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The Mechanism of Secretion and Metabolism of Gut-Derived 5-Hydroxytryptamine.
Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of tryptophan and is reported to modulate the development and neurogenesis of the enteric nervous system, gut motility, secretion, inflammation, sensation, and epithelial development. Approximately 95% of 5-HT in the body is synthesized and secreted by enterochromaffin (EC) cells, the most common type of neuroendocrine cells in the gastrointestinal (GI) tract, through sensing signals from the intestinal lumen and the circulatory system. Gut microbiota, nutrients, and hormones are the main factors that play a vital role in regulating 5-HT secretion by EC cells. Apart from being an important neurotransmitter and a paracrine signaling molecule in the gut, gut-derived 5-HT was also shown to exert other biological functions (in autism and depression) far beyond the gut. Moreover, studies conducted on the regulation of 5-HT in the immune system demonstrated that 5-HT exerts anti-inflammatory and proinflammatory effects on the gut by binding to different receptors under intestinal inflammatory conditions. Understanding the regulatory mechanisms through which 5-HT participates in cell metabolism and physiology can provide potential therapeutic strategies for treating intestinal diseases. Herein, we review recent evidence to recapitulate the mechanisms of synthesis, secretion, regulation, and biofunction of 5-HT to improve the nutrition and health of humans.
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The chemo-gut study: investigating the long-term effects of chemotherapy on gut microbiota, metabolic, immune, psychological and cognitive parameters in young adult Cancer survivors; study protocol.
BACKGROUND: The gut microbiota is an important modulator of immune, metabolic, psychological and cognitive mechanisms. Chemotherapy adversely affects the gut microbiota, inducing acute dysbiosis, and alters physiological and psychological function. Cancer among young adults has risen 38% in recent decades. Understanding chemotherapy's long-term effects on gut microbiota and psycho-physiological function is critical to improve survivors' physical and mental health, but remains unexamined. Restoration of the gut microbiota via targeted therapies (e.g. probiotics) could potentially prevent or reverse the psycho-physiological deficits often found in young survivors following chemotherapy, ultimately leading to reduced symptom burden and improved health. METHODS: This longitudinal study investigates chemotherapy induced long-term gut dysbiosis, and associations between gut microbiota, and immune, metabolic, cognitive and psychological parameters using data collected at < 2 month (T1), 3-4 months (T2), and 5-6 months (T3) post-chemotherapy. Participants will be 18-39 year old blood or solid tumor cancer survivors (n = 50), and a healthy sibling, partner or friend as a control (n = 50). Gut microbiota composition will be measured from fecal samples using 16 s RNA sequencing. Psychological and cognitive patient reported outcome measures will include depression, anxiety, post-traumatic stress disorder symptoms, pain, fatigue, and social and cognitive function. Dual-energy X-ray Absorptiometry (DXA) will be used to measure fat and lean mass, and bone mineral concentration. Pro-inflammatory cytokines, C-reactive protein (CRP), lipopolysaccharide (LPS), serotonin, and brain derived neurotrophic factor (BDNF) will be measured in serum, and long-term cortisol will be assayed from hair. Regression and linear mixed model (LMM) analyses will examine associations across time points (T1 - T3), between groups, and covariates with gut microbiota, cognitive, psychological, and physiological parameters. CONCLUSION: Knowing what bacterial species are depleted after chemotherapy, how long these effects last, and the physiological mechanisms that may drive psychological and cognitive issues among survivors will allow for targeted, integrative interventions to be developed, helping to prevent or reverse some of the late-effects of treatment that many young cancer survivors face. This protocol has been approved by the Health Research Ethics Board of Alberta Cancer Committee (ID: HREBA.CC-19-0018).
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Polyphenols in the management of brain disorders: Modulation of the microbiota-gut-brain axis.
The modulation of the microbiota-gut-brain axis with a view to preventing and treating brain disorders became recently a hot topic for the scientific community. Dietary polyphenols are multifaceted compounds that have demonstrated to be highly advantageous to counteract inflammation, oxidative stress, and neurodegeneration, among other pathological conditions, being useful in the prevention and treatment of several chronic disorders. The potential of these compounds to prevent and treat brain disorders has not been only related to their capacity to reach the brain, depending on their chemical structure, and interact directly with brain cells, but also to their ability to modulate the communication between the brain and the gut, interfering with multiple branches of this axis. Preclinical studies have demonstrated the potential of these food bioactive compounds in brain diseases, namely, neurodevelopmental, such as Down's syndrome and Autism spectrum disorder, neurodegenerative, such as Parkinson's disease and Alzheimer's disease, and psychiatric disorders, such as depression and anxiety. Until now, dietary polyphenols have been recognized as promising nutraceuticals to combat brain disorders. However, the impact of these compounds on the gut-brain interconnection remains poorly elucidated. Also, clinical assays are crucial to further support the beneficial effects of these compounds as demonstrated in preclinical research.
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ACTH(6-9)-Pro-Gly-Pro ameliorates anxiety-like and depressive-like behaviour and gut mucosal microbiota composition in rats under conditions of chronic restraint stress.
The effects of the peptide ACTH(6-9)-Pro-Gly-Pro at doses of 5; 50; 500 μg/kg on the Wistar rats' behaviour and gut mucosal microbiota composition under conditions of chronic immobilization stress (CRS) were studied. CRS increased anxiety-like and depressive-like behaviour, disturbances in locomotor activity and gut dysbiosis. Administration of ACTH(6-9)-Pro-Gly-Pro showed many phenotypic results. Peptide demonstrated anti-depressant activity at doses of 5 and 500 μg/kg by a decrease in the total immobile time in the FST. ACTH(6-9)-Pro-Gly-Pro administered at a dose of 50 μg/kg resulted in an anxiolytic effect which is shown by an increase in the time in the open arms of EPM (p < 0.05) and a decrease in the time in the closed arms (p < 0.05). Moreover, the peptide led to a decrease in alpha- and beta-diversity of the gut microbiota (p < 0.01). Correlation and linear regression analysis demonstrated central mechanisms of ACTH(6-9)-Pro-Gly-Pro anxiolytic activity and both central and peripheral ones in an anti-depressant effect. In this way, peptide ACTH(6-9)-Pro-Gly-Pro could prevent the development of behavioural disturbances and gut dysbiosis caused by chronic restraint stress.
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Gut microbiota mediated inflammation, neuroendocrine and neurotrophic functions involved in the antidepressant-like effects of diosgenin in chronic restraint stress.
BACKGROUND: Diosgenin is a well-known steroid saponin possessing neuroprotective activities. However, it is unknown whether diosgenin could alleviate depression-like symptoms. METHODS: The antidepressant-like effect of diosgenin was investigated in mice induced by chronic restraint stress. The effects of diosgenin on behaviors, inflammation, neuroendocrine, neurotrophic function, and gut microbiota were evaluated. RESULTS: The results showed that diosgenin alleviated the depressive-like behaviors in mice. In addition, diosgenin was found to reduce serum concentrations of proinflammatory cytokines and the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Besides, diosgenin could activate hippocampal brain-derived neurotrophic factor (BDNF)/TrkB/ERK/CREB signaling pathway and improve the expression of postsynaptic protein PSD95. Meanwhile, the neurogenesis which was inhibited by chronic restraint stress, was totally reversed by diosgenin. Moreover, diosgenin increased the abundance of phylum Firmicutes and the genus Lactobacillus in stressed mice. The results further showed that diosgenin caused a strong correlation between gut microbiota composition and inflammation, the HPA axis activity, or hippocampus neurotrophic function. LIMITATIONS: Only male mice were used for evaluation in the present study, which limits the understanding of effects of diosgenin on the both sexes. In addition, the results only indicate microbiota at the phylum or genus mediate the regulation of neuroinflammation, neuroendocrine, and neurotrophic function, but does not elucidate how microbiota modulate the systems via their primary or secondary metabolites. CONCLUSIONS: The present study shows that diosgenin exerts the antidepressant activity, which is associated with the enhancement of neurotrophic function and the inhibition of inflammatory and neuroendocrine activities via the regulation of gut microbiota.
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Sex Differences in Immune and Gut Microbiota Responses to Military Training.
PURPOSE: Military training includes multiple stressors that together may increase risk for illness by degrading immune function and altering gut microbiota. However, whether sex differences exist in those responses is undetermined. This study aimed to determine immune and gut microbiota responses during military training and identify sex differences in those responses. METHODS: Seventy-two military cadets (33% female) participated in an arduous 17-d training event. Blood, saliva, and stool were collected upon beginning (PRE) and completing (POST) training. Immune function was assessed by salivary secretory IgA (SIgA), latent virus reactivation, peripheral leukocyte distribution, circulating cytokines, and mitogen-stimulated cytokine profiles. Gut microbiota composition was assessed by 16S rRNA amplicon sequencing. RESULTS: Participants experienced a ~4% body weight loss and sex-independent increases in concentrations of cortisol, myoglobin, catecholamines, and multiple cytokines. The granulocyte-to-lymphocyte ratio increased and SIgA decreased PRE to POST in males but not females ( Pinteraction ≤ 0.02). Mitogen-stimulated cytokine profiles were generally reduced at POST versus PRE independent of sex. No differences in virus reactivation were observed. Sex differences in gut microbiota responses were limited to Bifidobacterium and Ruminococcus , which increased in males relative to females (log 2 fold change (FC) = 2.0-2.4; qinteraction = 0.19). Independent of sex, 24 genera differed at POST versus PRE with Lactobacillus demonstrating the largest decrease (log 2 FC = -0.90; qtime = 0.02) and Veillonella the largest increase (log 2 FC = 1.09; qtime = 0.03). Multiple correlations between markers of stress, immune function, and gut microbiota composition were observed ( q ≤ 0.15). CONCLUSIONS: Immune redistribution, leukocyte compromise, and interrelated changes in gut microbiota composition were evident within this training environment. Those responses demonstrated associations with markers of stress severity but also sex differences, suggesting a more pronounced depression of immune function in males.
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Phytic acid actions on hepatic lipids and gut microbiota in rats fed a diet high in sucrose is influenced by dietary fat level.
Phytic acid (PA) or myoinositol intake was recently reported by our group to suppress hepatic lipogenic gene expression and modulate gut microbiota in rats fed a high-sucrose diet (HSC). The aim of this study was to investigate the effect of PA and dietary fat level on fatty liver and gut microbiota in rats fed an HSC diet. Male Sprague-Dawley rats were fed a high-fat (HF), HSC diet or a low-fat (LF), HSC diet with or without 1.02% sodium PA for 12 days. Hepatic lipid levels, hepatic enzyme activity, and expression of the enzymes and transcriptional factors related to lipid metabolism, cecal organic acids, and fecal microbiota were evaluated. PA intake depressed hepatic total lipid and triglyceride levels; reduced hepatic activity and expression of lipogenic enzymes; elevated fecal proportion of Lactobacillus spp; and increased cecal succinate level in rats fed the LF diet. The HF diet, when compared with the LF diet, depressed hepatic total lipid and triglyceride levels; reduced hepatic activity and expression of lipogenic enzymes; increased hepatic expression of carnitine palmitoyl-transferase 1a and cAMP-responsive element binding protein 3-like 3; and elevated fecal proportions of Lactobacillus spp and Bifidobacterium spp. In the HF diet groups, PA intake did not affect the factors associated with hepatic lipid metabolism and gut microbiota. In conclusion, dietary fat level could change the effect of PA on hepatic lipid metabolism and gut microbiota and, in turn, could alter the degree of nutritional importance of PA in rats fed an HSC diet.
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Exercise mitigates a gut microbiota-mediated reduction in adult hippocampal neurogenesis and associated behaviours in rats.
Lifestyle factors, especially exercise, impact the manifestation and progression of psychiatric and neurodegenerative disorders such as depression and Alzheimer's disease, mediated by changes in hippocampal neuroplasticity. The beneficial effects of exercise may be due to its promotion of adult hippocampal neurogenesis (AHN). Gut microbiota has also been showed to be altered in a variety of brain disorders, and disturbances of the microbiota have resulted in alterations in brain and behaviour. However, whether exercise can counteract the negative effects of altered gut microbiota on brain function remains under explored. To this end, chronic disruption of the gut microbiota was achieved using an antibiotic cocktail in rats that were sedentary or allowed voluntary access to running wheels. Sedentary rats with disrupted microbiota displayed impaired performance in hippocampal neurogenesis-dependent tasks: the modified spontaneous location recognition task and the novelty suppressed feeding test. Performance in the elevated plus maze was also impaired due to antibiotics treatment. These behaviours, and an antibiotics-induced reduction in AHN were attenuated by voluntary exercise. The effects were independent of changes in the hippocampal metabolome but were paralleled by caecal metabolomic changes. Taken together these data highlight the importance of the gut microbiota in AHN-dependent behaviours and demonstrate the power of lifestyle factors such as voluntary exercise to attenuate these changes.
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Associations between self-reported psychological symptom severity and gut microbiota: further support for the microgenderome.
BACKGROUND: Research into the brain-gut-microbiota axis (BGMA) continues to reveal associations between gut microbiota (GM) and psychological symptom expression, inspiring new ways of conceptualising psychological disorders. However, before GM modulation can be touted as a possible auxiliary treatment option, more research is needed as inconsistencies in previous findings regarding these associations are prevalent. Additionally, the concept of the microgenderome, which proposes that GM may interact with sex hormones, has received limited attention in studies using human samples to date. However, such research has demonstrated sex specific associations between GM and psychological symptom expression. METHOD: This cross-sectional retrospective study explores associations between GM species (identified through faecal microbial analysis) and symptom severity across four psychological domains (Depressive, Neurocognitive, Stress and Anxiety, and Sleep and Fatigue) for males (N = 1143) and females (N = 3467) separately. RESULTS: GM species from several genera including Bifidobacterium, Clostridium, Enterococcus, and Leuconostoc were found to be differentially associated with psychological symptom severity for males and females. As such, the findings of the current study provide support for the concept of the microgenderome. CONCLUSION: While further research is needed before their implementation in psychological treatment plans, the current findings suggest that modulation of GM at the species level may hold promise as auxiliary diagnostic or treatment options. These findings may give further insight into a client's presenting problem from a more holistic, multidisciplinary perspective. The clear sex divergence in associations between GM and symptoms give insight into sex discrepancies in susceptibility to psychological disorders.
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Implication of microbiota gut-brain axis in the manifestation of obsessive-compulsive disorder: Preclinical and clinical evidence.
Recent research has highlighted the key role of gut microbiota in the development of psychiatric disorders. The adverse impact of stress, anxiety, and depression has been well documented on the commensal gut microflora. Thus, therapeutic benefits of gut microbiota-based interventions may not be avoided in central nervous system (CNS) disorders. In this review, we outline the current state of knowledge of gut microbiota with respect to obsessive-compulsive disorder (OCD). We discuss how OCD-generated changes corresponding to the key neurotransmitters, hypothalamic-pituitary-adrenal axis, and immunological and inflammatory pathways are connected with the modifications of the microbiota-gut-brain axis. Notably, administration of few probiotics such as Lactobacillus rhamnosus (ATCC 53103), Lactobacillus helveticus R0052, Bifidobacterium longum R0175, Saccharomyces boulardii, and Lactobacillus casei Shirota imparted positive effects in the management of OCD symptoms. Taken together, we suggest that the gut microbiota-directed therapeutics may open new treatment approaches for the management of OCD.