of ?50% in baseline Montgomery-?sberg Depression Rating Scale (MADRS) score at any postbaseline visit during the 5-year study. Secondary efficacy measures included remission. Results: Patients had chronic moderate to severe depression at baseline (the mean MADRS score was 29.3 [SD=6.9] for the treatment-as-usual group and 33.1 [SD=7.0] for the adjunctive VNS group). The registry results indicate that the adjunctive VNS group had better clinical outcomes than the treatment-as-usual group, including a significantly higher 5-year cumulative response rate (67.6% compared with 40.9%) and a significantly higher remission rate (cumulative first-time remitters, 43.3% compared with 25.7%). A subanalysis demonstrated that among patients with a history of response to ECT, those in the adjunctive VNS group had a significantly higher 5-year cumulative response rate than those in the treatment-as-usual group (71.3% compared with 56.9%). A similar significant response differential was observed among ECT nonresponders (59.6% compared with 34.1%). Conclusions: This registry represents the longest and largest naturalistic study of efficacy outcomes in treatment-resistant depression, and it provides additional evidence that adjunctive VNS has enhanced antidepressant effects compared with treatment as usual in this severely ill patient population.
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Background and AimsFecal microbial transplantation (FMT) is an established successful treatment modality for recurrent Clostridium difficile infection (CDI). The safety profile and potential therapeutic advantages of FMT for diseases associated with dysbiosis and immune dysfunction have led to many publications, mainly case series, and while many studies and reviews have been published on the use of FMT for inflammatory bowel disease (IBD), its potential use for other disease conditions has not been thoroughly reviewed. The aim of this review was to investigate the evidence surrounding the use of FMT in conditions other than IBD and CDI. MethodsA PubMed search was performed using the terms “Fecal microbiota transplantation” OR “FMT” OR “Bacteriotherapy.” ResultsA total of 26 articles describing the use of FMT in a variety of both intra-and extraintestinal disease conditions including gastrointestinal, hematologic, neurologic, metabolic, infectious, and autoimmune disorders have been included in this review and have demonstrated some positive results. The studies included were case reports, case series, controlled trials, and cohort studies. Conclusions The findings of these studies demonstrate that FMT, particularly in conditions associated with gastrointestinal dysbiosis, shows promise to provide another effective tool in the therapeutic armament of the practicing physician. FMT was found to be possibly effective in various diseases, mostly associated with enteric dysbiosis or with immune dysfunction. Randomized clinical studies on large populations should be performed to explore the effectiveness of this therapy, and basic research studies should be designed to gain understanding of the mechanisms through which impact these disorders.
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Suicide is a major and continuing public health concern in the United States. During 1999-2015, approximately 600,000 U.S. residents died by suicide, with the highest annual rate occurring in 2015 (1). Annual county-level mortality data from the National Vital Statistics System (NVSS) and annual county-level population data from the U.S. Census Bureau were used to analyze suicide rate trends during 1999-2015, with special emphasis on comparing more urban and less urban areas. U.S. counties were grouped by level of urbanization using a six-level classification scheme. To evaluate rate trends, joinpoint regression methodology was applied to the time-series data for each level of urbanization. Suicide rates significantly increased over the study period for all county groupings and accelerated significantly in 2007-2008 for the medium metro, small metro, and non-metro groupings. Understanding suicide trends by urbanization level can help identify geographic areas of highest risk and focus prevention efforts. Communities can benefit from implementing policies, programs, and practices based on the best available evidence regarding suicide prevention and key risk factors. Many approaches are applicable regardless of urbanization level, whereas certain strategies might be particularly relevant in less urban areas affected by difficult economic conditions, limited access to helping services, and social isolation.
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Background Patients suffering from depression experience significant mood, anxiety, and cognitive symptoms. Currently, most antidepressants work by altering neurotransmitter activity in the brain to improve these symptoms. However, in the last decade, research has revealed an extensive bidirectional communication network between the gastrointestinal tract and the central nervous system, referred to as the “gut–brain axis.” Advances in this field have linked psychiatric disorders to changes in the microbiome, making it a potential target for novel antidepressant treatments. The aim of this review is to analyze the current body of research assessing the effects of probiotics, on symptoms of depression in humans. MethodsA systematic search of five databases was performed and study selection was completed using the preferred reporting items for systematic reviews and meta-analyses process. ResultsTen studies met criteria and were analyzed for effects on mood, anxiety, and cognition. Five studies assessed mood symptoms, seven studies assessed anxiety symptoms, and three studies assessed cognition. The majority of the studies found positive results on all measures of depressive symptoms; however, the strain of probiotic, the dosing, and duration of treatment varied widely and no studies assessed sleep. Conclusion The evidence for probiotics alleviating depressive symptoms is compelling but additional double-blind randomized control trials in clinical populations are warranted to further assess efficacy.
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During childhood, our brain is exposed to a variety of environmental inputs that can sculpt synaptic connections and neuronal circuits, with subsequent influence on behavior and learning processes. Critical periods of neurodevelopment are windows of opportunity in which the neuronal circuits are extremely plastic and can be easily subjected to remodeling in response to experience. However, the brain is also more susceptible to aberrant stimuli that might lead to altered developmental trajectories. Intriguingly, postnatal brain development is paralleled by the maturation of the gut microbiota: the ecosystem of symbionts populating our gastro-intestinal tract. Recent discoveries have started to unveil an unexpected link between the gut microbiome and neurophysiological processes. Indeed, the commensal bacteria seem to be able to influence host behavioral outcome and neurochemistry through mechanisms which remain poorly understood. Remarkably, the efficacy of the gut flora action appears to be dependent on the timing during postnatal life at which the host gut microbes’ signals reaches the brain, suggesting the fascinating possibility of critical periods for this microbiota-driven shaping of host neuronal functions and behavior. Therefore, to understand the importance of the intestinal ecosystem’s impact on neuronal circuits functions and plasticity during development and the discovery of the involved molecular mechanisms, will pave the way to identify new and, hopefully, powerful microbiota-based therapeutic interventions for the treatment of neurodevelopmental and psychiatric diseases.
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Background: Cardiovascular disease occurs at lower incidence in premenopausal females compared with age-matched males. This variation may be linked to sex differences in inflammation. We prospectively investigated whether inflammation and components of the inflammatory response are altered in females compared with males. Methods: We performed 2 clinical studies in healthy volunteers. In 12 men and 12 women, we assessed systemic inflammatory markers and vascular function using brachial artery flow-mediated dilation (FMD). In a further 8 volunteers of each sex, we assessed FMD response to glyceryl trinitrate (GTN) at baseline and at 8 hours and 32 hours after typhoid vaccine. In a separate study in 16 men and 16 women, we measured inflammatory exudate mediators and cellular recruitment in cantharidin-induced skin blisters at 24 and 72 hours. Results: Typhoid vaccine induced mild systemic inflammation at 8 hours, reflected by increased white cell count in both sexes. Although neutrophil numbers at baseline and 8 hours were greater in females, the neutrophils were less activated. Systemic inflammation caused a decrease in FMD in males, but an increase in females, at 8 hours. In contrast, GTN response was not altered in either sex after vaccine. At 24 hours, cantharidin formed blisters of similar volume in both sexes; however, at 72 hours, blisters had only resolved in females. Monocyte and leukocyte counts were reduced, and the activation state of all major leukocytes was lower, in blisters of females. This was associated with enhanced levels of the resolving lipids, particularly D-resolvin. Conclusions: Our findings suggest that female sex protects against systemic inflammation-induced endothelial dysfunction. This effect is likely due to accelerated resolution of inflammation compared with males, specifically via neutrophils, mediated by an elevation of the D-resolvin pathway. Trial registration: ClinicalTrials.gov NCT01582321 and NRES: City Road and Hampstead Ethics Committee: 11/LO/2038. Funding: The authors were funded by multiple sources, including the National Institute for Health Research, the British Heart Foundation, and the European Research Council.
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The emerging concept of psychobiotics - live microorganisms with a potential mental health benefit - represents a novel approach for the management of stress-related conditions. The majority of studies have focused on animal models. Recent preclinical studies have identified the B. longum 1714 strain as a putative psychobiotic with an impact on stress-related behaviors, physiology and cognitive performance. Whether such preclinical effects could be translated to healthy human volunteers remains unknown. We tested whether psychobiotic consumption could affect the stress response, cognition and brain activity patterns. In a within-participants design, healthy volunteers (N=22) completed cognitive assessments, resting electroencephalography and were exposed to a socially evaluated cold pressor test at baseline, post-placebo and post-psychobiotic. Increases in cortisol output and subjective anxiety in response to the socially evaluated cold pressor test were attenuated. Furthermore, daily reported stress was reduced by psychobiotic consumption. We also observed subtle improvements in hippocampus-dependent visuospatial memory performance, as well as enhanced frontal midline electroencephalographic mobility following psychobiotic consumption. These subtle but clear benefits are in line with the predicted impact from preclinical screening platforms. Our results indicate that consumption of B. longum 1714 is associated with reduced stress and improved memory. Further studies are warranted to evaluate the benefits of this putative psychobiotic in relevant stress-related conditions and to unravel the mechanisms underlying such effects.
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The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression. Here we utilized two novel transgenic mouse strains to directly test the hypothesis that neurotoxic kynurenine metabolism causes depressive-like behavior following peripheral immune activation. Wild-type (WT) or kynurenine 3-monooxygenase (KMO)-deficient (KMO−/−) mice were administered either lipopolysaccharide (LPS, 0.5 mg kg⁻¹) or saline intraperitoneally. Depressive-like behavior was measured across multiple domains 24 h after immune challenge. LPS precipitated a robust depressive-like phenotype, but KMO−/− mice were specifically protected from LPS-induced immobility in the tail suspension test (TST) and reduced spontaneous alternations in the Y-maze. Direct administration of 3-hydroxykynurenine, the metabolic product of KMO, caused a dose-dependent increase in depressive-like behaviors. Mice with targeted deletion of 3-hydroxyanthranilic acid dioxygenase (HAAO), the enzyme that generates quinolinic acid, were similarly challenged with LPS. Similar to KMO−/− mice, LPS failed to increase immobility during the TST. Whereas kynurenine metabolism was generally increased in behaviorally salient brain regions, a distinct shift toward KMO-dependent kynurenine metabolism occurred in the dorsal hippocampus in response to LPS. Together, these results demonstrate that KMO is a pivotal mediator of hippocampal-dependent depressive-like behaviors induced by peripheral LPS challenge.
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The present study aimed at detecting the exogenously applied probiotic Lactobacillus farciminis in rats, after exposure to IBS-like chronic stress, based on 4-day Water Avoidance Stress (WAS). The presence of L. farciminis in both ileal and colonic mucosal tissues was demonstrated by FISH and qPCR, with ileum as the preferential niche, as for the SFB population. A different spatial distribution of the probiotic was observed: in the ileum, bacteria were organized in micro-colonies more or less close to the epithelium whereas, in the colon, they were mainly visualized far away from the epithelium. When rats were submitted to WAS, the L. farciminis population substantially decreased in both intestinal regions, due to a stress-induced increase in colonic motility and defecation, rather than a modification of bacterial binding to the intestinal mucin Muc2.
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This paper describes the effects of immune genes genetic variants and mRNA expression on depression’s risk, severity, and response to antidepressant treatment, through a systematic review on all papers published between 2000 and 2016. Our results, based largely on case–control studies, suggest that common genetic variants and gene-expression pathways are involved in both immune activation and depression. The most replicated and relevant genetic variants include polymorphisms in the genes for interleukin (IL)-1β, IL-6, IL-10, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, C-reactive protein, and phospholipase A2. Moreover, increased blood cytokines mRNA expression (especially of IL-1β) identifies patients that are less likely to respond to conventional antidepressants. However, even for the most replicated findings there are inconsistent results, not only between studies, but also between the immune effects of the genetic variants and the resulting effects on depression. We find evidence that these discrepant findings may be explained, at least in part, by the heterogeneity of the depression immunophenotype, by environmental influences and gene × environment interactions, and by the complex interfacing of genetic variants with gene expression. Indeed, some of the most robust findings have been obtained in patients developing depression in the context of treatment with interferon-alpha, a widely used model to mimic depression in the context of inflammation. Further ‘omics’ approaches, through GWAS and transcriptomics, will finally shed light on the interaction between immune genes, their expression, and the influence of the environment, in the pathogenesis of depression.Neuropsychopharmacology advance online publication, 26 October 2016; doi:10.1038/npp.2016.169.
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Reported values in the literature on the number of cells in the body differ by orders of magnitude and are very seldom supported by any measurements or calculations. Here, we integrate the most up-to-date information on the number of human and bacterial cells in the body. We estimate the total number of bacteria in the 70 kg "reference man" to be 3.8·1013. For human cells, we identify the dominant role of the hematopoietic lineage to the total count (≈90%) and revise past estimates to 3.0·1013 human cells. Our analysis also updates the widely-cited 10:1 ratio, showing that the number of bacteria in the body is actually of the same order as the number of human cells, and their total mass is about 0.2 kg.
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It has been reported that gut probiotics play a major role in the bidirectional communication between the gut and the brain. Probiotics may be essential to people with depression, which remains a global health challenge, as depression is a metabolic brain disorder. However, the efficacy of probiotics for depression is controversial. This study aimed to systematically review the existing evidence on the effect of probiotics-based interventions on depression. Randomized, controlled trials, identified through screening multiple databases and grey literature, were included in the meta-analysis. The meta-analysis was performed using Review Manager 5.3 software using a fixed-effects model. The meta-analysis showed that probiotics significantly decreased the depression scale score (MD (depressive disorder) = -0.30, 95% CI (-0.51-0.09), p = 0.005) in the subjects. Probiotics had an effect on both the healthy population (MD = -0.25, 95% CI (-0.47--0.03), p = 0.03) and patients with major depressive disorder (MDD) (MD = -0.73, 95% CI (-1.37--0.09), p = 0.03). Probiotics had an effect on the population aged under 60 (MD = -0.43, 95% CI (-0.72--0.13), p = 0.005), while it had no effect on people aged over 65 (MD = -0.18, 95% CI (-0.47-0.11), p = 0.22). This is the first systematic review and meta-analysis with the goal of determining the effect of probiotics on depression. We found that probiotics were associated with a significant reduction in depression, underscoring the need for additional research on this potential preventive strategy for depression.
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Aims: To review the burden of allergic and infectious diseases and the evidence for a link to microbial exposure, the human microbiome and immune system, and to assess whether we could develop lifestyles which reconnect us with exposures which could reduce the risk of allergic disease while also protecting against infectious disease. Methods: Using methodology based on the Delphi technique, six experts in infectious and allergic disease were surveyed to allow for elicitation of group judgement and consensus view on issues pertinent to the aim. Results: Key themes emerged where evidence shows that interaction with microbes that inhabit the natural environment and human microbiome plays an essential role in immune regulation. Changes in lifestyle and environmental exposure, rapid urbanisation, altered diet and antibiotic use have had profound effects on the human microbiome, leading to failure of immunotolerance and increased risk of allergic disease. Although evidence supports the concept of immune regulation driven by microbe–host interactions, the term ‘hygiene hypothesis’ is a misleading misnomer. There is no good evidence that hygiene, as the public understands, is responsible for the clinically relevant changes to microbial exposures. Conclusion: Evidence suggests a combination of strategies, including natural childbirth, breast feeding, increased social exposure through sport, other outdoor activities, less time spent indoors, diet and appropriate antibiotic use, may help restore the microbiome and perhaps reduce risks of allergic disease. Preventive efforts must focus on early life. The term ‘hygiene hypothesis’ must be abandoned. Promotion of a risk assessment approach (targeted hygiene) provides a framework for maximising protection against pathogen exposure while allowing spread of essential microbes between family members. To build on these findings, we must change public, public health and professional perceptions about the microbiome and about hygiene. We need to restore public understanding of hygiene as a means to prevent infectious disease.
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There is a growing awareness that gut commensal metabolites play a major role in host physiology and indeed the pathophysiology of several illnesses. The composition of the microbiota largely determines the levels of tryptophan in the systemic circulation and hence, indirectly, the levels of serotonin in the brain. Some microbiota synthesize neurotransmitters directly, e.g., gamma-amino butyric acid, while modulating the synthesis of neurotransmitters, such as dopamine and norepinephrine, and brain-derived neurotropic factor (BDNF). The composition of the microbiota determines the levels and nature of tryptophan catabolites (TRYCATs) which in turn has profound effects on aryl hydrocarbon receptors, thereby influencing epithelial barrier integrity and the presence of an inflammatory or tolerogenic environment in the intestine and beyond. The composition of the microbiota also determines the levels and ratios of short chain fatty acids (SCFAs) such as butyrate and propionate. Butyrate is a key energy source for colonocytes. Dysbiosis leading to reduced levels of SCFAs, notably butyrate, therefore may have adverse effects on epithelial barrier integrity, energy homeostasis, and the T helper 17/regulatory/T cell balance. Moreover, dysbiosis leading to reduced butyrate levels may increase bacterial translocation into the systemic circulation. As examples, we describe the role of microbial metabolites in the pathophysiology of diabetes type 2 and autism.
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