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Mucosal-associated invariant and γδ T cell subsets respond to initial Mycobacterium tuberculosis infection.
Innate immune responses that control early Mtb infection are poorly understood, but understanding these responses may inform vaccination and immunotherapy strategies. Innate T cells that respond to conserved bacterial ligands such as mucosal-associated invariant T (MAIT) and γδ T cells are prime candidates to mediate these early innate responses but have not been examined in subjects who have been recently exposed to Mtb. We recruited a cohort living in the same household with an active tuberculosis (TB) case and examined the abundance and functional phenotypes of 3 innate T cell populations reactive to M. tuberculosis: γδ T, invariant NK T (iNKT), and MAIT cells. Both MAIT and γδ T cells from subjects with Mtb exposure display ex vivo phenotypes consistent with recent activation. However, both MAIT and γδ T cell subsets have distinct response profiles, with CD4+ MAIT and γδ T cells accumulating after infection. Examination of exposed but uninfected contacts demonstrates that resistance to initial infection is accompanied by robust MAIT cell CD25 expression and granzyme B production coupled with a depressed CD69 and IFNγ response. Finally, we demonstrate that MAIT cell abundance and function correlate with the abundance of specific gut microbes, suggesting that responses to initial infection may be modulated by the intestinal microbiome.
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Small intestinal flora graft alters fecal flora, stool, cytokines and mood status in healthy mice.
Fecal microbiota transplantation is widely used. Large intestinal microbiota (LIM) is more similar to fecal microbiota than small intestinal microbiota (SIM). The SIM communities are very different from those of LIM. Therefore, SIM transplantation (SIMT) and LIM transplantation (LIMT) might exert different influences. Here, healthy adult male C57Bl/6 mice received intragastric SIMT, LIMT, or sterile PBS administration. Microbiota graft samples were collected from small/large intestine of healthy mice of the same age, sex, and strain background. Compared with PBS treatment, SIMT increased pellet number, stool wet weight, and stool water percentage; induced a fecal microbiota profile shift toward the microbial composition of the SIM graft; induced a systemic anti-inflammatory cytokines profile; and ameliorated depressive-like behaviors in recipients. LIMT, however, induced merely a slight alteration in fecal microbial composition and no significant influence on the other aspects. In sum, SIMT, rather than LIMT, affected defecation features, fecal microbial composition, cytokines profile, and depressive-like behaviors in healthy mice. This study reveals the different effects of SIMT and LIMT, providing an interesting clue for further researches involving gut microbial composition change.
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Multiomics Analysis Reveals Gut Virome-Bacteria-Metabolite Interactions and Their Associations with Symptoms in Patients with IBS-D.
The gut microbiota is involved in the pathogenesis of diarrhea-predominant irritable bowel syndrome (IBS-D), but few studies have focused on the role of the gut virome in IBS-D. We aimed to explore the characteristics of the gut virome in patients with IBS-D, its interactions with bacteria and metabolites, and the associations between gut multiomics profiles and symptoms. This study enrolled twelve patients with IBS-D and eight healthy controls (HCs). The stool samples were subjected to metavirome sequencing, 16S rRNA gene sequencing, and untargeted metabolomic analysis. The participants completed relevant scales to assess the severity of their gastrointestinal symptoms, depression, and anxiety. The results revealed unique DNA and RNA virome profiles in patients with IBS-D with significant alterations in the abundance of contigs from Siphoviridae, Podoviridae, Microviridae, Picobirnaviridae, and Tombusviridae. Single-omics co-occurrence network analyses demonstrated distinct differences in the gut virus, bacteria, and metabolite network patterns between patients with IBS-D and HCs. Multiomics networks revealed that short-chain fatty acid-producing bacteria occupied more core positions in IBS-D networks, but had fewer links to viruses. Amino acids and their derivatives exhibit unique connectivity patterns and centrality features within the IBS-D network. The gastrointestinal and psychological symptom factors of patients with IBS-D were highly clustered in the symptom-multiomics network compared with those of HCs. Machine learning models based on multiomics data can distinguish IBS-D patients from HCs and predict the scores of gastrointestinal and psychological symptoms. This study provides insights into the interactions among gut viruses, bacteria, metabolites, and clinical symptoms in patients with IBS-D, indicating further classification and personalized treatment for IBS-D.
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Gut-brain axis metabolic pathway regulates antidepressant efficacy of albiflorin.
The gut microbiota is increasingly recognized to influence brain function through the gut-brain axis. Albiflorin, an antidepressant natural drug in China with a good safety profile, is difficult to absorb and cannot be detected in the brain after oral administration. Accordingly, the antidepressant mechanism of albiflorin in vivo has not been elucidated clearly. Methods: We identified benzoic acid as the characteristic metabolite of albiflorin in vivo and in vitro, then discovered the roles of gut microbiota in the conversion of albiflorin by carboxylesterase. Pharmacodynamic and pharmacokinetic studies were performed for the antidepressant activities of albiflorin in animals, and the efficacy of benzoic acid in inhibiting D-amino acid oxidase (DAAO) in brain was further investigated. Results: We validated that gut microbiota transformed albiflorin to benzoic acid, a key metabolite in the intestine that could cross the blood-brain barrier and, as an inhibitor of DAAO in the brain, improved brain function and exerted antidepressant activity in vivo. Intestinal carboxylesterase was the crucial enzyme that generated benzoic acid from albiflorin. Additionally, the regulatory effect of albiflorin on the gut microbiota composition was beneficial to alleviate depression. Conclusion: Our findings suggest a novel gut-brain dialogue through intestinal benzoic acid for the treatment of depression and reveal that the gut microbiota may play a causal role in the pathogenesis and treatment of the central nervous system disease.
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The kinetics of gut microbial community composition in patients with irritable bowel syndrome following fecal microbiota transplantation.
BACKGROUND: Gut microbiota alterations are important in irritable bowel syndrome (IBS). The aim was to investigate the effect of fecal microbiota transplantation (FMT) on gut microbiota and the symptoms in patients with IBS. MATERIAL AND METHODS: The study included 13 IBS patients according to Rome III criteria and 13 healthy donors. Freshly donated feces were administered to the descending part of the duodenum via a gastroscope. Feces were collected from donors and patients before FMT, and from the patients at 1, 3 and 12 weeks and donors and patients at 20/28 weeks after FMT. Microbiota analysis was performed using GA-map Dysbiosis test (Genetic Analysis AS, Oslo, Norway). The patients completed the following questionnaires before and at the aforementioned weeks after FMT: IBS Symptom Questionnaire (IBS-SQ), IBS-Symptom Severity Scoring system (IBS-SSS), Short Form of Nepean Dyspepsia Index (SF-NDI), Bristol stool form scale, the Eysenck Personality Questionnaire-Neuroticism and Hospital Anxiety and Depression. RESULTS: Donors and IBS patients had significantly different bacterial strain signals before FMT (Ruminococcus gnavus, Actinobacteria and Bifidobacteria) that became non-significant after 3 weeks following FMT. The changes in gut microbiota were similar between donors and patients at 20/28 weeks after FMT. Thus, patients' microbiota profiles became more-or-less similar to donors. The scores of all the questionnaires were significantly improved at all time points following FMT. No reported adverse effects. CONCLUSIONS: FMT was associated with a change in gut microbiota and improvement in IBS symptoms and quality of life lasting for up to 28 weeks. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03333291.
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Diet and Neurocognition in Mood Disorders - An Overview of the Overlooked.
Bipolar disorder and major depression are associated with significant disability, morbidity, and reduced life expectancy. People with mood disorders have shown higher ratios of unhealthy lifestyle choices, including poor diet quality and suboptimal nutrition. Diet and nutrition impact on brain /mental health, but cognitive outcomes have been less researched in psychiatric disorders. Neurocognitive dysfunction is a major driver of social dysfunction and a therapeutic target in mood disorders, although effective cognitive-enhancers are currently lacking. This narrative review aimed to assess the potential cognitive benefits of dietary and nutritional interventions in subjects diagnosed with mood disorders. Eight clinical trials with nutrients were identified, whereas none involved dietary interventions. Efficacy to improve select cognitive deficits has been reported, but results are either preliminary or inconsistent. Methodological recommendations for future cognition trials in the field are advanced. Current evidence and future views are discussed from the perspectives of precision medicine, clinical staging, nutritional psychiatry, and the brain-gut-microbiota axis.
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The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology.
The human microbiota has a fundamental role in host physiology and pathology. Gut microbial alteration, also known as dysbiosis, is a condition associated not only with gastrointestinal disorders but also with diseases affecting other distal organs. Recently it became evident that the intestinal bacteria can affect the central nervous system (CNS) physiology and inflammation. The nervous system and the gastrointestinal tract are communicating through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the vagus nerve, the immune system, and bacterial metabolites and products. During dysbiosis, these pathways are dysregulated and associated with altered permeability of the blood-brain barrier (BBB) and neuroinflammation. However, numerous mechanisms behind the impact of the gut microbiota in neuro-development and -pathogenesis remain poorly understood. There are several immune pathways involved in CNS homeostasis and inflammation. Among those, the inflammasome pathway has been linked to neuroinflammatory conditions such as multiple sclerosis, Alzheimer's and Parkinson's diseases, but also anxiety and depressive-like disorders. The inflammasome complex assembles upon cell activation due to exposure to microbes, danger signals, or stress and lead to the production of pro-inflammatory cytokines (interleukin-1β and interleukin-18) and to pyroptosis. Evidences suggest that there is a reciprocal influence of microbiota and inflammasome activation in the brain. However, how this influence is precisely working is yet to be discovered. Herein, we discuss the status of the knowledge and the open questions in the field focusing on the function of intestinal microbial metabolites or products on CNS cells during healthy and inflammatory conditions, such as multiple sclerosis, Alzheimer's and Parkinson's diseases, and also neuropsychiatric disorders. In particular, we focus on the innate inflammasome pathway as immune mechanism that can be involved in several of these conditions, upon exposure to certain microbes.
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Oral administration of Lactococcus lactis WHH2078 alleviates depressive and anxiety symptoms in mice with induced chronic stress.
Depression is a mood disorder with a high prevalence rate globally, which is associated with abnormalities in 5-hydroxytryptamine (5-HT) metabolism. Emerging evidence suggests that certain probiotics that modulate 5-HT metabolism confer beneficial effects on depression. In this study, in vitro enterochromaffin RIN14B cells were used for screening potential antidepressant probiotic Lactococcus lactis strains. The L. lactis strain WHH2078 increased to high levels the 5-HT precursor 5-hydroxytryptophan (5-HTP) and the expression of tryptophan hydroxylase 1 (Tph1), which converts tryptophan to 5-HTP in RIN14B cells. The oral administration of WHH2078 (1 × 109 CFU mL-1) in mice with induced chronic unpredictable mild stress (CUMS) for 5 weeks significantly ameliorated depressive and anxiety-like behaviors in the tail suspension test, forced swim test, sucrose preference test, and open field test. Besides, WHH2078 significantly reduced the serum corticosterone level and restored the central levels of 5-HT, 5-HTP, and brain-derived neurotrophic factor in CUMS-induced mice. Moreover, WHH2078 also reversed the 5-HTP levels in the serum and colon, accompanied by an upregulation in colonic Tph1 gene expression. Using 16S rRNA high-throughput sequencing of feces, WHH2078 was shown to improve the CUMS-induced gut microbial dysbiosis, through restoring alpha diversity and the abundances of Firmicutes and Bacteroidetes. In summary, these results indicate that WHH2078 can alleviate rodent depressive and anxiety-like behaviors in response to CUMS, which is associated with the improvement of 5-HT metabolism and modulation of the gut microbiome composition. Therefore, supplementation of the L. lactis strain WHH2078 with antidepressant properties may serve as a promising therapeutic strategy for chronic stress-induced depression.
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Prolonged High-Fat Diet Consumption throughout Adulthood in Mice Induced Neurobehavioral Deterioration via Gut-Brain Axis.
Neuropsychiatric disorders have been one of the worldwide health problems contributing to profound social and economic consequences. It is reported that consumption of an excessive high-fat diet (HFD) in middle age could induce cognitive and emotional dysfunctions, whereas the mechanisms of the effects of long-term HFD intake on brain disorders have not been fully investigated. We propose a hypothesis that prolonged HFD intake throughout adulthood could lead to neurobehavioral deterioration via gut-brain axis. In this study, the adult C57BL/6J mice consuming long-term HFD (24 weeks) exhibited more anxiety-like, depression-like, and disruptive social behaviors and poorer performance in learning and memory than control mice fed with a normal diet (ND). In addition, the homeostasis of gut microbiota was impaired by long-term HFD consumption. Changes in some flora, such as Prevotellaceae_NK3B31_group and Ruminococcus, within the gut communities, were correlated to neurobehavioral alterations. Furthermore, the gut permeability was increased after prolonged HFD intake due to the decreased thickness of the mucus layer and reduced expression of tight junction proteins in the colon. The mRNA levels of genes related to synaptic-plasticity, neuronal development, microglia maturation, and activation in the hippocampus and prefrontal cortex of HFD-fed mice were lower than those in mice fed with ND. Interestingly, the transcripts of genes related to tight junction proteins, ZO-1 and Occludin involved in blood-brain-barrier (BBB), were decreased in both hippocampus and prefrontal cortex after long-term HFD consumption. Those results indicated that chronic consumption of HFD in mice resulted in gut microbiota dysbiosis, which induced decreased expression of mucus and tight junction proteins in the colon, in turn leading to local and systemic inflammation. Those changes could further contribute to the impairment of brain functions and neurobehavioral alterations, including mood, sociability, learning and memory. In short, long-term HFD intake throughout adulthood could induce behavioral phenotypes related to neuropsychiatric disorders via gut-brain axis. The observations of this study provide potential intervention strategies to reduce the risk of HFD via targeting the gut or manipulating gut microbiota.
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The Effect of A Whey-Protein and Galacto-Oligosaccharides Based Product on Parameters of Sleep Quality, Stress, and Gut Microbiota in Apparently Healthy Adults with Moderate Sleep Disturbances: A Randomized Controlled Cross-Over Study.
People experiencing sleep problems may benefit from nutrients supporting serotonin metabolism and stress reduction. We studied the effect of a dairy-based product (DP) containing protein, galacto-oligosaccharides, vitamins and minerals, on sleep quality, stress, and gut-microbiota. In a cross-over RCT (three weeks intervention; three weeks washout), adults (n = 70; 30-50 y) with sleep disturbances (Pittsburgh Sleep Quality Index (PSQI) ≥ 9) consumed products 1 h before bed-time. Sleep quality (PSQI) was measured weekly, stress at base- and end-line (Depression Anxiety Stress Scale and saliva cortisol). Fecal samples were collected in the 1st intervention period only. Compared to placebo (skimmed milk), PSQI was only lower at day 14 in the 2nd intervention period in intention-to-treat (ITT) (p = 0.017; n = 69) and per-protocol (PP) (p = 0.038; n = 64) analyses. Post-hoc analysis (modified-PP: n=47, with baseline PSQI ≥ 9, and endline day 14), however, showed a decrease in PSQI (-1.60 ± 2.53; p = 0.034). Early morning saliva cortisol decreased versus placebo (p = 0.045). Relative abundance of Bifidobacterium increased (p = 0.02). Redundancy analysis showed an inverse relationship between baseline microbiota composition and baseline PSQI (p = 0.046). Thus, although DP did not improve sleep quality in ITT and PP populations, it did in the modPP. DP reduced salivary cortisol and stimulated Bifidobacterium, which possibly is important for sleep improvement.