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Nature Reviews. Microbiology Aug 2019Perturbations in the intestinal microbiome are implicated in inflammatory bowel disease (IBD). Studies of treatment-naive patients have identified microbial taxa... (Review)
Review
Perturbations in the intestinal microbiome are implicated in inflammatory bowel disease (IBD). Studies of treatment-naive patients have identified microbial taxa associated with disease course and treatment efficacy. To gain a mechanistic understanding of how the microbiome affects gastrointestinal health, we need to move from census to function. Bacteria, including those that adhere to epithelial cells as well as several Clostridium species, can alter differentiation of T helper 17 cells and regulatory T cells. Similarly, microbial products such as short-chain fatty acids and sphingolipids also influence immune responses. Metagenomics and culturomics have identified strains of Ruminococcus gnavus and adherent invasive Escherichia coli that are linked to IBD and gut inflammation. Integrated analysis of multiomics data, including metagenomics, metatranscriptomics and metabolomics, with measurements of host response and culturomics, have great potential in understanding the role of the microbiome in IBD. In this Review, we highlight current knowledge of gut microbial factors linked to IBD pathogenesis and discuss how multiomics data from large-scale population studies in health and disease have been used to identify specific microbial strains, transcriptional changes and metabolic alterations associated with IBD.
Topics: Bacterial Adhesion; Biological Factors; Gastrointestinal Microbiome; Host-Pathogen Interactions; Humans; Immunologic Factors; Inflammatory Bowel Diseases; Microbiota; T-Lymphocytes, Regulatory; Th17 Cells
PubMed: 31249397
DOI: 10.1038/s41579-019-0213-6 -
FEMS Microbiology Reviews Mar 2023Ruminococcus gnavus was first identified in 1974 as a strict anaerobe in the gut of healthy individuals, and for several decades, its study has been limited to specific... (Review)
Review
Ruminococcus gnavus was first identified in 1974 as a strict anaerobe in the gut of healthy individuals, and for several decades, its study has been limited to specific enzymes or bacteriocins. With the advent of metagenomics, R. gnavus has been associated both positively and negatively with an increasing number of intestinal and extraintestinal diseases from inflammatory bowel diseases to neurological disorders. This prompted renewed interest in understanding the adaptation mechanisms of R. gnavus to the gut, and the molecular mediators affecting its association with health and disease. From ca. 250 publications citing R. gnavus since 1990, 94% were published in the last 10 years. In this review, we describe the biological characterization of R. gnavus, its occurrence in the infant and adult gut microbiota and the factors influencing its colonization of the gastrointestinal tract; we also discuss the current state of our knowledge on its role in host health and disease. We highlight gaps in knowledge and discuss the hypothesis that differential health outcomes associated with R. gnavus in the gut are strain and niche specific.
Topics: Adult; Humans; Gastrointestinal Microbiome; Gastrointestinal Tract; Ruminococcus
PubMed: 37015876
DOI: 10.1093/femsre/fuad014 -
Journal of the International Society of... 2016Fatigue, mood disturbances, under performance and gastrointestinal distress are common among athletes during training and competition. The psychosocial and physical... (Review)
Review
Fatigue, mood disturbances, under performance and gastrointestinal distress are common among athletes during training and competition. The psychosocial and physical demands during intense exercise can initiate a stress response activating the sympathetic-adrenomedullary and hypothalamus-pituitary-adrenal (HPA) axes, resulting in the release of stress and catabolic hormones, inflammatory cytokines and microbial molecules. The gut is home to trillions of microorganisms that have fundamental roles in many aspects of human biology, including metabolism, endocrine, neuronal and immune function. The gut microbiome and its influence on host behavior, intestinal barrier and immune function are believed to be a critical aspect of the brain-gut axis. Recent evidence in murine models shows that there is a high correlation between physical and emotional stress during exercise and changes in gastrointestinal microbiota composition. For instance, induced exercise-stress decreased cecal levels of spp and increased which have well defined roles in intestinal mucus degradation and immune function. Diet is known to dramatically modulate the composition of the gut microbiota. Due to the considerable complexity of stress responses in elite athletes (from leaky gut to increased catabolism and depression), defining standard diet regimes is difficult. However, some preliminary experimental data obtained from studies using probiotics and prebiotics studies show some interesting results, indicating that the microbiota acts like an endocrine organ (e.g. secreting serotonin, dopamine or other neurotransmitters) and may control the HPA axis in athletes. What is troubling is that dietary recommendations for elite athletes are primarily based on a low consumption of plant polysaccharides, which is associated with reduced microbiota diversity and functionality (e.g. less synthesis of byproducts such as short chain fatty acids and neurotransmitters). As more elite athletes suffer from psychological and gastrointestinal conditions that can be linked to the gut, targeting the microbiota therapeutically may need to be incorporated in athletes' diets that take into consideration dietary fiber as well as microbial taxa not currently present in athlete's gut.
Topics: Athletes; Athletic Performance; Brain; Diet; Food; Gastrointestinal Microbiome; Gastrointestinal Tract; Hormones; Humans; Probiotics; Sports Nutritional Physiological Phenomena; Stress, Psychological
PubMed: 27924137
DOI: 10.1186/s12970-016-0155-6 -
Journal of Affective Disorders Jun 2019Depression is the leading cause of disability worldwide; with evidence suggesting that decreased gut barrier function and inflammation are correlated with depressive... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Depression is the leading cause of disability worldwide; with evidence suggesting that decreased gut barrier function and inflammation are correlated with depressive symptoms. We conducted a clinical trial to determine the effect of consumption of probiotic supplements (Winclove's Ecologic® Barrier) on depressive symptoms in a sample of participants with mild to severe depression.
METHOD
71 participants were randomly allocated to either probiotic or placebo, which was, consumed daily over eight weeks. Pre- and post-intervention measures of symptoms and vulnerability markers of depression as well as gut microbiota composition were compared. Clinical trial participants were also compared on psychological variables and gut microbiota composition to a non-depressed group (n = 20).
RESULTS
All clinical trial participants demonstrated improvement in symptoms, suggesting non-specific therapeutic effects associated with weekly monitoring visits. Participants in the probiotic group demonstrated a significantly greater reduction in cognitive reactivity compared with the placebo group, particularly in the mild/moderate subgroup. Probiotics did not significantly alter the microbiota of depressed individuals, however, a significant correlation was found between Ruminococcus gnavus and one depression metric.
LIMITATIONS
There was a high attrition rate, which may be attributed to weekly monitoring visits. Additionally, modulation of the gut microbiota may need more specific testing to distinguish subtle changes.
CONCLUSIONS
While microbiota composition was similar between all groups, probiotics did affect a psychological variable associated with susceptibility to depression. Further research is needed to investigate how probiotics can be utilised to modify mental wellbeing, and whether they can act as an adjunct to existing treatments.
Topics: Adult; Depression; Dietary Supplements; Female; Gastrointestinal Microbiome; Humans; Male; Placebos; Probiotics; Research Design
PubMed: 31078831
DOI: 10.1016/j.jad.2019.04.097 -
Cell Sep 2020The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to...
The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. VIDEO ABSTRACT.
Topics: Animals; Bile Acids and Salts; Biopsy; Butyrates; Chromatography, Liquid; Cross-Sectional Studies; Epigenomics; Feces; Female; Gastrointestinal Microbiome; Gene Expression Regulation; Host Microbial Interactions; Humans; Hypoxanthine; Irritable Bowel Syndrome; Longitudinal Studies; Male; Metabolome; Mice; Observational Studies as Topic; Prospective Studies; Purines; Software; Tandem Mass Spectrometry; Transcriptome
PubMed: 32916129
DOI: 10.1016/j.cell.2020.08.007 -
Cell Host & Microbe Mar 2023The intestinal microbiota plays an important role in colorectal cancer (CRC) progression. However, the effect of tissue-resident commensal bacteria on CRC immune...
The intestinal microbiota plays an important role in colorectal cancer (CRC) progression. However, the effect of tissue-resident commensal bacteria on CRC immune surveillance remains poorly understood. Here, we analyzed the intratissue bacteria from CRC patient colon tissues. We found that the commensal bacteria belonging to the Lachnospiraceae family, including Ruminococcus gnavus (Rg), Blautia producta (Bp), and Dorea formicigenerans (Df), were enriched in normal tissues, while Fusobacterium nucleatum (Fn) and Peptostreptococcus anaerobius (Pa) were abundant in tumor tissues. Tissue-resident Rg and Bp reduced colon tumor growth and promoted the activation of CD8 T cells in immunocompetent mice. Mechanistically, intratissue Rg and Bp degraded lyso-glycerophospholipids that inhibited CD8 T cell activity and maintained the immune surveillance function of CD8 T cells. Lyso-glycerophospholipids alone promoted tumor growth that was abrogated with Rg and Bp injection. Collectively, intratissue Lachnospiraceae family bacteria facilitate the immune surveillance function of CD8 T cells and control colorectal cancer progression.
Topics: Animals; Mice; Colorectal Neoplasms; CD8-Positive T-Lymphocytes; Carcinogenesis; Colonic Neoplasms; Fusobacterium nucleatum
PubMed: 36893736
DOI: 10.1016/j.chom.2023.01.013 -
Cell Host & Microbe Jan 2023Diarrhea-predominant irritable bowel syndrome (IBS-D), a globally prevalent functional gastrointestinal (GI) disorder, is associated with elevated serotonin that...
Diarrhea-predominant irritable bowel syndrome (IBS-D), a globally prevalent functional gastrointestinal (GI) disorder, is associated with elevated serotonin that increases gut motility. While anecdotal evidence suggests that the gut microbiota contributes to serotonin biosynthesis, mechanistic insights are limited. We determined that the bacterium Ruminococcus gnavus plays a pathogenic role in IBS-D. Monocolonization of germ-free mice with R. gnavus induced IBS-D-like symptoms, including increased GI transit and colonic secretion, by stimulating the production of peripheral serotonin. R. gnavus-mediated catabolism of dietary phenylalanine and tryptophan generated phenethylamine and tryptamine that directly stimulated serotonin biosynthesis in intestinal enterochromaffin cells via a mechanism involving activation of trace amine-associated receptor 1 (TAAR1). This R. gnavus-driven increase in serotonin levels elevated GI transit and colonic secretion but was abrogated upon TAAR1 inhibition. Collectively, our study provides molecular and pathogenetic insights into how gut microbial metabolites derived from dietary essential amino acids affect serotonin-dependent control of gut motility.
Topics: Animals; Mice; Irritable Bowel Syndrome; Serotonin; Diarrhea
PubMed: 36495868
DOI: 10.1016/j.chom.2022.11.006 -
Proceedings of the National Academy of... Jun 2019A substantial and increasing number of human diseases are associated with changes in the gut microbiota, and discovering the molecules and mechanisms underlying these...
A substantial and increasing number of human diseases are associated with changes in the gut microbiota, and discovering the molecules and mechanisms underlying these associations represents a major research goal. Multiple studies associate , a prevalent gut microbe, with Crohn's disease, a major type of inflammatory bowel disease. We have found that synthesizes and secretes a complex glucorhamnan polysaccharide with a rhamnose backbone and glucose sidechains. Chemical and spectroscopic studies indicated that the glucorhamnan was largely a repeating unit of five sugars with a linear backbone formed from three rhamnose units and a short sidechain composed of two glucose units. The rhamnose backbone is made from 1,2- and 1,3-linked rhamnose units, and the sidechain has a terminal glucose linked to a 1,6-glucose. This glucorhamnan potently induces inflammatory cytokine (TNFα) secretion by dendritic cells, and TNFα secretion is dependent on toll-like receptor 4 (TLR4). We also identify a putative biosynthetic gene cluster for this molecule, which has the four biosynthetic genes needed to convert glucose to rhamnose and the five glycosyl transferases needed to build the repeating pentasaccharide unit of the inflammatory glucorhamnan.
Topics: Animals; Cells, Cultured; Clostridiales; Crohn Disease; Gastrointestinal Microbiome; Mice; Mice, Inbred C57BL; Polysaccharides, Bacterial; Tumor Necrosis Factor-alpha
PubMed: 31182571
DOI: 10.1073/pnas.1904099116 -
Cell Host & Microbe Jun 2018Tryptamine, a tryptophan-derived monoamine similar to 5-hydroxytryptamine (5-HT), is produced by gut bacteria and is abundant in human and rodent feces. However, the...
Tryptamine, a tryptophan-derived monoamine similar to 5-hydroxytryptamine (5-HT), is produced by gut bacteria and is abundant in human and rodent feces. However, the physiologic effect of tryptamine in the gastrointestinal (GI) tract remains unknown. Here, we show that the biological effects of tryptamine are mediated through the 5-HT receptor (5-HTR), a G-protein-coupled receptor (GPCR) uniquely expressed in the colonic epithelium. Tryptamine increases both ionic flux across the colonic epithelium and fluid secretion in colonoids from germ-free (GF) and humanized (ex-GF colonized with human stool) mice, consistent with increased intestinal secretion. The secretory effect of tryptamine is dependent on 5-HTR activation and is blocked by 5-HTR antagonist and absent in 5-HTR mice. GF mice colonized by Bacteroides thetaiotaomicron engineered to produce tryptamine exhibit accelerated GI transit. Our study demonstrates an aspect of host physiology under control of a bacterial metabolite that can be exploited as a therapeutic modality. VIDEO ABSTRACT.
Topics: Animals; Bacteroides thetaiotaomicron; Colon; Epithelium; Feces; Gastrointestinal Microbiome; Humans; Intestinal Secretions; Mice; Mice, 129 Strain; Mice, Knockout; Primary Cell Culture; Receptors, Serotonin, 5-HT4; Sex Factors; Specific Pathogen-Free Organisms; Tryptamines
PubMed: 29902441
DOI: 10.1016/j.chom.2018.05.004 -
Genome Medicine Nov 2017Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract that is associated with changes in the gut microbiome. Here, we...
BACKGROUND
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract that is associated with changes in the gut microbiome. Here, we sought to identify strain-specific functional correlates with IBD outcomes.
METHODS
We performed metagenomic sequencing of monthly stool samples from 20 IBD patients and 12 controls (266 total samples). These were taxonomically profiled with MetaPhlAn2 and functionally profiled using HUMAnN2. Differentially abundant species were identified using MaAsLin and strain-specific pangenome haplotypes were analyzed using PanPhlAn.
RESULTS
We found a significantly higher abundance in patients of facultative anaerobes that can tolerate the increased oxidative stress of the IBD gut. We also detected dramatic, yet transient, blooms of Ruminococcus gnavus in IBD patients, often co-occurring with increased disease activity. We identified two distinct clades of R. gnavus strains, one of which is enriched in IBD patients. To study functional differences between these two clades, we augmented the R. gnavus pangenome by sequencing nine isolates from IBD patients. We identified 199 IBD-specific, strain-specific genes involved in oxidative stress responses, adhesion, iron-acquisition, and mucus utilization, potentially conferring an adaptive advantage for this R. gnavus clade in the IBD gut.
CONCLUSIONS
This study adds further evidence to the hypothesis that increased oxidative stress may be a major factor shaping the dysbiosis of the microbiome observed in IBD and suggests that R. gnavus may be an important member of the altered gut community in IBD.
Topics: Adult; Aged; Feces; Gastrointestinal Microbiome; Genome, Bacterial; Humans; Inflammatory Bowel Diseases; Middle Aged; Oxidative Stress; Phylogeny; Ruminococcus; Species Specificity; Young Adult
PubMed: 29183332
DOI: 10.1186/s13073-017-0490-5