Article

Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170: 1179-1188

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Abstract

The concept that intestinal microbial composition not only affects the health of the gut, but also influences centrally-mediated systems involved in mood, is supported by a growing body of literature. Despite the emergent interest in brain-gut communication and its possible role in the pathogenesis of psychiatric disorders such as depression, particularly subtypes with accompanying gastrointestinal (GI) symptoms, there are few studies dedicated to the search for therapeutic solutions that address both central and peripheral facets of these illnesses. This study aims to assess the potential benefits of the probiotic Bifidobacterium infantis in the rat maternal separation (MS) model, a paradigm that has proven to be of value in the study of stress-related GI and mood disorders. MS adult rat offsprings were chronically treated with bifidobacteria or citalopram and subjected to the forced swim test (FST) to assess motivational state. Cytokine concentrations in stimulated whole blood samples, monoamine levels in the brain, and central and peripheral hypothalamic-pituitary-adrenal (HPA) axis measures were also analysed. MS reduced swim behavior and increased immobility in the FST, decreased noradrenaline (NA) content in the brain, and enhanced peripheral interleukin (IL)-6 release and amygdala corticotrophin-releasing factor mRNA levels. Probiotic treatment resulted in normalization of the immune response, reversal of behavioral deficits, and restoration of basal NA concentrations in the brainstem. These findings point to a more influential role for bifidobacteria in neural function, and suggest that probiotics may have broader therapeutic applications than previously considered.

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... Thus, early life stress causes an inflammatory immune phenotype characterized by increased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), which are also associated with depression (Hodes et al., 2015;Dutcher et al., 2020). In maternal separated rats, probiotic interventions reversed stress-induced behavioral deficits as well as normalized blood cytokines levels (Desbonnet et al., 2010). ...
... The beneficial effect of pre-and probiotic interventions on emotional responses seems to be more pronounced following stress. Accordingly, probiotic supplementation was effective in decreasing depressive-like behavior in stressed rats but not in non-stressed rats (Desbonnet et al., 2010). In healthy humans, probiotic supplementation for 30 days alleviated physiological distress (Messaoudi et al., 2011). ...
... The prenatal stress and the disruption of mother-infant bond lead to stress related behavioral disorders as well as changes in the gut microbiota. Adult rats exposed to maternal separation show behavioral deficits, which can be reversed by the chronic treatment with Bifidobacteria or by anti-depressive citalopram treatment (Desbonnet et al., 2010). Furthermore, a significant reduction in Lactobacillus species has also been observed in maternally separated pups (Gareau et al., 2007). ...
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The endocannabinoid system, with its receptors and ligands, is present in the gut epithelium and enteroendocrine cells, and is able to modulate brain functions, both indirectly through circulating gut-derived factors and directly through the vagus nerve, finally acting on the brain’s mechanisms regarding metabolism and behavior. The gut endocannabinoid system also regulates gut motility, permeability, and inflammatory responses. Furthermore, microbiota composition has been shown to influence the activity of the endocannabinoid system. This review examines the interaction between microbiota, intestinal endocannabinoid system, metabolism, and stress responses. We hypothesize that the crosstalk between microbiota and intestinal endocannabinoid system has a prominent role in stress-induced changes in the gut-brain axis affecting metabolic and mental health. Inter-individual differences are commonly observed in stress responses, but mechanisms underlying resilience and vulnerability to stress are far from understood. Both gut microbiota and the endocannabinoid system have been implicated in stress resilience. We also discuss interventions targeting the microbiota and the endocannabinoid system to mitigate metabolic and stress-related disorders.
... Moreover, both groups of rats (injected and not-injected with beta-amyloid), when nourished by probiotics, improved their spatial memory (85). In another study on rats, prolonged administration of probiotics also weakened cytokine response to mitogen stimulation and reduced apoptosis susceptibility in the limbic system (86). ...
... However, a group of scientists found no difference in the expression of corticotropin-releasing factor in the hypothalamus between the control group of rats and the animals, which had been exposed to stress by separation from their mothers (86). Despite this, they achieved an alleviation in depression-like behavior and a normalization of immune response following probiotic supplementation (86). ...
... However, a group of scientists found no difference in the expression of corticotropin-releasing factor in the hypothalamus between the control group of rats and the animals, which had been exposed to stress by separation from their mothers (86). Despite this, they achieved an alleviation in depression-like behavior and a normalization of immune response following probiotic supplementation (86). ...
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Depression is the major cause of disability globally. Apart from lowered mood and accompanying symptoms, it leads to cognitive impairment that altogether predicts disadvantaged social functioning. Reduced cognitive function in depression appears a bit neglected in the field of clinical and molecular psychiatry, while it is estimated to occur in two-thirds of depressed patients and persist in at least one third of remitted patients. This problem, therefore, requires elucidation at the biomolecular and system levels and calls for improvement in therapeutic approach. In this review study, we address the above-mentioned issues by discussing putative mechanisms of cognitive decline in depression: (1) increased oxidative stress and (2) inflammation, (3) disturbed hypothalamus-pituitary-adrenals axis, and (4) reduced monoamines functionality. Moreover, we acknowledge additional underpinnings of cognitive impairment in depressed elderly: (5) vascular-originated brain ischemia and (6) amyloid-beta plaque accumulation. Additionally, by reviewing molecular, pre-clinical and clinical evidence, we propose gut microbiota-targeted strategies as potential adjuvant therapeutics. The study provides a consolidated source of knowledge regarding mechanisms of cognitive impairment in depression and may path the way toward improved treatment options.
... Accumulating evidence suggests that alterations in the gut microbiota composition are associated with the pathogenesis of depression (Desbonnet et al., 2010;Friswell et al., 2010;Aizawa et al., 2016;Zheng et al., 2020). In the present study, stress exposure did not change the number of Lactobacillus, Bifidobacterium, or A. muciniphila. ...
... Furthermore, we also observed increased levels of Bifidobacterium and Lactobacillus after OLL2809 treatment. Oral intake of Bifidobacterium, a genus of gram-positive anaerobic bacteria, was recently reported to improve depressive behavior in SDS-exposed mice (Yang et al., 2017) and in the maternal separation model (Desbonnet et al., 2010). Bifidobacterium reduces intestinal endotoxin levels and improves mucosal barrier function (Griffiths et al., 2004; FIGURE 6 | Effects of Lactobacillus paragasseri OLL2809 administration on relative abundance of gut microorganisms that showed significant correlation with immobility time in the forced swim test. ...
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Lactobacillus paragasseri OLL2809 is a probiotic bacterial strain isolated from healthy human feces. While OLL2809 has been studied for its immunomodulatory activities, its effect on depressive-like behaviors remains unclear. In this study, we used a mouse model of social defeat stress (SDS) to investigate whether oral administration of OLL2809 ameliorates depressive-like behavior. C57BL6 male mice were administered OLL2809 for 2 weeks following a 4-week period of SDS. Although OLL2809 did not affect serum corticosterone levels, it ameliorated depression-like behaviors, and it induced neurite outgrowth in the hippocampal dentate gyrus. The 16S rRNA amplicon sequence analyses revealed that family level gut microbiota composition was affected by stress and OLL2809 administration. Additionally, Akkermansia muciniphila, Bifidobacterium, and Lactobacillus were significantly increased by OLL2809 treatment. LEfSe analysis suggested that the antidepressive effect of OLL2809 may be mediated by increases in other microorganisms, such as Erysipelotrichaceae uncultured. Our findings suggest that L. paragasseri OLL2809 may have potential in microbiome therapeutics.
... Recent research found that inflammation can increase the permeability of the blood-brain barrier (Varatharaj and Galea, 2017) to allow cytokines to cross. At the same time, microbes can modulate gut-associated lymphoid tissue, resulting in various cytokines (Desbonnet et al., 2010;Rudzki and Szulc, 2018). Therefore, quantification of inflammation may assist in developing treatment regimens for depression. ...
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The multifaceted and heterogeneous nature of depression presents challenges in pinpointing treatments. Among these contributions are the interconnections between the gut microbiome and neurological function termed the gut-brain axis. A diverse range of microbiome-produced metabolites interact with host signaling and metabolic pathways through this gut-brain axis relationship. Therefore, biosensor detection of gut metabolites offers the potential to quantify the microbiome’s contributions to depression. Herein we review synthetic biology strategies to detect signals that indicate gut-brain axis dysregulation that may contribute to depression. We also highlight future challenges in developing living diagnostics of microbiome conditions influencing depression.
... It has been proposed that probiotics indirectly improve the regulation of the HPA axis and neurotransmitter activity by ameliorating GI integrity and decreasing gut inflammation in hosts. The performance of probiotic-fed early-life stress (ELS) rats in the force swimming test improved and the concentration of proinflammatory cytokine IL-6 reduced (Desbonnet et al., 2010). In comparison to control rats, both the parameters were normalized in probiotic-fed ELS rats, suggesting a close relationship between probiotics and anti-inflammatory responses in improving brain health. ...
Article
Owing to their long history of safe use, probiotic microorganisms, typically from the genus Lactobacillus, have long been recognized, especially in traditional and fermented food industries. Although conventionally used for dairy, meat, and vegetable fermentation, the use of probiotics in health foods, supplements, and nutraceuticals has gradually increased. Over the past two decades, the importance of probiotics in improving gut health and immunity as well as alleviating metabolic diseases has been recognized. The new concept of a gut-heart-brain axis has led to the development of various innovations and strategies related to the introduction of probiotics in food and diet. Probiotics influence gut microbiota profiles, inflammation, and disorders and directly impact brain neurotransmitter pathways. As brain health often declines with age, the concept of probiotics being beneficial for the aging brain has also gained much momentum and emphasis in both research and product development. In this review, the concept of the aging brain, different in vivo aging models, and various aging-related benefits of probiotics are discussed.
... There are many types of probiotics; one of these, termed psychobiotics can affect the central nervous system by modulating the microbiota-gut-brain axis. 1 Several preclinical studies have demonstrated that the probiotics Bifidobacterium infantis and Lactobacillus plantarum PS128 could reduce depression-like behaviors in mice in a maternal separation depression animal model. 2,3 Lactobacillus rhamnosus can further reduce stressinduced anxiety-and depression-like behaviors in mice. 4 Similarly, Bifidobacterium longum 1714 and Lactobacillus helveticus NS8 improved the cognitive functions of anxious BALB/C mice and chronically stressed rats, respectively. ...
Article
Probiotic supplements are potential therapeutic agents for age-related cognitive deficits. A prior study showed that probiotic Lactobacillus paracasei PS23 (PS23) supplementation delayed age-related cognitive decline in mice. However, the underlying mechanisms remain unclear. This study aimed to investigate the effects of live or heat-killed PS23 (HK-PS23) on cognitive function in D-galactose (D-gal)-induced aging mice and explore the underlying mechanisms. We designed four groups of mice: control, D-gal aging mice, and PS23 supplemented and HK-PS23 supplemented D-gal aging mice. We evaluated memory function and anxiety using Morris water maze and open field tests, respectively. Neural monoamines and activities of superoxide dismutase (SOD) in the hippocampus were evaluated. RNA-seq was used to evaluate hippocampal gene expression profiles in each group, and the composition of the gut microbiota was analyzed. We revealed that PS23 and HK-PS23 supplementation ameliorated D-gal-induced memory deficits and improved motor and anxiety-behaviors in aging mice. In the hippocampus, serotonin levels (5-HT) were increased and the genes involved in neuroplasticity, anti-inflammatory, and antioxidant functions were upregulated in PS23 and HK-PS23 supplemented groups. The gut microbiota showed specific changes. Our results suggest that PS23 and HK-PS23 supplements could ameliorate age-related cognitive decline, possibly by upregulating the genes involved in synaptic plasticity and preventing oxidation and inflammation.
... Special attention has recently been paid to probiotics due to wide clinical purposes and health-promoting effects to manage several clinical conditions, such as chronic and acute gastrointestinal and non-gastrointestinal problems [15]. Probiotics have numerous health-promoting effects, and the gut microbiota are vital for the regulation of metabolic and mood processes [16]. Patients with multiple sclerosis showed an improvement in general health, depression, and anxiety and stress scales following twelve weeks of probiotic supplementation in a study by Kouchaki et al. [17]. ...
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Introduction: Patients under methadone maintenance treatment programs (MMTPs) are susceptible to numerous complications (e.g., mental and metabolic disorders). This study evaluated the effects of probiotics on clinical symptoms, biomarkers of oxidative stress, inflammation, insulin resistance, and serum lipid content in patients receiving MMTPs. Materials and methods: A randomized, double-blind, placebo-controlled trial was conducted among 70 patients receiving MMTPs to receive either 1.8 × 109 CFU/day probiotics (n = 35) or placebo (n = 35) for 12 weeks. Clinical symptoms and metabolic profiles were measured before and after the intervention in patients receiving MMTPs. Results: Compared with the placebo group, probiotic supplementation resulted in a significant improvement in the severity of depression (P < 0.05). In addition, probiotic administration significantly decreased fasting plasma glucose (FPG), total cholesterol, and low-density lipoprotein cholesterol (LDL cholesterol) (P < 0.05). Furthermore, probiotics resulted in a significant reduction in high-sensitivity C-reactive protein (hs-CRP) and a significant elevation in total antioxidant capacity (TAC) and total glutathione (GSH) levels (P < 0.05). Conclusion: Treatment with probiotics for 12 weeks to patients receiving MMTPs had beneficial effects on symptoms of depression, as well as several metabolic profiles. Clinical Trial Registration: this study was registered in the Iranian website (https://www.irct.ir) for clinical trials registration (https://fa.irct.ir/trial/46363/IRCT20170420033551N9). The registration date is March 22, 2020.
... While eliminating harmful bacteria with antibiotics can reduce anxiety-like behavior, it has also been shown that supplementing the microbiome with beneficial bacteria via probiotic treatment can also reduce anxiety-like and depressive-like behavior. Probiotic treatment causes a reduction of anxiety-like and depressive-like behaviors, even in rats experiencing maternal separation during neonatal development, an event known to increase depressive like behavior in adulthood (21,22). The probiotic effects are comparable to results from antidepressant treatment. ...
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Substance use disorder (SUD) is a prevalent disease that has caused hundreds of thousands of deaths and affected the lives of even more. Despite its global impact, there is still no known cure for SUD, or the psychological symptoms associated with drug use. Many of the behavioral consequences of drug use prevent people from breaking the cycle of addiction or cause them to relapse back into the cycle due to the physical and psychological consequences of withdrawal. Current research is aimed at understanding the cause of these drug related behaviors and therapeutically targeting them as a mechanism to break the addiction cycle. Research on opioids suggests that the changes in the microbiome during drug use modulated drug related behaviors and preventing these microbial changes could attenuate behavioral symptoms. This review aims to highlight the relationship between the changes in the microbiome and behavior during opioid treatment, as well as highlight the additional research needed to understand the mechanism in which the microbiome modulates behavior to determine the best therapeutic course of action.
... Dietary interventions as strategies to ameliorate MS-induced psychopathology have proven effective with studies in rats using probiotics reporting a reversal of MS-induced depressive (Desbonnet et al., 2010) and anxiety-like behaviours (McVey Neufeld et al., 2019), as well as MS-induced gut barrier dysfunction (Gareau et al., 2007b). Modulation of diet for the symptomatic relief of GI disorders has also proven effective with probiotics having been shown to reduce abdominal pain in children with irritable bowel syndrome (Guandalini et al., 2010), as well as reduce the frequency and intensity of abdominal pain occurrences in school-aged children with functional GI disorders (Newlove-Delgado et al., 2017). ...
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Nutritional approaches have emerged over the past number of years as suitable interventions to ameliorate the enduring effects of early life stress. Maternal separation (MS) is a rodent model of early life stress which induces widespread changes across the microbiota-gut-brain axis. Milk fat globule membrane (MFGM) is a neuroactive membrane structure that surrounds milk fat globules in breast milk and has been shown to have positive health effects in infants, yet mechanisms behind this are not fully known. Here, we investigated the effects of MFGM supplementation from birth on a variety of gut-brain signalling pathways in MS and non-separated control animals across the lifespan. Specifically, visceral sensitivity as well as spatial and recognition memory were assessed in adulthood, while gut barrier permeability, enteric nervous system (ENS) and glial network structure were evaluated in both early life and adulthood. MS resulted in visceral hypersensitivity, which was ameliorated to a greater extent by supplementation with MFGM from birth. Modest effects of both MS and dietary supplementation were noted on spatial memory. No effects of MS were observed on enteric neuronal or glial networks in early life or adulthood, however an increase in the immunoreactivity of βIII-tubulin in adult colonic myenteric ganglia was noted in the MFGM intervention non-separated group. In conclusion, dietary supplementation with MFGM from birth is sufficient to block MS-induced visceral hypersensitivity, highlighting its potential value in visceral pain-associated disorders, but future studies are required to fully elucidate the mechanistic role of this supplementation on MS-induced visceral pain.
... This beautifully complex genetic regulatory process was very well articulated almost 20 years ago in Nature via Nurture, by Matt Ridley (Ridley, 2003 The core work of Golden Goose team, Drs. Meaney and Szyf, and colleagues has been expanded considerably by others to include alterations in gut microbiota in pups experiencing maternal deprivation (Ghia et al., 2008) and attenuation of maternal deprivation induced gut and brain alterations in adulthood after probiotic treatment (Gareau et al., 2007;Desbonnet et al., 2010). Gender differences in the effects of maternal deprivation on susceptibility to depression (Mourlon et al., 2010) and pain have also been identified (Ströher et al., 2019). ...
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The quality of one’s adult health and the chances of maintaining cognitive ability in aging stem directly from the quality of care one receives as an infant. Formal studies of maternal care can be traced back at least a century. Revelations of behavioral outcomes after maternal deprivation in primates were followed by discoveries of systemic and brain growth factors mediated by the caregiver–offspring relationship in rodents. More recently, much of the genetic/epigenetic bases of maternal care has been defined and positively linked to adult health and cognitive ability in senescence. The history of this field is both tragic and fascinating. The early primate work, while informative, was abusive. The initial rodent work was ridiculed before its importance was recognized. The final lesson learned is that infant/toddler care matters a lot. Today, we have a better understanding of the biology underlying maternal care and its transmission across generations as well as a scientific basis for massaging premature infants and hugging our children.
... On the other hand, earlylife stress induced by maternal separation induces dysbiosis in the adult offspring displaying depressive phenotype (O'Mahony et al., 2009;de Palma et al., 2015). Likewise, chronic probiotic treatment significantly improves depressive phenotype induced by maternal separation in the adult offspring (Desbonnet et al., 2010). Of note, the beneficial effects of probiotic administration are independent to dysbiosis, such that chronic treatment with a Lactobacillus strain reduces anxiety-and depressionlike behavior in the physiological condition and reduces corticosterone reactivity in response to acute stress (Bravo et al., 2011). ...
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Depression and anxiety are devastating disorders. Understanding the mechanisms that underlie the development of depression and anxiety can provide new hints on novel treatments and preventive strategies. Here, we summarize the latest findings reporting the novel roles of gut microbiota and microRNAs (miRNAs) in the pathophysiology of depression and anxiety. The crosstalk between gut microbiota and the brain has been reported to contribute to these pathologies. It is currently known that some miRNAs can regulate bacterial growth and gene transcription while also modulate the gut microbiota composition, suggesting the importance of miRNAs in gut and brain health. Treatment and prevention strategies for neuropsychiatric diseases, such as physical exercise, diet, and probiotics, can modulate the gut microbiota composition and miRNAs expressions. Nonetheless, there are critical questions to be addressed to understand further the mechanisms involved in the interaction between the gut microbiota and miRNAs in the brain. This review summarizes the recent findings of the potential roles of microbiota and miRNA on the neuropathology of depression and anxiety, and its potential as treatment strategies.
... There are several mechanisms by which the gut microbiome influences brain function (Mayer et al., 2015). For example, it has been shown that gut bacteria can alter systemic levels of neurotransmitter precursors and thus influence central neurotransmitters (Desbonnet et al., 2010). It has also been shown that Candida, Streptococcus and Enterococcus can produce neurotransmitters such as serotonin (Lyte, 2013(Lyte, , 2014Wall et al., 2014;Yano et al., 2015), Bacillus and Saccharomyces species can produce noradrenaline (Dinan and Cryan, 2017), while Lactobacillus and Bifidobacterium species can synthesize and release GABA (Dinan and Cryan, 2017). ...
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Functional dyspepsia is one of the most commonly diagnosed disorders of the gut-brain interaction worldwide. The precise pathogenesis of functional dyspepsia is complex and remains incompletely understood. Therefore, advances in the understanding of functional dyspepsia could change clinical practice. The aim of this review is to highlight the relevance of psychotherapy and probiotics in the context of the microbiota-gut-brain axis in the pathophysiology and especially in the treatment of functional dyspepsia. Therefore, studies which have been conducted to investigate the role of psychotherapy and probiotics in FD and the microbiota-gut-brain axis in the pathophysiology of functional dyspepsia were examined, and the outcomes of this research summarized. There might be a link between changes in the microbiome and functional dyspepsia. Even though, specific alterations in the microbiome that may be pathognomonic in functional dyspepsia remain unclear, the use of probiotics became a viable treatment option for patients with functional dyspepsia. Since mental illness also plays an important role in the pathophysiology of functional dyspepsia, psychotherapy is a useful treatment method, with additional study results indicating that psychotherapy may also shift the microbiome in a favorable direction. Moreover, other findings suggest that probiotics can be used not only to alleviate gastrointestinal symptoms in functional dyspepsia, but also to treat or even prevent mental disorders in these patients. In summary, in this review we highlight the bi-directionality of the microbiota-gut-brain axis in the pathophysiology of functional dyspepsia. Although there are multiple treatment approaches, the burden of disease in patients with functional dyspepsia is still enormous and a definitive therapy to cure this disease does not (yet) exist. Lastly, there is a lack of studies on the impact of dysbiosis, mental health and probiotics on pathophysiology and symptomatology in functional dyspepsia which should be investigated in future studies.
... This beneficial effect is related to its influence on enteric neurons and vagus nerve signals (Savignac et al., 2014). Preclinical and clinical studies have shown that Bifidobacteria may have therapeutic effects on mood disorders (Desbonnet et al., 2010). In addition to its beneficial effect on human health, Bifidobacteria was also shown to affect TCM efficacy. ...
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Bifidobacteria is an important microbe that inhabits the human gut. It is capable of metabolizing complex compounds in the human diet. Albiflorin, an antidepressant natural product from Radix Paeoniae Alba in China, is difficult to absorb after oral administration, and its metabolism has been proven to be closely related to the gut microbiota. In this study, we demonstrated in vitro that several Bifidobacteria species were able to convert albiflorin to benzoic acid, and four esterases (B2, B3, B4, and BL) from Bifidobacterium breve and Bifidobacterium longum were found through genome mining and modeled by SWISS-MODEL. B2 and B3 presented the strongest albiflorin metabolism ability. The optimal conditions, including temperature, buffer, and pH, for the conversion of albiflorin by the four esterases were investigated. Furthermore, the effect of esterase on the metabolism of albiflorin in vivo was confirmed by transplanting bacteria containing esterase B2. This study demonstrated the vital role of esterases from Bifidobacteria in the metabolism of natural compounds containing ester bonds, which could contribute to the development of new enzymes, microbial evolution, and probiotic adjuvant compounds for treatment.
... Control MS rats displayed immobility in the FST, decreased brain noradrenaline, elevated IL-6, and enhanced amygdala corticotropinreleasing factor mRNA levels. However, probiotic treatment normalized the immune response and noradrenaline concentrations and reversed behavioral deficits of MS rats [94]. This study further supports the idea that Bifidobacterium infantis has an impact on neural function and neurotransmitter activity. ...
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... Gut microbiota intervention targeting the specific dysbiosis in the gut profile may help PWE improve their depressive condition, without side effects and in a cost-effective manner, compared to current medication strategy (anti-depressants). Currently available gut microbiota interventions such as ketogenic diet and probiotic supplementation have been proven to be effective not only in preclinical studies (Desbonnet et al., 2010;Kilinc et al., 2021) but also in PWE (Gómez-Eguílaz et al., 2018;Lindefeldt et al., 2019;Williams & Cervenka, 2017) and people with depression (Messaoudi et al., 2011;Ricci et al., 2020;Wallace & Milev, 2017). Thus, it may not be a far stretch for these interventions to also be speculated for its beneficial effects in PWE and depression. ...
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Epilepsy is a debilitating disorder that affects about 70 million people in the world currently. Most patients with epilepsy (PWE) often reported at least one type of comorbid disorder. These may include neuropsychiatric disorders, cognitive deficits, migraine, cardiovascular dysfunction, systemic autoimmune disorders and others. Current treatment strategies against epilepsy-associated comorbidities have been based on targeting each disorder separately with either anti-seizure medications (ASMs), anti-inflammatories or anti-depressant drugs, which have often given inconsistent and ineffective results. Gut dysbiosis may be a common pathological pathway between epilepsy and its comorbid disorders, and thus may serve as a possible intervention target. Therefore, this narrative review aimed to elucidate the potential pathological and therapeutic role of the gut microbiota in adult epilepsy-associated comorbidities. This review noticed a scarcity in the current literature on studies investigating the direct role of the gut microbiota in relation to epilepsy-associated comorbidities. Nevertheless, gut dysbiosis have been implicated in both epilepsy and its associated comorbidities, with similarities seen in the imbalance of certain gut microbiota phyla (Firmicutes), but differences seen in the mechanism of action. Current gut-related interventions such as probiotics have been consistently reported across studies to provide beneficial effects in correcting gut dysbiosis and improving various disorders, independent of epilepsy. However, whether these beneficial effects may translate towards epilepsy-associated comorbidities have yet to be determined. Thus, future studies determining the therapeutic potential of gut microbiota interventions in PWE with epilepsy-associated comorbidities may effectively improve their quality of life.
... BF treatment was successful in reversing the behavioral deficit induced by PPA treatment in male rats. BF treatment has been implemented in humans and animals and has shown improvements in different behavioral measures (Desbonnet et al. 2010;Tian et al. 2019;Li et al. 2018) (38-40). The presence of Bifidobacterium in the gut can be linked to behavioral changes in some specific neurological disorders, as these strains can stimulate the production of gamma-aminobutyric acid (GABA), which plays an important role in anxiety and depression (Duranti et al. 2020). ...
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Gut microbiota plays a major role in neurological disorders, including autism. Modulation of the gut microbiota through fecal microbiota transplantation (FMT) or probiotic administration, such as Bifidobacteria, is suggested to alleviate autistic symptoms; however, their effects on the brain are not fully examined. We tested both approaches in a propionic acid (PPA) rodent model of autism as treatment strategies. Autism was induced in Sprague–Dawley rats by administering PPA orally (250 mg/kg) for 3 days. Animals were later treated with either saline, FMT, or Bifidobacteria for 22 days. Control animals were treated with saline throughout the study. Social behavior and selected brain biochemical markers related to stress hormones, inflammation, and oxidative stress were assessed. PPA treatment induced social impairments, which was rescued by the treatments. In the brain, Bifidobacteria treatment increased oxytocin relative to control and PPA groups. Moreover, Bifidobacteria treatment rescued the PPA-induced increase in IFN-γ levels. Both treatments increased GST levels, which was diminished by the PPA treatment. These findings indicate the potential of gut microbiota-targeted therapeutics in ameliorating behavioral deficit and underlying neural biochemistry.
... Other probiotics, like Bifidobacterium infantis 35624, showed antianxiety effects on rats with maternal separation (MS) model. The treatment of Bifidobacterium infantis 35624 restored the decreased noradrenaline concentrations in MS rat brainstem (Desbonnet et al., 2010). Another Bifidobacterium strain, Bifidobacterium longum BL999 (BL999), was reported to lead to gut microbiota profile of formula-fed human babies similar to that of breast-fed infants (Hascoët et al., 2011), showing a trend toward fewer respiratory tract infections (Puccio et al., 2007). ...
Article
Certain strains of Lactiplantibacillus were found to have a positive impact on host neuromodulation through the gut-brain axis and thus ameliorate emotional and behavioral problems. A number of researches have been performed on humans, mice and rats; however, studies on dogs are limited. Forty-five dogs with behavioral problems were enrolled in this study, including aggression (n=22), separation anxiety (n=15), compulsive disorder (n=7) and unclassifiable inappropriate behavior (n=1, excessive barking). The behavioral diagnosis was made based on the primary behavioral consultation questionnaires and the careful interrogations at interviews. Lactiplantibacillus plantarum PS128 (PS128) probiotic was administered to these physically healthy dogs with behavioral problems over a course of two weeks to determine the probiotic effectiveness on canine behaviors. Dogs were evaluated and scored using the Evaluation of Dog’s Emotional and cognitive Disorders (EDED) scale and the Canine Behavioral Checklist (CBC) questionnaire at the visits before and after the probiotic treatment. Plasma serotonin levels were measured using high-performance liquid chromatography- electrochemical detection (HPLC-ECD) and the serotonin turnover ratios (5-HIAA/5-HT) were compared pre- and post-treatment. The results showed that the general behavioral stability was improved, and the problems of aggression and separation anxiety were ameliorated after treatment. A significant decrease in 5-HIAA/5-HT ratio was observed in dogs with separation anxiety, suggesting a serotonin-related mechanism. These results proved that PS128 was beneficial for emotional stabilization, which might be useful as a therapeutic supplement for canine aggression and separation anxiety.
... A treatment with Bacterium infantis 35624 resulted in the normalization of the immune response, reversing behavioral deficits, and restoring basal NE concentrations in the brainstem [99]. B. infantis 35624 was found to be effective on depression-like behaviors. ...
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Major depressive disorder (MDD) is a common mental illness. Evidence suggests that the gut microbiota play an essential role in regulating brain functions and the pathogenesis of neuropsychiatric diseases, including MDD. There are numerous mechanisms through which the gut microbiota and brain can exchange information in a continuous, bidirectional communication. Current research emphasizes the interexchange of signals influenced by the gut microbiota that are detected and transduced in information from the gut to the nervous system involving neural, endocrine, and inflammatory mechanisms, suggesting a relationship between oxidative stress and the pathophysiology of MDD via the hyperactivation of inflammatory responses. Potential sources of inflammation in the plasma and hippocampus of depressed individuals could stem from increases in intestinal permeability. Some nutraceuticals, such as specific probiotics, namely psychobiotics, polyphenols, carotenoids, butyrate, and prebiotics, have been demonstrated to exert an antidepressant activity, but most of them need to be metabolized and activated by gut microorganisms. By inducing changes in the gut microbiota composition, physical exercise might also exert a role in alleviating depression-like symptoms. The mutual relationships among nutraceuticals, exercise, and depression will be discussed, and the potential role of the gut microbiota as a therapeutic target to treat depression will be explored.
... These studies imply the gut microbial composition and the compromised gut epithelial barrier function affect the immune system, which then may contribute to schizophrenia (82,83). ...
Chapter
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Many efforts have been devoted to study the cause and treatment of schizophrenia. Interestingly, growing evidence shows that, nutrition, a key factor for the development of the brain, plays an important role in both the cause and management of schizophrenia (4-10). In this chapter, we first provide an introduction to schizophrenia, including its symptomatic presentations, pathophysiology, and risk factors. After which, we will discuss the relation between schizophrenia, diet and nutrition.
... It has been shown that various stressors or stressful stimuli may impact the abundance of Lactobacilli, Bacteroides, and Clostridium in animal models affecting barrier integrity as well (Misiak et al., 2020). Studies have shown that probiotics based on Bifidobacterium and Lactobacillus species restore stress-induced HPA axis dysfunction and improve depression-and anxiety-like symptoms (Eutamene et al., 2007;Desbonnet et al., 2010). The intestinal microbiota can influence the HPA axis by increase in levels of cytokines, release of LPS and peptidoglycan (cell wall components of the bacteria) and by short chain fatty acid (SCFA) production (Misiak et al., 2020). ...
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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.
... These days, co-fermentation with different strains is a very popular method to increase the productivity of GABA. In other words, in the fermentation industry, usually more than one microorganism is used, because co-culture strains produce some substances which can improve each other's growth [36]. ...
Conference Paper
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Today, a number of studies conclusively show that certain bacterial strains, mainly from lactic acid bacteria (LAB), influence the functioning of the central nervous system, leading to confer mental health benefits through interactions with commensal gut bacteria. Such strains serve as the basis for developing probiotics with curative potential for the central nervous system-psychobiotic. Some compounds produced by bacteria, such as gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter of the central nervous system, are potential mediators between bacterial cells and the host. GABA is distributed throughout the human body and it is involved in the regulation of cardiovascular conditions such as blood pressure and heart rate, and plays a role in the reduction of anxiety and pain. Although researchers had produced GABA by chemical method earlier it became less acceptable as it pollutes the environment. Researchers now use a more promising microbial method for the production of GABA. In the drug and food industry, demand for GABA is immense. So, large scale conversion of GABA by microbes has got much attention. This review focuses on the functions of GABA and its mechanism of action. We also summarize the LAB's potential for GABA production in large scale.
... They additionally observed a correlation between gut microbiota composition and behavioral changes with anxiety-like symptoms [74], thus indicating that alterations in gut microbiota composition could affect the progression of anxiety-like symptoms. Furthermore, probiotics has also been suggested to contribute to the stress resilience response by reducing corticosterone release, anxiety symptoms, and depression symptoms in animal models [75,76], as well as by improving mood disturbances and reducing anxiety symptoms in human patients [77][78][79]. For example, a 12-weeks randomized double-blind and placebo study using the oral administration of Lactobacillus plantarum P8 showed a reduction in IFN-γ and TNF-α levels, accompanied by enhanced memory and cognitive functions in treated patients compared to a placebo group [80]. ...
Article
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A growing body of evidence from preclinical and clinical studies has associated alterations of the gut microbiota–brain axis with the progression and development of a number of pathological conditions that also affect cognitive functions. Spinal cord injuries (SCIs) can be produced from traumatic and non-traumatic causes. It has been reported that SCIs are commonly associated with anxiety and depression-like symptoms, showing an incidence range between 11 and 30% after the injury. These psychological stress-related symptoms are associated with worse prognoses in SCIs and have been attributed to psychosocial stressors and losses of independence. Nevertheless, emotional and mental modifications after SCI could be related to changes in the volume of specific brain areas associated with information processing and emotions. Additionally, physiological modifications have been recognized as a predisposing factor for mental health depletion, including the development of gut dysbiosis. This condition of imbalance in microbiota composition has been shown to be associated with depression in clinical and pre-clinical models. Therefore, the understanding of the mechanisms underlying the relationship between SCIs, gut dysbiosis and psychological stress could contribute to the development of novel therapeutic strategies to improve SCI patients’ quality of life.
... For human gut microbiome analysis, recent advances in sequencing techniques and bioinformatics have increased our knowledge of the complex microbial communities and their interactions. It is now well established that these microbes play important roles in relation to inflammation (7), metabolic disease (8,9), mental disorders (10,11), aging (12,13), and several other diseases and health conditions (14)(15)(16)(17)(18). However, different approaches to sample processing can introduce human error variability or technical biases through inappropriate sample handling or storage. ...
Article
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While a range of methods for stool collection exist, many require complicated, self-directed protocols and stool transfer. In this study, we introduce and validate a novel, wipe-based approach to fecal sample collection and stabilization for metagenomics analysis. A total of 72 samples were collected across four different preservation types: freezing at -20°C, room temperature storage, a commercial DNA preservation kit, and a dissolvable wipe used with DESS (dimethyl sulfoxide, ethylenediaminetetraacetic acid, sodium chloride) solution. These samples were sequenced and analyzed for taxonomic abundance metrics, bacterial metabolic pathway classification, and diversity analysis. Overall, the DESS wipe results validated the use of a wipe-based capture method to collect stool samples for microbiome analysis, showing an R2 of 0.96 for species across all kingdoms, as well as exhibiting a maintenance of Shannon diversity (3.1-3.3) and species richness (151-159) compared to frozen samples. Moreover, DESS showed comparable performance to the commercially available preservation kit (R2 of 0.98), and samples consistently clustered by subject across each method. These data support that the DESS wipe method can be used for stable, room temperature collection and transport of human stool specimens.
... Manipulation of the gut microbiota using probiotic bacteria (living microorganisms which, if consumed in adequate amounts, confer a health effect on the host [8]) has been shown to improve cognition and stress response in preclinical [9][10][11][12][13][14] and clinical studies [15][16][17][18][19]. However, only a few of those studies have specifically investigated brain responses to acute stressors or cognitive tasks [17,18]. ...
Article
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Probiotics are suggested to impact physiological and psychological stress responses by acting on the gut-brain axis. We investigated if a probiotic product containing Bifidobacterium longum R0175, Lactobacillus helveticus R0052 and Lactiplantibacillus plantarum R1012 affected stress processing in a double-blinded, randomised, placebo-controlled, crossover proof-of-concept study (NCT03615651). Twenty-two healthy subjects (24.2 ± 3.4 years, 6 men/16 women) underwent a probiotic and placebo intervention for 4 weeks each, separated by a 4-week washout period. Subjects were examined by functional magnetic resonance imaging while performing the Montreal Imaging Stress Task (MIST) as well as an autonomic nervous system function assessment during the Stroop task. Reduced activation in regions of the lateral orbital and ventral cingulate gyri was observed after probiotic intervention compared to placebo. Significantly increased functional connectivity was found between the upper limbic region and medioventral area. Interestingly, probiotic intervention seemed to predominantly affect the initial stress response. Salivary cortisol secretion during the task was not altered. Probiotic intervention did not affect cognitive performance and autonomic nervous system function during Stroop. The probiotic intervention was able to subtly alter brain activity and functional connectivity in regions known to regulate emotion and stress responses. These findings support the potential of probiotics as a non-pharmaceutical treatment modality for stress-related disorders.
... Campylobacterlerin ağız yoluyla verildiği kobaylarda kaygı bozukluğu geliştiği görülmüştür (Lyte, 1998). Bağırsakları steril hale getirilmiş germ free kobaylarda görülen adrenal (HPA) eksen refleksi ve depresyon, psikiyatrik hastalıklarda faydalı olduğu düşünülen Bifidobacterium sp'nin ağız yoluyla verilmesiyle tedavi edilmiştir (Desbonnet, 2010). Bifidobacterium infantis sadece anne sütüyle beslenen 0-6 ay bebeklerin bağırsağında ve probiyotik ilaçlarda baskın şekilde bulunmaktadır. ...
... Normalizes hippocampal BDNF levels and inflammation [111,150,159] Fructo-oligosaccharides and B-immuno galacto-oligosaccharide Stimulate the growth of beneficial bacteria, i.e., B. longum, which leads to reduction of stress-induced activation of the HPA axis, corticosterone levels, and pro-inflammatory cytokines, and increased BDNF [22,146,157,160,161] Bifidobacterium infantis 35624 Reduces depressive-like behavior via alleviating 5-HT [82,109,162] Bifidobacterium breve Stimulates 5-HT receptors in intestinal cells of rats [163] Bifidobacterium longum PS128 ...
Article
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Depression is a highly common mental disorder, which is often multifactorial with sex, genetic, environmental, and/or psychological causes. Recent advancements in biomedical research have demonstrated a clear correlation between gut dysbiosis (GD) or gut microbial dysbiosis and the development of anxiety or depressive behaviors. The gut microbiome communicates with the brain through the neural, immune, and metabolic pathways, either directly (via vagal nerves) or indirectly (via gut- and microbial-derived metabolites as well as gut hormones and endocrine peptides, including peptide YY, pancreatic polypeptide, neuropeptide Y, cholecystokinin, corticotropin-releasing factor, glucagon-like peptide, oxytocin, and ghrelin). Maintaining healthy gut microbiota (GM) is now being recognized as important for brain health through the use of probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), etc. A few approaches exert antidepressant effects via restoring GM and hypothalamus–pituitary–adrenal (HPA) axis functions. In this review, we have summarized the etiopathogenic link between gut dysbiosis and depression with preclinical and clinical evidence. In addition, we have collated information on the recent therapies and supplements, such as probiotics, prebiotics, short-chain fatty acids, and vitamin B12, omega-3 fatty acids, etc., which target the gut–brain axis (GBA) for the effective management of depressive behavior and anxiety.
... Several studies suggest that probiotic use confers physical and mental health benefits to the host [37][38][39], including as treatments for depression. In preclinical studies, administration of the probiotic Bifidobacterium infantis to rats has been shown to reverse experimentallyinduced stress and depression [40], while supplementation with Lactobacillus rhamnosus for 28 days results in a decline in depressive symptom ratings [35]. A more recent study by Li and colleagues (2018) showed that in a chronic mild stress mouse model of depression and anxiety, there was a reduction in Lactobacillus species, and an increase in the inflammatory markers IFN-γ, TNF-α, and indoleamine 2,3-dioxygenase-1 levels in the hippocampus. ...
Article
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An emerging body of literature demonstrates differences in the gut microbiome (GMB) of patients with major depressive disorder (MDD) compared to healthy controls (HC), as well as the potential benefits of prebiotic, probiotic, and synbiotic treatment. We conducted a systematic review of 24 observational studies (n = 2817), and 19 interventional trials (n = 1119). We assessed alpha diversity, beta diversity, and taxa abundance changes in patients with MDD relative to HC, as well as the effect of prebiotics, probiotics, and synbiotics on depressive symptoms in individuals with clinical or subclinical depression. We observed no significant differences in alpha diversity but a significant difference in beta diversity between patients with MDD and HC. There were fluctuations in the abundance of specific taxa in patients with MDD relative to HC. Probiotic and synbiotic, but not prebiotic, treatment showed a modest benefit in reducing depressive symptoms in patients with MDD over four to nine weeks. The GMB profiles of patients with MDD differ significantly from HC, but further studies are needed to elucidate the benefits of prebiotic, probiotic and synbiotic treatments relative to antidepressants and over longer follow-up before these therapies are implemented into clinical practice.
... The main bacterial genera used as probiotics in preclinical and clinical studies are the Lactobacillus and Bifidobacterium genera (Genedi et al., 2019). Studies involving animal models demonstrated that probiotics improved cognition, mood, anxiety, and stress (Sudo et al., 2004;Desbonnet et al., 2010;Bravo et al., 2011;Ait-Belgnaoui et al., 2014;Smith et al., 2014;Mohle et al., 2016;Bruce-Keller et al., 2018;Chunchai et al., 2018;Hadizadeh et al., 2019). Probiotics have also been studied in non-psychiatric individuals, and initial work showed improvements in cognitive function (Marotta et al., 2019) along with reducing constipation in different populations (Chmielewska and Szajewska, 2010;Miller and Ouwehand, 2013;Dimidi et al., 2014). ...
Article
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Depression is a severe mental disorder that places a significant economic burden on public health. The reciprocal link between the trillions of bacteria in the gut, the microbiota, and depression is a controversial topic in neuroscience research and has drawn the attention of public interest and press coverage in recent years. Mounting pieces of evidence shed light on the role of the gut microbiota in depression, which is suggested to involve immune, endocrine, and neural pathways that are the main components of the microbiota-gut-brain axis. The gut microbiota play major roles in brain development and physiology and ultimately behavior. The bidirectional communication between the gut microbiota and brain function has been extensively explored in animal models of depression and clinical research in humans. Certain gut microbiota strains have been associated with the pathophysiology of depression. Therefore, oral intake of probiotics, the beneficial living bacteria and yeast, may represent a therapeutic approach for depression treatment. In this review, we summarize the findings describing the possible links between the gut microbiota and depression, focusing mainly on the inflammatory markers and sex hormones. By discussing preclinical and clinical studies on probiotics as a supplementary therapy for depression, we suggest that probiotics may be beneficial in alleviating depressive symptoms, possibly through immune modulation. Still, further comprehensive studies are required to draw a more solid conclusion regarding the efficacy of probiotics and their mechanisms of action.
... Bifidobacteria strains demonstrated attenuated pro-inflammation responses in rodents (Desbonnet et al., 2008;Messaoudi et al., 2011a), and restored a balance of anti-inflammatory and pro-inflammatory cytokines in irritable bowel syndrome patients (O'Mahony et al., 2005). Also, B. infantis increased plasma concentration of tryptophan, a precursor for serotonin, which plays a crucial role in emotion processing and mood disorders such as depression and anxiety (Desbonnet et al., 2008(Desbonnet et al., , 2010. Thus, potential anxiolytic effects of B. infantis supplementation during early-life may have multiple plausible mediators, such as the pro-inflammatory cytokines and brain monoamines. ...
Article
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Development of the gut-brain axis during early-life is an important contributor of brain structural and functional development. Human milk oligosaccharides and gut microbiota have potential beneficial effects on various aspects of development; however, the effects of 2′-fucosyllactose (2′-FL) and Bifidobacterium longum subsp. infantis Bi-26 (Bi-26) administration during infancy separately and combined are still not clear. Therefore, we investigated the effects of early administration of dietary 2′-FL and Bi-26 on brain structural and functional development in the young pig. From postnatal day (PND) 2–34 or 35, fifty-two intact male pigs were randomly assigned to treatment groups in a 2 × 2 factorial arrangement and provided ad libitum access to a nutritionally adequate milk replacer without or with 1.0 g of 2′-FL/L of reconstituted liquid. Pigs within each diet group were further stratified to receive a daily oral dose of glycerol stock without or with Bi-26 (109 CFU). Pigs were subjected to the novel object recognition (NOR) task from PND 27–31 to assess recognition memory and subsequently underwent magnetic resonance imaging procedures at PND 32 or 33 to assess brain macrostructure and microstructure. Pigs that received Bi-26 had smaller absolute brain volumes for 9 of 27 brain regions of interest, and smaller relative volumes for 2 regions associated with kinesthesia (P < 0.05). Synbiotic administration of 2′-FL and Bi-26 elicited interactive effects (P < 0.05) on several microstructural brain components, where dual supplementation negated the effects of each test article alone. Behavioral outcomes indicated that pigs did not express novelty preference, regardless of treatment group, demonstrating no effects of 2′-FL and Bi-26 on recognition memory when supplemented alone or in combination. Interactive effects (P < 0.05) were observed for the number of all object visits, latency to the first object visit, and number of familiar object visits. Pigs that did not receive Bi-26 supplementation exhibited less time interacting with the familiar object in total (P = 0.002) and on average (P = 0.005). In conclusion, supplementation of 2′-FL and/or Bi-26 elicited some alterations in object exploratory behaviors and macro/micro-structures of the brain, but changes in recognition memory were not observed. Specifically in brain microstructure, synbiotic administration of 2′-FL and Bi-26 appeared to negate effects observed when each dietary article was supplemented separately.
... Rat and mouse Reduce the concentration of proinflammatory cytokines and the level of tryptophan metabolism in plasma, reduce inflammation, and improve physiological and cognitive abnormalities (Desbonnet et al., 2008(Desbonnet et al., , 2010Gareau et al., 2011) Vagus nerve pathways Bifidobacterium longum Mouse Prevent the anxiety behavior through the vagus nerve and the abnormal expression of brainderived neurotrophic factor mrna in the hippocampus (Bercik et al., 2011;Clarke et al., 2012) Lactobacillus johnsonii Rat Affect renal sympathetic nerve and gastric vagus nerve activity through histamine (Tanida et al., 2005) Lactobacillus rhamnosus Mouse Affect brain function through the vagus nerve (Bravo et al., 2011) Neuroendocrine pathways Lactobacillus reuteri Mouse Increase the ot level of the hypothalamus and stimulate neurons in the ventral tegmental region of the midbrain (Buffington et al., 2016) Lactobacillus helveticus Rat Reduce corticosterone and adrenocorticotropic hormone levels in plasma, restore hippocampal 5-HT and norepinephrine levels, and increase hippocampal brainderived neurotrophic factor mrna expression Lactobacillus fermentum Rat Increase the levels of mineralocorticoid and aspartate receptors in the hippocampus Lactobacillus rhamnosus Mouse Reduce corticosterone levels, change the nerve conduction of the inhibitory neurotransmitter GABA and its expression in specific brain regions, resulting in a reduction in the hippocampus, amygdala, and locus coeruleus, and an increase in cortical areas (Bravo et al., 2011) Probiotics Reduce nerve signal levels of toxic gases (Oleskin & Shenderov, 2016) Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
Article
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Objectives Autism spectrum disorder (ASD) is a neurodevelopmental disorder that often occurs in children and seriously affects daily life. In recent years, many studies have shown that intestinal microbial imbalance and intestinal-brain dysfunction may be the critical mechanism for the formation of ASD. This article reviews the changes in the gut microbiota of patients and their impact mechanisms, and the current mechanisms of probiotic and traditional Chinese medicine therapies. Methods A review of contemporary peer-reviewed studies. Pubmed and Cnki were the databases used to identify the studies. Results The majority of the reviewed studies demonstrated that changes in the gut microbiota can directly or indirectly induce ASD by affecting the immune system, nervous system, and endocrine system. Probiotics can improve brain function by affecting the vagus nerve, and improve metabolism by regulating the expression of neuroendocrine hormones. According to the Chinese medicine theory, there are three leading causes of ASD such as deficiency of kidney essence, stagnation of liver qi, and malnutrition of heart spirit. Conclusions The fermentation of Chinese herbal medicine and probiotics can be further studied and may become a new type of treatment for ASD in the future.
... Similarly, Ma et al. [11] supported that probiotic could improve the mental well-being of IBS and this improvement was possibly mediated by restoration of microbial balance and the brain-gut axis. Probiotics could not only normalize noradrenaline levels in the brainstem region that regulates emotion, but also alter other brain neurotransmitters, such as gamma-aminobutyric acid and serotonin [24,25], which might be the influencing factors to mental health. ...
Article
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Objective Gut microbiota might play a crucial role in the pathogenesis of irritable bowel syndrome (IBS), and probiotics supplement may be an effective treatment option. This study aims to explore the therapeutic effects of Golden bifid on the diarrhea-predominant IBS (IBS-D). Methods Twenty-one consecutive IBS-D patients were recruited based on Rome IV criteria. All patients took 2000 mg Golden bifid triple daily for 4 weeks. Gastrointestinal (GI) symptoms, psychological symptoms, small intestine bacterial overgrowth (SIBO) and fecal microbiota characteristics were evaluated in IBS-D patients before and after treatment. Results After 4-week treatment of Golden bifid, the GI symptoms such as abdominal pain (2.90 ± 1.04 vs. 1.90 ± 1.26, P = 0.002), abdominal distension (2.00 ± 1.34 vs. 1.29 ± 1.31, P = 0.007), diarrhea (3.24 ± 1.37 vs. 1.81 ± 1.21, P = 0.001), defecatory urgency (3.48 ± 1.03 vs. 2.33 ± 1.35, P = 0.000) and incomplete evacuation (2.71 ± 1.15 vs. 1.76 ± 1.26, P = 0.003) were significantly alleviated in IBS-D patients. The Self-Rating Depression Scale (SDS) decreased significantly (46.19 ± 11.36 vs. 43.33 ± 9.65, P = 0.041), and SIBO could be eradicated in 25% (4/16) of IBS-D patients with SIBO. Meanwhile, the abundance of Unclassified Lachnospiraceae and Dorea in genus level and Unclassified Lachnospiraceae , Bacterium Dorea , Bacterium Butyricicoccus and Dorea formicigenerans ATCC 27755 in species level were increased in fecal microbiota ( P < 0.05). Conclusions Golden bifid could improve most of GI symptoms and depressive symptoms in IBS-D patients and eradicate a small proportion of SIBO in those IBS-D patients with SIBO. What's more, Golden bifid could also modulate the fecal microbiota in IBS-D patients, which implied that the Golden bifid might improve IBS-D via microbiota modulation.
... Interestingly, the indigenous microbiota also modulates hippocampal 5-HT levels by influencing the availability of tryptophan, the 5-HT precursor, suggesting a role of the microbiota in regulating the serotonergic system of the brain (Clarke et al., 2013;Yano et al., 2015). Several previous studies report that ingestion of Bifidobacteria or Lactobacilli beneficially disrupts either anxiety or depression-like behaviors, both under pathological conditions and in healthy animals (Desbonnet et al., 2010;Bravo et al., 2011;Messaoudi et al., 2011). A previous study shows that Lactobacillus both decreased the abundance of Firmicutes, Clostridia, and Clostridiales, along with a marked decrease in the level of colonic 5-HT as compared to the rat model with chronic unpredictable mild stress . ...
Article
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Chang-Kang-Fang formula (CKF), a multi-herb traditional Chinese medicine, has been used in clinical settings to treat irritable bowel syndrome (IBS). Recent studies show that 5.0 g/kg/d CKF can alleviate the symptoms of IBS rats by modulating the brain-gut axis through the production of brain-gut peptides (BGPs), thus relieving pain, and reversing the effects of intestinal propulsion disorders. However, the exact mechanisms underlying the therapeutic effects of CKF in IBS remain unclear. The microbiota-gut-brain axis (MGBA) is central to the pathogenesis of IBS, regulating BGPs, depression-like behaviors, and gut microbiota. Given that CKF ameliorates IBS via the MGBA, we performed metabolomic analyses, evaluated the gut microbiota, and system pharmacology to elucidate the mechanisms of action of CKF. The results of intestinal tract motility, abdominal withdrawal reflex (AWR), sucrose preference test (SPT), and the forced swimming test (FST) showed that the male Sprague–Dawley rats subjected to chronic acute combining stress (CACS) for 22 days exhibited altered intestinal motility, visceral hypersensitivity, and depression-like behaviors. Treatment of IBS rats with CKF normalized dysfunctions of CACS-induced central and peripheral nervous system. CKF regulated BDNF and 5-HT levels in the colon and hippocampus as well as the expressions of the related BGP pathway genes. Moreover, the system pharmacology assays were used to assess the physiological targets involved in the action of CKF, with results suggesting that CKF putatively functioned through the 5-HT-PKA-CREB-BDNF pathway. LC-MS-based metabolomics identified the significantly altered 5-HT pathway-related metabolites in the CKF treatment group, and thus, the CKF-related signaling pathways were further examined. After pyrosequencing-based analysis of bacterial 16S rRNA (V3 + V4 region) using rat feces, the Lefse analysis of gut microbiota suggested that CKF treatment could induce structural changes in the gut microbiota, thereby regulating it by decreasing Clostridiales, and the F-B ratio while increasing the levels of Lactobacillus. Furthermore, the integrated analysis showed a correlation of CKF-associated microbes with metabolites. These findings showed that CKF effectively alleviated IBS, which was associated with the altered features of the metabolite profiles and the gut microbiota through a bidirectional communication along the microbiota-gut-brain axis.
... In addition, part of the gut-brain axis includes the effects of gut flora on the brain, behavior, and health. For example, taking probiotics can treat certain aspects of depressive and anxious behavior (61)(62)(63)(64)(65). Some probiotics may improve intestinal barrier dysfunction, but it is unclear whether intestinal barrier therapy is associated with anxiety and depression. ...
Article
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Methamphetamine (METH) is an illegal drug widely abused in many countries. Methamphetamine abuse is a major health and social problem all over the world. However, the effects of METH on the digestive system have rarely been reported. Previous studies and clinical cases have shown that METH use can lead to the impaired intestinal barrier function and severe digestive diseases. METH can cause multiple organ dysfunction, especially in the central nervous system (CNS). The gut microbiota are involved in the development of various CNS-related diseases via the gut-brain axis (GBA). Here, we describe the related effects of METH on the intestinal barrier via cytokines and the underlying mechanisms by which METH may occur in the brain-gut axis.
Chapter
Chronic fatigue syndrome (CFS) is a combination of complex illness characterized by tiredness or intense fatigue that may worsen with too much exertion. Among the wide range of neuropsychological symptoms, 97% CFS patients have been reported with neuronal disorders such as headaches and symptoms in the emotional realm. Patients with CFS also show noticeable alterations in microflora, lowering level of Lactobacilli and Bifidobacterium. Recent researches explain that probiotics in the gastrointestinal tract (GIT) can greatly influence the neuronal pathways and central nervous system (CNS) to modulate behavior. Various studies expressed the benefit of probiotic therapy in normalizing fatigue patients and also restored mitochondrial electron transport function in patients with CFS. In this chapter, we provided a historical skeleton, bidirectional communication pathophysiology, selection criteria of probiotics, CFS treatment, and clinical implications of gut–brain connections. In summary, various aspects concerning the potential and safety of probiotics in the management of chronic fatigue syndrome are discussed in this chapter.
Chapter
Neurodegenerative sicknesses, viz., Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and the spinocerebellar ataxias pose a significant risk to human well-being. These disorders are known to progress inexorably to severe inability and death. Presently, about 30 million people in India are known to suffer from one or the other forms of neurodegenerative disorders with an average prevalence rate of 2394 patients per 1,00,000 of the population. Probiotics are defined as “live microorganisms which, when administered in adequate amounts, confer health benefits on the host.” A novel class of probiotics called “Psychobiotics,” a group of probiotics that has ability to affect the central nervous system (CNS) and its related functions and behaviors are currently reviewed by scientific community for its potential application in the treatment of mental illness. An abundance of information has demonstrated that psychobiotics residing in gut play crucial roles in the prevention and treatment of various neurodegenerative disorders. Emerging evidences demonstrate that these psychobiotics protect CNS by positively modulating gut–brain axis (GBA) via immune, humoral, neural, and metabolic pathways. Furthermore, preclinical trials involving animal models have claimed the therapeutic benefit of several psychobiotics. However, recognizing appropriate animal model is vital for evaluating the therapeutic efficiency of psychobiotics. Thus, this chapter outlines the advantages and challenges of current animal models and discusses future research directions of neurodegenerative disorders.
Article
Xylo‐oligosaccharides (XOS) is a functional oligosaccharide with prebiotic properties, and could be fermented by gut microbiota. In this study, the modulatory effects of XOS on emotions and behaviors at different dose were investigated base on the mouse model of chronic unpredictable mild stress‐induced depression. The result showed that 0.23 and 0.50 g/kg doses of XOS significantly increased sucrose preference index and decreased the immobility time in tail suspension and forced swimming tests. Meanwhile, the dose of 0.23 g/kg/day XOS significantly increased the concentration of neurotransmitters, such as 5‐hydroxytryptamine and γ‐ aminobutyric acid. Furthermore, the analysis of the fecal microbiota with XOS intervention showed a higher relative abundance of Akkermania, Bifidobacterium, and Lactobacillus, fewer Desulfovibrio, and the SCFA concentrations increased with XOS prevention treatment. These results suggested that the dietary supplementation XOS could improve chronic stress‐induced depressive‐like behavior by modulating neurotransmitters and reverting gut microbiota changes in mice. These findings present XOS as a potential prebiotic targeting to the gut microbiota for mood disorders.
Chapter
Abstract- Depressive disorders are repetitive, enervative, degenerating with ever lasting impact on socio-economic and prompt with life-threatening illness. Recent development in area of probiotics states that in state of chronic illness and stress there is marked decrease in levels of potentially beneficial bacteria. Bacterial presence in an intestinal tract are involved in various processes like synthesis of vitamins, triggering of immune response, protection of defense barrier system with production of certain bio protective molecules and neutralization of various toxins. Adaptation of western culture and modernization of lifestyle encounters with certain stressful events in daily life which leads to slow prognosis of depression and serious episodes of many disorders. Research on certain animals and humans states that stress have negative impact on an intestinal microflora, as well as affects gastro-intestinal motility, imbalance in certain chemicals which will directly affect the local flora. Gastro intestinal tract is house of around 100 million neurons, immune responsive cells and certain microorganism. Many researchers have linked certain inflammatory responses which affects the mood of humans due to intestinal disturbances. Probiotics can proved to be as an adjuvant therapy along with management therapy with futuristic exploration which is still underestimated. Some attention must be drawn towards potential benefits of already marketed probiotics in market. In this book chapter a comprehensive literature review on certain factors which are associated with depressive disorders and probiotics as supplements for countering depressive disorders.
Chapter
Probiotics are live microorganisms which work for the human benefit by improving their intestinal microbial balance. Originally they were used to enhance both animals and humans health by modulating intestinal microbiota. There is a biological connection between probiotics and brain as they can communicate via neurotransmitters system, anti-oxidative defence mechanism and neuroinflammatory pathways. Probiotic bacteria are also involved in the production of neuroactive molecules that act on the brain–gut axis. Probiotic treatments that help to improve mood, anxiety and strengthen memory using them in the form of food or supplements to alter the gut microbiota and treat psychiatric conditions are considered as psychobiotics. Dietary ingestion such as prebiotics, probiotics and polyphenol can influence gut microbiota composition. Dysbiosis of the gut microbiota is associated with brain dysfunctions. Regulation of microbiota by probiotics and prebiotics may help to restore gut equilibrium. The impact of nutrients on microbiota composition strengthens the reports that regulating a therapeutic microbiota is essential for a healthy brain. They could be useful as novel therapeutics to protect the brain from neurodegeneration. But research is still needed, mainly clinical and translational studies to determine pharmacokinetics and pharmacodynamics of probiotics.
Article
Depression is a debilitating mental disorder that affects >322 million people worldwide. Despite the availability of several antidepressant agents, many patients remain treatment refractory. A growing literature study has indicated the role of gut microbiota in neuropsychiatric disorders. Herein, we examined the psychobiotic-like activity of multi-strain probiotic formulation in maternal separation (MS) and chronic unpredictable mild stress (CUMS) models of anxiety- and depression-like phenotypes in Sprague-Dawley rats. Early- and late-life stress was employed in both male and female rats by exposing them to MS and CUMS. The multi-strain probiotic formulation (Cognisol) containing Bacillus coagulans Unique IS-2, Lactobacillus plantarum UBLP-40, Lactobacillus rhamnosus UBLR-58, Bifidobacterium lactis UBBLa-70, Bifidobacterium breve UBBr-01, and Bifidobacterium infantis UBBI-01 at a total strength of 10 billion cfu along with l-glutamine was administered for 6 weeks via drinking water. Neurobehavioral assessment was done using the forced swim test (FST), sucrose preference test (SPT), elevated plus maze (EPM), and open field test (OFT). Animals were sacrificed after behavioral assessment, and blood, brain, and intestine samples were collected to analyze the levels of cytokines, metabolites, and neurotransmitters and histology. Animals exposed to stress showed increased passivity, consumed less sucrose solution, and minimally explored the open arms in the FST, SPT, and EPM, respectively. Administration of multi-strain probiotics along with l-glutamine for 6 weeks ameliorated the behavioral abnormalities. The locomotor activity of animals in the OFT and their body weight remained unchanged across the groups. Cognisol treatment reversed the decreased BDNF and serotonin levels and increased CRP, TNF-α, and dopamine levels in the hippocampus and/or frontal cortex. Administration of Cognisol also restored the plasma levels of l-tryptophan, l-kynurenine, kynurenic-acid, and 3-hydroxyanthranilic acid; the Firmicutes-to-Bacteroides ratio; the levels of acetate, propionate, and butyrate in fecal samples; the villi/crypt ratio; and the goblet cell count, which manifested in the restoration of intestinal functions. We suggest that the multi-strain probiotic and glutamine formulation (Cognisol) ameliorated the MS + UCMS-generated anxiety- and depression-like phenotypes by reshaping the gut microbiome-brain activity in both sexes.
Article
Introduction: : Subsets of pediatric obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) respectively have been associated with respiratory tract infections and alterations in the intestinal microbiome. Pediatric Acute-onset Neuropsychiatric Syndromes (PANS) refers to the sudden onset of neuropsychiatric symptoms that are triggered by several different infectious and non-infectious factors. Clinical studies and animal modeling are consistent with the proposal that inflammation plays an important etiological role in PANS, as well as in ASD associated with gut dysbiosis. Areas covered: The authors provide an overview of clinical studies of PANS and ASD associated with gastrointestinal symptoms, as well as the current strategies for studying these syndromes in rodent models. Finally, the authors highlight similarities between these syndromes that may provide clues to common etiological mechanisms. Expert opinion: Although data from existing animal models are consistent with an important role for anti-neuronal antibodies in PANS triggered by GAS infection, we lack models for identifying pathophysiological mechanisms of PANS associated with other infectious and non-infectious triggers. The authors propose a strategy for developing such models that incorporates known vulnerability and triggering factors for PANS into the modeling process. This novel strategy should expand our understanding of the pathophysiology of PANS, as well as facilitate the development of new pharmacological treatments for PANS and related syndromes.
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There is an intricate relationship between the human microbiome and its host with the microbiome‐derived metabolites playing a crucial role in the establishment and maintenance of human health. An imbalance in the composition of the gut microbiome is associated with a wide array of disease states. Herein, we discuss some of the molecular mechanisms by which the gut microbiome is linked to the development of various metabolic disorders and present examples of microbiome engineering using wild type or genetically modified probiotics that have been evaluated in preclinical models and clinical trials for their therapeutic efficacy.
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Growing evidence has suggested that the consumption of probiotics can decrease depressive symptoms. However, even the results of meta-analyses are conflicting. In this regard, we performed an umbrella meta-analysis and proposed the decisive impacts of probiotics on depressive symptoms. The following international databases were searched up to July 2021: PubMed/Medline, Web of Science, Scopus, EMBASE, and Google Scholar. Meta-analyses investigating the impact of supplementation of probiotics on depression symptoms in adults were included. According to the studies, random-effects model was used to perform the analysis. Subgroup analysis was performed by dosage of probiotics, duration of supplementation and total sample size. Publication bias was assessed using Egger's, Begg's and visual inspection of funnel plot. Ten meta-analyses (n = 8886 participants) were included in study. The pooled data indicated that probiotic supplementation significantly reduced depression symptoms (ES= -1.41; 95% CI: -2.53, -0.30, p = 0.016; I2 = 99.4, p = <0.001). Subgroup analysis of studies with intervention duration >8 weeks and dosage >10 × 109 CFU demonstrated a more robust effect of probiotics on decreasing depression symptoms. There was also significant between-study heterogeneity in which dosage was identified as source of it. The results of present umbrella meta-analysis suggest administration of probiotics for relieving depression symptoms for >8 weeks with dosage of >10 × 109 CFU.
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Chemotherapy adversely affects the gut microbiota, inducing dysbiosis, and negatively impacts gastrointestinal (GI) and psychosocial health during treatment, but little is known about the long-term effects or how these factors are related. Methods: This cross-sectional pilot study investigated the effects of chemotherapy on the gut microbiota, GI symptoms, and psychosocial outcomes in cancer survivors aged 18-39 years old, compared to healthy controls. Gut microbial diversity and composition were assessed from stool samples using 16S rRNA gene sequencing. Results: Survivors (n = 17) and healthy controls (n = 18) participated. Mean age at diagnosis was 31 years (±5.3). Mean time off treatment was 16.9 months (±16.4). Survivors had more severe GI symptoms, poorer psychosocial health, and increased relative abundance of Selenomondales, Veilloneliaceae, and Intestinibacter. In survivors, Lachnospiraceae, Ruminococcaceae and Intestinibacter correlated with psychosocial symptoms, while diarrhea correlated positively with Lachnospiraceae. Results are statistically significant. Survivors ≤6 months post-treatment had lower alpha diversity than survivors >6 months post-treatment (p = 0.04) and controls (p = 0.19). Conclusion: This small exploratory study demonstrates potential long-term gut microbial dysbiosis in cancer survivors, which may be associated with psychosocial symptoms. Larger trials concurrently and longitudinally examining gut microbiota, GI symptoms, and psychosocial outcomes are needed.
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Background. Increased attention has been paid to the gut–brain axis recently, but little is known so far regarding how this translates into pain susceptibility. Aim. The aim of this review is to determine whether gastroenterological disorders and sleep disorders (directly or indirectly) contribute to an increased susceptibility to depression and chronic orofacial pain. Method. A search was performed in the U.S. National Library of Medicine (PubMed) database in order to find studies published before 19 December 2021. We used the following terms: gut microbiome, OR sleep quality, OR melatonin, OR GERD, OR IBS, AND: depression OR chronic pain, in different configurations. Only papers in English were selected. Given the large number of papers retrieved in the search, their findings were described and organized narratively. Results. A link exists between sleep disorders and gastroenterological disorders, which, by adversely affecting the psyche and increasing inflammation, disturb the metabolism of tryptophan and cause excessive microglial activation, leading to increased susceptibility to pain sensation and depression. Conclusions. Pain therapists should pay close attention to sleep and gastrointestinal disorders in patients with chronic pain and depression.
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Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone (CRH) can produce these physiological and behavioral changes, we measured the cerebrospinal fluid (CSF) levels each hour for 30 consecutive hours in controls and in patients with melancholic depression. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were obtained every 30 min. Depressed patients had significantly higher CSF NE and plasma cortisol levels that were increased around the clock. Diurnal variations in CSF NE and plasma cortisol levels were virtually superimposable and positively correlated with each other in both patients and controls. Despite their hypercortisolism, depressed patients had normal levels of plasma ACTH and CSF CRH. However, plasma ACTH and CSF CRH levels in depressed patients were inappropriately high, considering the degree of their hypercortisolism. In contrast to the significant negative correlation between plasma cortisol and CSF CRH levels seen in controls, patients with depression showed no statistical relationship between these parameters. These data indicate that persistent stress-system dysfunction in melancholic depression is independent of the conscious stress of the disorder. These data also suggest mutually reinforcing bidirectional links between a central hypernoradrenergic state and the hyperfunctioning of specific central CRH pathways that each are driven and sustained by hypercortisolism. We postulate that α-noradrenergic blockade, CRH antagonists, and treatment with antiglucocorticoids may act at different loci, alone or in combination, in the treatment of major depression with melancholic features.
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The enteric flora comprise approximately 95% of the total number of cells in the human body and are capable of eliciting immune responses while also protecting against microbial pathogens. However, the resident bacterial flora of the gastrointestinal tract (GIT) may also be implicated in the pathogenesis of several chronic conditions such as inflammatory bowel disease (IBD). The University College Cork-based Probiotic Research Group has successfully isolated and identified lactic acid bacteria (LAB) which exhibit beneficial probiotic traits. These characteristics include the demonstration of bile tolerance; acid resistance; adherence to host epithelial tissue; and in vitro antagonism of potentially-pathogenic micro-organisms or those which have been implicated in promoting inflammation. The primary objective of this report is to describe the strategy adopted for the selection of potentially effective probiotic bacteria. The study further describes the evaluation of two m embers of the resulting panel of micro-organisms (Lactobacillus salivarius subsp. salivarius UCC118 and Bifidobacterium longum infantis 35624) under in vitro conditions and throughout in vivo murine and human feeding trials. Specifically, an initial feeding study completed in Balb/c mice focused upon (i) effective delivery of the probiotic micro-organisms to the GIT and evaluation of the ability of the introduced strains to survive transit through, and possibly colonise, the murine GIT; (ii) accepting the complexity of the hostile GIT and faecal environments, development of a method of enumerating the introduced bacterial strains using conventional microbiological techniques; and (iii) assessment of the effects of administered bacterial strains on the numbers of specific recoverable indigenous bacteria in the murine GIT and faeces. Additional research, exploiting the availability of murine models of inflammatory bowel disease, demonstrated the beneficial effects of administering probi otic combinations of Lactobacillus salivarius UCC118 and Bifidobacterium longum infantis 35624 in prevention of illness-related weight loss. A further ethically-approved feeding trial, successfully conducted in 80 healthy volunteers, demonstrated that yoghurt can be used as a vehicle for delivery of Lactobacillus salivarius strain UCC118 to the human GIT with considerable efficacy in influencing gut flora and colonisation.
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Gastrointestinal disease is a major cause of morbidity and mortality worldwide each year. Treatment of chronic inflammatory gastrointestinal conditions such as ulcerative colitis and Crohn's disease is difficult due to the ambiguity surrounding their precise aetiology. Infectious gastrointestinal diseases, such as various types of diarrheal disease are also becoming increasingly difficult to treat due to the increasing dissemination of antibiotic resistance among microorganisms and the emergence of the so-called 'superbugs'. Taking into consideration these problems, the need for novel therapeutics is essential. Although described for over a century probiotics have only been extensively researched in recent years. Their use in the treatment and prevention of disease, particularly gastrointestinal disease, has yielded many successful results, some of which we outline in this review. Although promising, many probiotics are hindered by inherent physiological and technological weaknesses and often the most clinically promising strains are unusable. Consequently we discuss various strategies whereby probiotics may be engineered to create designer probiotics. Such innovative approaches include; a receptor mimicry strategy to create probiotics that target specific pathogens and toxins, a patho-biotechnology approach using pathogen-derived genes to create more robust probiotic stains with increased host and processing-associated stress tolerance profiles and meta-biotechnology, whereby, functional metagenomics may be used to identify novel genes from diverse and vastly unexplored environments, such as the human gut, for use in biotechnology and medicine.
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Early life events influence vulnerability to psychiatric illness. This has been modelled in rats and it has been demonstrated that different durations of maternal separation shape adult endocrine and behavioural stress reactivity. One system through which maternal separation may act is the locus coeruleus (LC)-norepinephrine system that regulates emotional arousal. Here we demonstrate that different durations of maternal separation have distinct effects on LC physiology and dendritic morphology. Rat pups were separated from the dam for 15 min/d (HMS-15) or 180 min/d (HMS-180) from post-natal days 2-14. Others were either undisturbed (HMS-0) or were vendor-purchased controls. LC characteristics were compared at age 22-35 d using whole-cell recordings in vitro. Cells were filled with biocytin for morphological analysis. LC neurons of HMS-180 rats were tonically activated compared to HMS-15 and control rats, with firing rates that were 2-fold higher than these groups. Corticotrophin-releasing factor (CRF) application did not further activate LC neurons of HMS-180 rats but increased LC firing rate in HMS-0 and control rats. LC neurons of HMS-15 rats were resistant to excitation by CRF. Maternal separation also affected LC dendritic morphology. LC dendrites of HMS-15 rats exhibited less branching and decreased total dendritic length, an effect that could decrease the probability of contacting limbic afferents that terminate in the pericoerulear region. This effect may provide a structural basis for an attenuated magnitude of emotional arousal. Together, these results demonstrate long-term consequences of early life events on the LC-norepinephrine system that may shape adult behaviour.
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Myocardial infarction (MI) stimulates the release of pro-inflammatory substances that induce apoptosis in the limbic system. Pro-inflammatory cytokines are considered as the root cause of apoptosis, although the mechanism is not fully explained and/or understood at this time. In addition, depression may induce gastrointestinal perturbations that maintain the elevated levels of pro-inflammatory cytokines. It has been shown that some specific probiotic formulations may reduce gastrointestinal problems induced by stress and the pro/anti-inflammatory cytokine ratio. Therefore, we hypothesised that probiotics, when given prophylactically, may diminish the apoptosis propensity in the limbic system following a MI. Male adult Sprague-Dawley rats were given probiotics (Lactobacillus helveticus and Bifidobacterium longum in combination) or placebo in their drinking-water for four consecutive weeks. A MI was then induced in the rats by occluding the left anterior coronary artery for 40 min. Rats were killed following a 72 h reperfusion period. Infarct size was not different in the two groups. Bax/Bcl-2 (pro-apoptotic/anti-apoptotic) ratio and caspase-3 (pro-apoptotic) activity were reduced in the amygdala (lateral and medial), as well as in the dentate gyrus in the probiotics group when compared with the placebo. Akt activity (anti-apoptotic) was increased in these same three regions. No significant difference was observed in Ca1 and Ca3 for the different markers measured. In conclusion, the probiotics L. helveticus and B. longum, given in combination as preventive therapy, reduced the predisposition of apoptosis found in different cerebral regions following a MI.
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Stressful events during early life have been suggested to play an important role in the development of the irritable bowel syndrome (IBS). In this study, we evaluate whether an exposure to severe wartime conditions during gestation and in early life are associated with an increased prevalence of IBS. We assessed the prevalence of IBS using the Rome II questionnaire among 816 men and women (aged 58+/-1 years) who were born as term singletons in Wilhelmina Gasthuis, Amsterdam, The Netherlands around the time of World War II. Of a total of 816 participants, 9.6% (n=78, 52F) met the criteria for IBS. Exposure to severe wartime conditions in utero was not associated with the prevalence of IBS in adulthood (8.3%). Early-life exposure to severe wartime conditions was associated with an increased prevalence of IBS. The prevalence of IBS among individuals exposed up to 0.5 years of age, 1 year of age, and 1.5 years of age was 8.1%, 12.5%, and 15.3%, respectively. The increased IBS prevalence was not associated with an increased stress response. Our data indicate that exposure to severe wartime conditions in early life is associated with an increased risk of developing IBS. To what extent this is attributable to the stressful environment of war, to severe undernutrition, or to the increased prevalence of infectious diseases is, however, unclear.
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Evidence is accumulating to suggest that gut microbes (microbiota) may be involved in neural development and function, both peripherally in the enteric nervous system and centrally in the brain. There is an increasing and intense current interest in the role that gut bacteria play in maintaining the health of the host. Altogether the mass of intestinal bacteria represents a virtual inner organ with 100 times the total genetic material contained in all the cells in the human body. Surprisingly, the characterization of this extraordinarily diverse population is only just beginning, since some 60% of these microbes have never been cultured. Commensal organisms live in a state of harmonious symbiosis with each other and their host, however, a disordered balance amongst gut microbes is now thought to be an associated or even causal factor for chronic medical conditions as varied as obesity and inflammatory bowel diseases. While evidence is still limited in psychiatric illnesses, there are rapidly coalescing clusters of evidence which point to the possibility that variations in the composition of gut microbes may be associated with changes in the normal functioning of the nervous system. This review focuses on these data and suggests that the concept should be explored further to increase our understanding of mood disorders, and possibly even uncover missing links to a number of co-morbid medical diseases.
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Irritable bowel syndrome (IBS) is a common disorder with widespread prevalence. Due to its heterogeneous pathogenesis, efficacious treatments are lacking. The few medications that are effective for treating global IBS symptoms have either been withdrawn or restricted due to detrimental side effects; thus, safe and effective alternatives are urgently needed. Increasing data have revealed that inflammatory changes may play a role in the development of IBS, and probiotics, commensal organisms with inherent health benefits, may alter that milieu. Although their exact mechanisms of action remain elusive, it is clear that the beneficial properties inherent to each probiotic species are strain specific. Bifidobacterium infantis 35624 ( B infantis 35624; Bifantis, The Procter & Gamble Company, Cincinnati, OH), is a probiotic with unique abilities to reduce intestinal inflammation. Two randomized, controlled trials have validated its efficacy for treating both individual and global IBS symptoms without evidence to suggest an increase in adverse events. B. infantis 35624 appears safe and effective for the treatment of IBS.
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Chronic fatigue syndrome (CFS) is complex illness of unknown etiology. Among the broad range of symptoms, many patients report disturbances in the emotional realm, the most frequent of which is anxiety. Research shows that patients with CFS and other so-called functional somatic disorders have alterations in the intestinal microbial flora. Emerging studies have suggested that pathogenic and non-pathogenic gut bacteria might influence mood-related symptoms and even behavior in animals and humans. In this pilot study, 39 CFS patients were randomized to receive either 24 billion colony forming units of Lactobacillus casei strain Shirota (LcS) or a placebo daily for two months. Patients provided stool samples and completed the Beck Depression and Beck Anxiety Inventories before and after the intervention. We found a significant rise in both Lactobacillus and Bifidobacteria in those taking the LcS, and there was also a significant decrease in anxiety symptoms among those taking the probiotic vs controls (p = 0.01). These results lend further support to the presence of a gut-brain interface, one that may be mediated by microbes that reside or pass through the intestinal tract.
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Although irritable bowel syndrome (IBS) is highly comorbid with depressive and anxiety disorders, information on the clinical implications of this comorbidity is limited. We investigated whether a history of depressive and/or anxiety disorders was associated with response to treatment in a double-blind, randomized, placebo-controlled trial of paroxetine controlled release (CR) in IBS. Seventy-two IBS subjects (diagnosed using Rome II criteria) were recruited from August 2003 to November 2005 and randomly assigned to receive flexibly dosed paroxetine CR (dose, 12.5-50 mg/day) or placebo for 12 weeks. The Mini-International Neuropsychiatric Interview (MINI-Plus version) was used to ascertain current (exclusionary) or past diagnoses of depressive and anxiety disorders. Subjective depression, anxiety, and stress were assessed at entry and throughout the trial using the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Perceived Stress Scale (PSS). Severity of IBS symptoms was determined by the Composite Pain Score (CPS), administered via Interactive Voice Response System, and the Clinical Global Impressions scale (CGI). The primary outcome was treatment response defined as ≥ 25% reduction in CPS from randomization to end of treatment. A post hoc analysis (multivariate logistic regression) was done to evaluate whether a history of depressive and/or anxiety disorder was associated with response to medication. Baseline demographic and clinical characteristics (CPS, BDI, BAI, PSS, CGI scores) were similar between groups (history of depressive/anxiety disorder vs. no history). In multivariate logistic regression analysis, treatment response was not predicted by history of depressive and/or anxiety disorder (OR = 0.58, CI = 0.29 to 1.68, p = .32) or drug status (paroxetine CR vs. placebo) (OR = 1.26, CI = 0.68 to 3.21, p = .19). Drug status was significantly associated with the secondary outcome variable of treatment response as defined by a CGI improvement score of 1 to 2 (OR = 12.14, CI = 2.9 to 48.4, p < .001). Paroxetine CR was safe and well tolerated during the study. History of depressive and/or anxiety disorder was not associated with response of IBS symptoms to paroxetine CR. Conclusions are limited due to insufficient statistical power. Further research is needed to clarify the role of selective serotonin reuptake inhibitors in the treatment of IBS and to elucidate the treatment ramifications of comorbid psychiatric disorders. clinicaltrials.gov Identifier: NCT00610909.
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The vagus nerve is an important pathway signaling immune activation of the gastrointestinal tract to the brain. Probiotics are live organisms that may engage signaling pathways of the brain-gut axis to modulate inflammation. The protective effects of Lactobacillus rhamnosus [corrected] (LR) and Bifidobacterium infantis (BI) during intestinal inflammation were studied after subdiaphragmatic vagotomy in acute dextran sulfate sodium (DSS) colitis in BALB/c mice and chronic colitis induced by transfer of CD4(+) CD62L(+) T lymphocytes from BALB/c into SCID mice. LR and BI (1 x 10(9)) were given daily. Clinical score, myeloperoxidase (MPO) levels, and in vivo and in vitro secreted inflammatory cytokine levels were found to be more severe in mice that were vagotomized compared with sham-operated animals. LR in the acute DSS model was effective in decreasing the MPO and cytokine levels in the tissue in sham and vagotomized mice. BI had a strong downregulatory effect on secreted in vitro cytokine levels and had a greater anti-inflammatory effect in vagotomized- compared with sham-operated mice. Both LR and BI retained anti-inflammatory effects in vagotomized mice. In SCID mice, vagotomy did not enhance inflammation, but BI was more effective in vagotomized mice than shams. Taken together, the intact vagus has a protective role in acute DSS-induced colitis in mice but not in the chronic T cell transfer model of colitis. Furthermore, LR and BI do not seem to engage their protective effects via this cholinergic anti-inflammatory pathway, but the results interestingly show that, in the T cell, transfer model vagotomy had a biological effect, since it increased the effectiveness of the BI in downregulation of colonic inflammation.
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Aerobic and anaerobic cultural techniques and histological methods were used in a study of the effects of environmental and dietary stress on the indigenous microbiota of the gastrointestinal tract of mice. Mice previously inoculated with Salmonella typhimurium were examined in a similar manner. Three strains of mice (CD-1, Ha/ICr, and C57BL) were used. Control animals previously inoculated with S. typhimurium had low population levels of Salmonella bacteria in the small and large bowel. Mice previously inoculated with Salmonella and then deprived of food, water, and bedding for 48 h harbored high population levels of these bacteria in their small and large bowels. Coliforms increased in numbers in the large bowel of stressed mice inoculated with Salmonella and in the jejunum-ileum and cecum of stressed mice not previously inoculated with Salmonella. Control mice had high population levels of lactobacilli inhabiting the keratinized squamous epithelium of the stomach. Stressed mice showed dramatic reductions in these populations of lactobacilli. Populations of fusiform-shaped bacteria associated with the mucosal epithelium of the cecum and colon in control mice were reduced in stressed mice as determined by microscope examination of histological sections. Total anaerobic counts were similar, however, in both stressed and control animals. Environmental and dietary stress markedly alter the gastrointestinal microbiota in mice. Therefore, such stressful conditions profoundly affect the factors that regulate the localization and population levels of microorganisms in the stomach and intestines.
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The effects of crowding and heat stress on the intestinal flora, body-weight gains and feed efficiencies of rats and chicks were investigated. For the condition of crowding 25 rats were kept in a cage and 3 rats were kept in a cage for the control group. For the condition of heat stress, rats were kept at 31°C and 25°C for the control. The chicks were kept at 35°C for the heat stress and 25°C for the control. Irrespective of the types of stress and host species, aerobic bacteria, i.e., staphylococci and one or two bacterial groups of streptococci, enterobacteria and corynebacteria increased commonly in the small intestine. Sometimes anaerobes, i.e., peptococcaceae and bacteroides in rats increased under crowding condition and peptococcaceae and clostridia in chicks increased under heat stress. The changes of flora in the large intestine showed the similar tendency as in the small intestine. Body-weight gains and feed efficiencies were markedly suppressed under these stress conditions. These results showed that the changes of the intestinal flora and growth of host were affected with environmental stress.
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The adrenal glucocorticoids and catecholamines comprise a frontline of defense for mammalian species under conditions which threaten homeostasis (conditions commonly referred to as stress). Glucocorticoids represent the end product of the hypothalamic-pituitary-adrenal (HPA) axis and along with the catecholamines serve to mobilize the production and distribution of energy substrates during stress. The increased secretion of pituitary-adrenal hormones in response to stress is stimulated by the release of corticotropin-releasing hormone (CRH) and/or arginine vasopressin (AVP) from neurons in the nucleus paraventricularis. In this way, a neural signal associated with the stressor is transduced into a set of endocrine and sympathetic responses. The development of the HPA response to stressful stimuli is altered by early environmental events. Animals exposed to short periods of infantile stimulation or handling show decreased HPA responsivity to stress, whereas maternal separation, physical trauma and endotoxin administration enhance HPA responsivity to stress. In all cases, these effects persist throughout the life of the animal and are accompanied by increased hypothalamic levels of the mRNAs for CRH and often AVP. The inhibitory regulation of the synthesis for these ACTH releasing factors is achieved, in part, through a negative feedback loop whereby circulating glucocorticoids act at various neural sites to decrease CRH and AVP gene expression. Such inhibitory effects are initiated via an interaction between the adrenal steroid and an intracellular receptor (either the mineralocorticoid or glucocorticoid receptor). We have found that these early environmental manipulations regulate glucocorticoid receptor gene expression in the hippocampus and frontal cortex, regions that have been strongly implicated as sites for negative-feedback regulation of CRH and AVP synthesis. When the differences in glucocorticoid receptor density are transiently reversed, so too are those in HPA responses to stress. Taken together, our findings indicate that the early postnatal environment alters the differentiation of hippocampal neurons. This effect involves an altered rate of glucocorticoid receptor gene expression, resulting in changes in the sensitivity of the system to the inhibitory effects of glucocorticoids on the synthesis of CRH and AVP in hypothalamic neurons. Changes in CRH and AVP levels, in turn, determine the responsivity of the axis to subsequent stressors; increased releasing factor production is associated with increased HPA responses to stress. Thus, the early environment can contribute substantially to the development of stable individual differences in HPA responsivity to stressful stimuli. These data provide examples of early environmental programming of neural systems. One major objective of our research is to understand how such programming occurs within the brain.
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Interleukin-6 (IL-6) and IL-6 receptor mRNA and protein have been reported in different brain regions under normal and pathophysiological conditions. Although much is known about the hypothalamic-pituitary-adrenal (HPA) axis stimulation after acute administration, less is known about the chronic effects of IL-6 on the function of the HPA axis. In the present study, we examined the function of the HPA axis in transgenic mice in which constitutive expression of IL-6 under the control of the glial fibrillary acidic protein (GFAP) promoter was targeted to astrocytes in the CNS. GFAP-IL6 mice heterozygous or homozygous for the IL-6 transgene had normal basal plasma corticosterone levels but, after restraint stress, showed abnormally increased levels in a gene dose-dependent manner. The increased plasma corticosterone levels in the IL-6 transgenic mice were associated with increased adrenal corticosterone content and hyperplasia of both adrenal cortex and medulla. Notably, plasma adrenocorticotrophic hormone (ACTH) levels and pituitary ACTH content were either not changed or decreased in these mice, whereas plasma arginine vasopressin (AVP) was increased, supporting a role for AVP in response to acute immobilization stress. The reduced ACTH response together with the adrenal hyperplasia in the IL-6 transgenic mice suggests direct activation at the level of the adrenal gland that may be directly activated by AVP or sensitized to ACTH. A similar mechanism may play a role in the blunted ACTH response and elevated corticosterone levels under pathophysiological conditions observed in humans with high brain levels of IL-6.
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Increasing numbers of functional foods and pharmaceutical preparations are being promoted with health claims based on the potential probiotic characteristics of lactic acid bacteria and on their capacity for stimulating the host immune system. However, the specific immune effects of oral administration of these microbes still remains undefined. In this study, we tested the hypothesis that production of immunologic mediators by leukocytes in mice is affected by orally administered lactic acid bacteria. The specific objectives of this study were to evaluate the effects of exposure to eight different lactic acid bacteria in mice on ex vivo cytokine and nitric oxide production in leukocyte cultures. Mice were gavaged with 1 X 10(9) viable bacteria and peritoneal, Peyer's patch and splenic leukocytes were isolated 8 h later. These were cultured for 2 or 5 days in the presence or absence of mitogens and then interleukin (IL)-6, IL-12, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and nitric oxide production was measured. The results revealed that Lactobacillus acidophilus and L. casei potentiated IL-6 and IL-12 production by peritoneal cells whereas L. acidophilus upregulated IFN-gamma and nitric oxide. In contrast, L. helveticus, L. gasseri, L. reuteri, and Bifidobacterium attenuated the production of IL-6, IFN-gamma, and nitric oxide by peritoneal cells. TNF-alpha was not detectable in peritoneal cultures. None of the bacteria altered ex vivo production of cytokines or nitric oxide by Peyer's patch or spleen cell cultures. Taken together, the results suggest that prior oral exposure to lactic acid bacteria could differentially potentiate or attenuate subsequent cytokine and nitric oxide production by peritoneal cells.
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This study investigated the combined effect of neonatal maternal separation and acute psychological stress on pain responses in adult rats. Long-Evans dams and their male pups were reared under two conditions: 1) 180 min daily maternal separation (MS180) on postnatal days 2-14 or 2) no handling or separation (NH). At 2 mo of age, visceromotor responses to graded intensities of phasic colorectal distension (10-80 mmHg) at baseline as well as following acute 60 min water avoidance stress (WA) were significantly higher in MS180 rats. Both groups showed similar stress-induced visceral hyperalgesia in the presence of naloxone (20 mg/kg ip). MS180 rats had smaller stress-induced cutaneous analgesia in the tail-flick test compared with NH rats, with a residual naloxone-resistant component. MS180 rats showed an enhanced fecal pellet output following WA or exposure to a novel environment. These data suggest that early life events predispose adult Long-Evans rats to develop visceral hyperalgesia, reduced somatic analgesia, and increased colonic motility in response to an acute psychological stressor, mimicking the cardinal features of irritable bowel syndrome.
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A number of clinical investigations and postmortem brain studies have provided evidence that excessive corticotropin-releasing hormone (CRH) secretion and neurotransmission is involved in the pathophysiology of depressive illness, and several studies have suggested that the hyperactivity in CRH neurotransmission extends beyond the hypothalamus involving several extra-hypothalamic brain regions. The present study was designed to test the hypothesis that CRH levels are increased in specific brainstem regions of suicide victims with a diagnosis of major depression. Frozen tissue sections of the pons containing the locus coeruleus and caudal raphe nuclei from 11 matched pairs of depressed suicide and control male subjects were processed for radioimmunocytochemistry using a primary antiserum to CRH and a ([125])I-IgG secondary antibody. The optical density corresponding to the level of CRH-immunoreactivity (IR) was quantified in specific pontine regions from the film autoradiographic images. The level of CRH-IR was increased by 30% in the locus coeruleus, 39% in the median raphe and 45% in the caudal dorsal raphe in the depressed suicide subjects compared to controls. No difference in CRH-IR was found in the dorsal tegmentum or medial parabrachial nucleus between the subject groups. These findings reveal that CRH-IR levels are specifically increased in norepinephrine- and serotonin-containing pontine nuclei of depressed suicide men, and thus they are consistent with the hypothesis that CRH neurotransmission is elevated in extra-hypothalamic brain regions of depressed subjects.
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The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-DeltaDeltaCr) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-DeltaDeltaCr) method. In addition, we present the derivation and applications of two variations of the 2(-DeltaDeltaCr) method that may be useful in the analysis of real-time, quantitative PCR data. (C) 2001 Elsevier science.
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Early environment exerts profound effects on mammalian behavioral and neural development. The aim of this study was to describe changes in adult neurochemistry in the rat following repeated neonatal maternal separation (RMS) during the preweaning period, a procedure known to induce enduring behavioral effects. Following RMS, rats show an attenuated locomotor response to novelty, to D-amphetamine, and attenuated behavioral responses for conditioned incentives as adults. These behavioral effects are broadly opposite in direction to those found following postweaning isolation rearing. Isolation rearing-induced behavioral changes are associated with profound changes in central monoamine function. Following RMS, adult rats had increased tissue levels of dopamine in both dorsal and ventral striatum. The turnover of dopamine, as determined by the ratio of DOPAC to dopamine, was decreased in the mPFC of RMS subjects. Serotonin levels were reduced in dorsal hippocampus of RMS rats of both sexes and in the mPFC of male RMS rats. Noradrenaline levels were increased in the dorsal hippocampus in female, but not in male, RMS rats. These data provide evidence that, in addition to the adult behavioral consequences, RMS leads to profound, region-, and gender-specific changes in brain monoamine content. The developmental specificity of these results is discussed with respect to their possible role in altered behavioral development and psychopathology. Synapse 40:1–10, 2001. © 2001 Wiley-Liss, Inc.
Article
The in vivo effect of the serotonin (5-HT) reuptake inhibitor antidepressant citalopram, administered in the locus coeruleus (LC), on noradrenergic transmission was evaluated in the rat brain. In dual-probe microdialysis assays, citalopram (0.1–100 μM), in a concentration-dependent manner, increased extracellular noradrenaline (NA) in the LC and simultaneously decreased extracellular NA in the cingulate cortex (Cg). These effects of citalopram were abolished by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (400 mg/kg, i.p.). When the α2-adrenoceptor antagonist RS79948 (1 μM) was perfused in the LC, local citalopram increased NA dialysate in the LC but no longer modified NA dialysate in the Cg. In electrophysiological experiments, the administration of citalopram (100 μM) in the LC by reversal dialysis, decreased the firing rate of LC neurones. The results demonstrate in vivo that local administration of citalopram in the LC leads to a decreased release of NA in the Cg. This modulation seems to be the result of an increase in NA concentration in the LC and the subsequent inhibition of LC neurones via α2-adrenoceptors. The effects of citalopram are dependent on the presence of endogenous 5-HT in the LC.
Article
Evidence indicates that noradrenaline elicits anti-inflammatory actions in the central nervous system (CNS), and plays a neuroprotective role where inflammatory events contribute to pathology. Here we examined the ability of pharmacological enhancement of central noradrenergic tone to impact upon activation of the IL-1 system in rat brain. Treatment with the noradrenaline reuptake inhibitor reboxetine combined with the alpha(2)-adrenoceptor antagonist idazoxan induced expression of IL-1beta as well as its negative regulators, IL-1 receptor antagonist (IL-1ra) and IL-1 type II receptor (IL-1RII) in rat cortex. The ability of reboxetine/idazoxan treatment to activate the IL-1 system was mediated by beta-adrenoceptors, as the aforementioned effects were blocked by the beta-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant beta(2)-adrenoceptor agonist clenbuterol induced expression of IL-1beta, IL-1ra and IL-1RII in rat brain. This action was selective to the IL-1 system, as other inflammatory cytokines including TNF-alpha, IL-6 or IFN-gamma were not induced by clenbuterol. Induction of IL-1beta was accompanied by activation of NFkappaB and of the MAP kinase ERK, and clenbuterol also induced expression of the IL-1beta-inducible gene CINC-1. The ability of clenbuterol to activate the IL-1 system was blocked by propranolol, and was mimicked by the highly selective beta(2)-adrenoceptor agonist formoterol. Despite the ability of clenbuterol to activate the central IL-1 system, it largely combated the neuroinflammatory response induced by systemic inflammatory stimulus (bacterial lipopolysaccharide; LPS). Specifically, whilst the ability of clenbuterol to induce expression of IL-1RII and IL-1Ra was maintained following the inflammatory challenge, its ability to induce IL-1beta was reduced. In addition, clenbuterol suppressed LPS-induced expression of the inflammatory cytokines TNF-alpha and IL-6, the inflammatory chemokines RANTES and IP-10, the co-stimulatory molecules CD40 and ICAM-1. Thus overall, clenbuterol suppresses the innate inflammatory response in rat brain.
Article
While the effects of maternal separation on pups are well studied, the impact on dams has attracted little attention. The consumption of palatable food is known to dampen stress responses in animals, and emotions influence food choice in humans. Here we examined the early- and long-term impacts of maternal separation on behavioral profile of the dams, and the effects of palatable cafeteria high-fat diet (HFD). After littering, Sprague-Dawley female rats were subjected to prolonged separation, S180 (180 min) or brief separation, S15 (15 min/day) from postnatal days (PND) 2-14. At 4 weeks postpartum, half the dams were assigned to HFD. Anxiety and depression-like behaviors were assessed pre- and post-diet. Compared to S15 dams, S180 dams consuming chow demonstrated increased anxiety and depression-like behaviors assessed by elevated plus maze (EPM) and forced swim (FST) tests, respectively. These behavioral deficits were observed at 4 weeks, and persisted until 17 weeks postpartum. The S180 dams also had increased plasma corticosterone concentration compared to S15 dams, which coincided with increased hypothalamic CRH mRNA and reduced hippocampal GR mRNA expression, suggesting possible dysregulation of hypothalamic-pituitary-adrenal axis activity. Interestingly, continuous provision of HFD improved the behavioral deficits observed in S180 dams with significant reduction of hypothalamic CRH mRNA expression. These data are the first to describe long-term detrimental behavioral impacts of separation in dams, suggesting this may provide a model of postpartum depression. Moreover, they support the notion of long-term beneficial effects of 'comfort food' on stress responses.
Article
The central nucleus of the amygdala (CeA) has been traditionally viewed in fear conditioning to serve as an output neural center that transfers conditioned information formed in the basolateral amygdala to brain structures that generate emotional responses. Recent studies suggest that the CeA may also be involved in fear memory consolidation. In addition, corticotropin-releasing factor systems were shown to facilitate memory consolidation in the amygdala, which contains a high density of CRF immunoreactive cell bodies and fibers in the lateral part of the CeA (CeAl). However, the involvement of CeA CRF in contextual fear conditioning remains poorly understood. Therefore, we first conducted a series of studies using fiber-sparing lesion and reversible inactivation methods to assess the general role of the CeA in contextual fear. We then used identical training and testing procedures to compare and evaluate the specific function of CeA CRF using CRF antisense oligonucleotides (CRF ASO). Rats microinjected with ibotenic acid, muscimol, or a CRF ASO into the CeA before contextual fear conditioning showed typical levels of freezing during acquisition training but exhibited significant reductions in contextual freezing in a retention test 48 h later. Furthermore, CeA inactivation induced by either muscimol or CRF ASO administration immediately before retention testing did not impair freezing, suggesting that the previously observed retention deficits were caused by inhibition of consolidation rather than fear expression. Collectively, our results suggest CeA involvement in the consolidation of contextual fear memory and specifically implicate CeA CRF as an important mediator.
Article
The digestive tract works through a complex network of integrative functions. At the level of the gut, this integration occurs between the immune, neuromotor and enteroendocrine systems, coordinating the physical and chemical elements of the intestinal barrier in order to facilitate digestion whilst protecting the gut from unwanted components of the luminal contents. Gastrointestinal function is controlled and coordinated by the central nervous system to ensure effective motility, secretion, absorption and mucosal immunity. It follows that perturbations in this complex network could lead to gut dysfunction and symptom generation. Recently, attention has been focused on the emerging hypothesis that gut luminal content contributes to determine normal GI function and on the therapeutic possibilities arising from modulating its impact on gut physiology and immunity using probiotic bacteria. In this issue of Neurogastroenterology and Motility, two papers explore the effect of specific probiotic bacteria on spinal neuronal activation and in vitro muscle contractility. These papers support the notion that the composition of the intestinal microbiota can influence gut neuro-motor function and enhance our understanding on the mechanisms of action underlying the effects of specific probiotics on gut functional disorders.
Article
To provide a critical update of the literature linking depression and inflammation, together with possible underlying mechanisms and longer term risk of cardiovascular disease. The current literature lends further support to the view that major depression is associated with a proinflammatory response, as indexed by elevation in C-reactive protein and cytokines such as interleukin 6 and tumour necrosis factor-alpha. Antidepressants suppress the inflammatory response, whereas electroconvulsive therapy acutely increases proinflammatory cytokine levels. Most, though not all, studies support a link between depression, inflammation and cardiovascular events. Depression is an inflammatory state that may increase the risk of cardiac disease. Whether or not the immune system is an appropriate target for antidepressant development has yet to be established.
Article
Gut microflora-mucosal interactions may be involved in the pathogenesis of irritable bowel syndrome (IBS). To investigate the efficacy of a novel prebiotic trans-galactooligosaccharide in changing the colonic microflora and improve the symptoms in IBS sufferers. In all, 44 patients with Rome II positive IBS completed a 12-week single centre parallel crossover controlled clinical trial. Patients were randomized to receive either 3.5 g/d prebiotic, 7 g/d prebiotic or 7 g/d placebo. IBS symptoms were monitored weekly and scored according to a 7-point Likert scale. Changes in faecal microflora, stool frequency and form (Bristol stool scale) subjective global assessment (SGA), anxiety and depression and QOL scores were also monitored. The prebiotic significantly enhanced faecal bifidobacteria (3.5 g/d P < 0.005; 7 g/d P < 0.001). Placebo was without effect on the clinical parameters monitored, while the prebiotic at 3.5 g/d significantly changed stool consistency (P < 0.05), improved flatulence (P < 0.05) bloating (P < 0.05), composite score of symptoms (P < 0.05) and SGA (P < 0.05). The prebiotic at 7 g/d significantly improved SGA (P < 0.05) and anxiety scores (P < 0.05). The galactooligosaccharide acted as a prebiotic in specifically stimulating gut bifidobacteria in IBS patients and is effective in alleviating symptoms. These findings suggest that the prebiotic has potential as a therapeutic agent in IBS.
Article
Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.