Review

Authors: Emmanuelle H Crost, Erika Coletto, Andrew Bell...

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; Ruminococcus; Gastrointestinal Microbiome; Humans; Gastrointestinal Tract; Clostridiales

PubMed: 37015876
DOI: 10.1093/femsre/fuad014

Review

Authors: Melanie Schirmer, Ashley Garner, Hera Vlamakis...

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

Comparative Study Randomized Controlled Trial

Authors: Bahia Chahwan, Sophia Kwan, Ashling Isik...

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

Review

Authors: Allison Clark, Núria Mach

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

Authors: Lixiang Zhai, Chunhua Huang, Ziwan Ning...

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: Serotonin; Clostridiales; Mice; Animals; Irritable Bowel Syndrome; Diarrhea

PubMed: 36495868
DOI: 10.1016/j.chom.2022.11.006

Authors: Xusheng Zhang, Dou Yu, Di Wu...

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

Review

Authors: Alexander C Ford, Stephen Vanner, Purna C Kashyap...

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

Topics: Humans; Visceral Pain; Chronic Pain; Animals; Quality of Life; Signal Transduction

PubMed: 38325759
DOI: 10.1053/j.gastro.2024.01.045

Authors: Arnau Vich Vila, Shixian Hu, Sergio Andreu-Sánchez...

OBJECTIVE

Inflammatory bowel disease (IBD) is a multifactorial immune-mediated inflammatory disease of the intestine, comprising Crohn's disease and ulcerative colitis. By characterising metabolites in faeces, combined with faecal metagenomics, host genetics and clinical characteristics, we aimed to unravel metabolic alterations in IBD.

DESIGN

We measured 1684 different faecal metabolites and 8 short-chain and branched-chain fatty acids in stool samples of 424 patients with IBD and 255 non-IBD controls. Regression analyses were used to compare concentrations of metabolites between cases and controls and determine the relationship between metabolites and each participant's lifestyle, clinical characteristics and gut microbiota composition. Moreover, genome-wide association analysis was conducted on faecal metabolite levels.

RESULTS

We identified over 300 molecules that were differentially abundant in the faeces of patients with IBD. The ratio between a sphingolipid and L-urobilin could discriminate between IBD and non-IBD samples (AUC=0.85). We found changes in the bile acid pool in patients with dysbiotic microbial communities and a strong association between faecal metabolome and gut microbiota. For example, the abundance of was positively associated with tryptamine levels. In addition, we found 158 associations between metabolites and dietary patterns, and polymorphisms near strongly associated with coffee metabolism.

CONCLUSION

In this large-scale analysis, we identified alterations in the metabolome of patients with IBD that are independent of commonly overlooked confounders such as diet and surgical history. Considering the influence of the microbiome on faecal metabolites, our results pave the way for future interventions targeting intestinal inflammation.

Topics: Humans; Genome-Wide Association Study; Inflammatory Bowel Diseases; Colitis, Ulcerative; Metabolome; Feces; Arylamine N-Acetyltransferase

PubMed: 36958817
DOI: 10.1136/gutjnl-2022-328048

Authors: Ruben A T Mars, Yi Yang, Tonya Ward...

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

Authors: Blanda Di Luccia, Martina Molgora, Darya Khantakova...

The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of in the gut microbiota. Gavage of wild-type mice with enhanced anti-PD-1-mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4 T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.

Topics: Animals; Mice; Gastrointestinal Microbiome; Immune Checkpoint Inhibitors; Immunotherapy; Intestines; Macrophages; Membrane Glycoproteins; Mice, Inbred C57BL; Mice, Knockout; Programmed Cell Death 1 Receptor; Receptors, Immunologic

PubMed: 38758808
DOI: 10.1126/sciimmunol.adi5374