The human gut microbiome is linked to many states of human health and disease1. The metabolic repertoire of the gut microbiome is vast, but the health implications of these bacterial pathways are poorly understood. In this study, we identify a link between members of the genus Veillonella and exercise performance. We observed an increase in Veillonella relative abundance in marathon runners postmarathon and isolated a strain of Veillonella atypica from stool samples. Inoculation of this strain into mice significantly increased exhaustive treadmill run time. Veillonella utilize lactate as their sole carbon source, which prompted us to perform a shotgun metagenomic analysis in a cohort of elite athletes, finding that every gene in a major pathway metabolizing lactate to propionate is at higher relative abundance postexercise. Using 13C3-labeled lactate in mice, we demonstrate that serum lactate crosses the epithelial barrier into the lumen of the gut. We also show that intrarectal instillation of propionate is sufficient to reproduce the increased treadmill run time performance observed with V. atypica gavage. Taken together, these studies reveal that V. atypica improves run time via its metabolic conversion of exercise-induced lactate into propionate, thereby identifying a natural, microbiome-encoded enzymatic process that enhances athletic performance.
Interactions between gut microbiota and skeletal muscle
The gut microbiota is now recognized as a major contributor to the host’s nutrition, metabolism, immunity, and neurological functions. Imbalanced microbiota (ie, dysbiosis) is linked to undernutrition-induced stunting, inflammatory and metabolic diseases, and cancers. Skeletal muscle also takes part in the interorgan crosstalk regulating substrate metabolism, immunity, and health. Here, we review the reciprocal influence of gut microbiota and skeletal muscle in relation to juvenile growth, performance, aging, and chronic diseases. Several routes involving the vascular system and organs such as the liver and adipose tissue connect the gut microbiota and skeletal muscle, with effects on fitness and health. Therapeutic perspectives arise from the health benefits observed with changes in gut microbiota and muscle activity, further encouraging multimodal therapeutic strategies.
Regulation of Intestinal Barrier Function by Microbial Metabolites
The human gastrointestinal tract (GI) harbors a diverse population of microbial life that continually shapes host pathophysiological responses. Despite readily available abundant metagenomic data, the functional dynamics of gut microbiota remain to be explored in various health and disease conditions. Microbiota generate a variety of metabolites from dietary products that influence host health and pathophysiological functions. Since gut microbial metabolites are produced in close proximity to gut epithelium, presumably they have significant impact on gut barrier function and immune responses.
The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic T<sub>reg</sub> Cell Homeostasis
Protecting the Guts Regulatory T cells (T regs ) in the gut are important sentinels in maintaining the peace between our gut and its trillions of resident bacteria and have been shown to be regulated by specific strains of bacteria in mouse models. Smith et al. (p. 569 , published online 4 July; see the Perspective by Bollrath and Powrie ) asked whether metabolite(s) generated by resident bacterial species may regulate T regs in the gut. Indeed, short-chain fatty acids (SCFAs), bacterial fermentation products of dietary fibers produced by a range of bacteria, restored colonic T reg numbers in mice devoid of a gut microbiota and increased T reg numbers in colonized mice. The effects of SCFAs on T regs were mediated through GPCR43, a receptor for SCFAs, which is expressed on colonic T regs . Mice fed SCFAs were protected against experimentally induced colitis in a manner that was dependent on GPR43-expressing T regs . , Bacterial fermentation products regulate the number and function of regulatory T cells in the mouse colon. [Also see Perspective by Bollrath and Powrie ] , Regulatory T cells (T regs ) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate T reg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic T regs . We determined that short-chain fatty acids, gut microbiota–derived bacterial fermentation products, regulate the size and function of the colonic T reg pool and protect against colitis in a Ffar2 -dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.
From the gut to the lung: microbiota-associated metabolites as regulators of respiratory immunometabolism
The development and progression of respiratory diseases are influenced by both the local pulmonary microenvironment and the intestinal ecosystem. Research on the gut-lung axis has shown that diverse small-molecule metabolites produced or modified by the gut microbiota can cross the intestinal barrier and enter the systemic circulation, where they may modulate immune-cell response thresholds, functional polarisation, and inflammatory dynamics in the distal lung. The local respiratory microbiota may also contribute to the pulmonary metabolic microenvironment, although its role in metabolite production and immune regulation remains less clearly defined.
Gut microbiota and bone metabolism
Abstract Osteoporosis is the most common metabolic skeletal disease. It is characterized by the deterioration of the skeletal microarchitecture and bone loss, leading to ostealgia, and even bone fractures. Accumulating evidence has indicated that there is an inextricable relationship between the gut microbiota (GM) and bone homeostasis involving host–microbiota crosstalk. Any perturbation of the GM can play an initiating and reinforcing role in disrupting the bone remodeling balance during the development of osteoporosis. Although the GM is known to influence bone metabolism, the mechanisms associated with these effects remain unclear. Herein, we review the current knowledge of how the GM affects bone metabolism in health and disease, summarize the correlation between pathogen‐associated molecular patterns of GM structural components and bone metabolism, and discuss the potential mechanisms underlying how GM metabolites regulate bone turnover. Deciphering the complicated relationship between the GM and bone health will provide new insights into the prevention and treatment of osteoporosis.
Mucus barrier, mucins and gut microbiota: the expected slimy partners?
The gastrointestinal tract is often considered as a key organ involved in the digestion of food and providing nutrients to the body for proper maintenance. However, this system is composed of organs that are extremely complex. Among the different parts, the intestine is viewed as an incredible surface of contact with the environment and is colonised by hundreds of trillions of gut microbes. The role of the gut barrier has been studied for decades, but the exact mechanisms involved in the protection of the gut barrier are various and complementary. Among them, the integrity of the mucus barrier is one of the first lines of protection of the gastrointestinal tract. In the past, this ‘slimy’ partner was mostly considered a simple lubricant for facilitating the progression of the food bolus and the stools in the gut. Since then, different researchers have made important progress, and currently, the regulation of this mucus barrier is gaining increasing attention from the scientific community. Among the factors influencing the mucus barrier, the microbiome plays a major role in driving mucus changes. Additionally, our dietary habits (ie, high-fat diet, low-fibre/high-fibre diet, food additives, pre- probiotics) influence the mucus at different levels. Given that the mucus layer has been linked with the appearance of diseases, proper knowledge is highly warranted. Here, we debate different aspects of the mucus layer by focusing on its chemical composition, regulation of synthesis and degradation by the microbiota as well as some characteristics of the mucus layer in both physiological and pathological situations.
The gut microbiota in osteoarthritis: where do we stand and what can we do?
Osteoarthritis (OA) is one of the most frequent musculoskeletal diseases characterized by degeneration of articular cartilage, subchondral bone remodeling, and synovial membrane inflammation, which is a leading cause of global disability, morbidity, and decreased quality of life. Interpreting the potential mechanisms of OA pathogenesis is essential for developing novel prevention and disease-modifying therapeutic interventions. Gut microbiota is responsible for a series of metabolic, immunological, and structural and neurological functions, potentially elucidating the heterogeneity of OA phenotypes and individual features. In this narrative review, we summarized research evidence supporting the hypothesis of a “gut-joint axis” and the interaction between gut microbiota and the OA-relevant factors, including age, gender, genetics, metabolism, central nervous system, and joint injury, elucidating the underlying mechanisms of this intricate interaction. In the context, we also speculated the promising manipulation of gut microbiota in OA management, such as exercise and fecal microbiota transplantation (FMT), highlighting the clinical values of gut microbiota. Additionally, future research directions, such as more convincing studies by the interventions of gut microbiota, the gene regulation of host contributing to or attributed to the specific phenotypes of gut microbiota related to OA, and the relevance of distinct cell subgroups to gut microbiota, are expected. Moreover, gut microbiota is also the potential biomarker related to inflammation and gut dysbiosis that is able to predict OA progression and monitor the efficacy of therapeutic intervention.
The contribution of gut bacterial metabolites in the human immune signaling pathway of non-communicable diseases
The interaction disorder between gut microbiota and its host has been documented in different non-communicable diseases (NCDs) such as metabolic syndrome, neurodegenerative disease, and autoimmune ...
Probiotic <i>Lactobacillus reuteri</i> Prevents Postantibiotic Bone Loss by Reducing Intestinal Dysbiosis and Preventing Barrier Disruption
ABSTRACT Antibiotic treatment, commonly prescribed for bacterial infections, depletes and subsequently causes long-term alterations in intestinal microbiota composition. Knowing the importance of the microbiome in the regulation of bone density, we investigated the effect of postantibiotic treatment on gut and bone health. Intestinal microbiome repopulation at 4-weeks postantibiotic treatment resulted in an increase in the Firmicutes:Bacteroidetes ratio, increased intestinal permeability, and notably reduced femoral trabecular bone volume (approximately 30%, p < 0.01). Treatment with a mucus supplement (a high-molecular-weight polymer, MDY-1001 [MDY]) prevented the postantibiotic-induced barrier break as well as bone loss, indicating a mechanistic link between increased intestinal permeability and bone loss. A link between the microbiome composition and bone density was demonstrated by supplementing the mice with probiotic bacteria. Specifically, Lactobacillus reuteri, but not Lactobacillus rhamnosus GG or nonpathogenic Escherichia coli, reduced the postantibiotic elevation of the Firmicutes:Bacteroidetes ratio and prevented femoral and vertebral trabecular bone loss. Consistent with causing bone loss, postantibiotic-induced dysbiosis decreased osteoblast and increased osteoclast activities, changes that were prevented by both L. reuteri and MDY. These data underscore the importance of microbial dysbiosis in the regulation of intestinal permeability and bone health, as well as identify L. reuteri and MDY as novel therapies for preventing these adverse effects. © 2018 American Society for Bone and Mineral Research.
Host Immunity Influences the Composition of Murine Gut Microbiota
The influence of gut microbiota on host immunity is widely studied, and its disturbance has been linked to several immune-mediated disorders. Conversely, whether and how inherently disturbed canonical Th1 (pro-inflammatory) and/or Th2 (anti-inflammatory) immune pathways modify the host microbiome is not sufficiently investigated. Here, we characterized the humoral, cellular, and cytokine immunity, and associated alterations in gut microbiota of naïve wild-type mice (C57BL/6 and BALB/c), and mice with deficiencies in Th2 responses (IL-4Rα and IL-33 knockout mice) or in both Th1 and Th2 responses (NOD scid gamma, NSG mice). A global analysis by de novo clustering of 16S rRNA profiles of the gut microbiota independently grouped wild-type immunocompetent (C57BL/6 and BALB/c), Th2-deficient (IL-4Rα-/- and IL-33-/-), and severely immunodeficient (NSG) mice; where wild-type mice, but not Th2 or severely immunodeficient mice, were enriched in gut bacteria that produce short-chain fatty acids. These include members of phyla Firmicutes, Verrucomicrobia, and Bacteroidetes such as Lactobacillus spp., Akkermansia muciniphila, and Odoribacter spp. Further comparison of the two naïve wild-type mouse strains showed higher microbial diversity (Shannon), primarily linked to higher richness (Chao1), as well as a distinct difference in microbial composition (weighted UniFrac) in BALB/c mice compared to C57BL/6. T-cell and blood cytokine analyses demonstrated a Th1-polarization in naïve adaptive immunity in C57BL/6 animals compared to BALB/c mice, and an expected Th2 deficient cellular response in IL-4Rα-/- and IL-33-/- mice compared to its genetic background BALB/c strain. Together, these data suggest that alterations in the Th1/Th2 balance or a complete ablation of Th1/Th2 responses can lead to major alterations in gut microbiota composition and function. Given the similarities between the human and mouse immune systems and gut microbiota, our finding that immune status is a strong driver of gut microbiota composition has important consequences for human immunodeficiency studies.
Species-specific CD4+ T cells enable prediction of mucosal immune phenotypes from microbiota composition
Determining the mechanisms by which the gut microbiome modulates the host immune system has translational potential for treating or preventing immune-mediated diseases. A key challenge is identifying the immunogenic bacterial strains in the setting of a complex microbiota. We use a combination of anaerobic culturing, in vitro T cell assays, gnotobiotic mouse models, and ex vivo T cell restimulations to explore the influence of species and strain diversity on the specificity of mucosal T cells. Our approach efficiently predicts the relative impact of individual bacterial strains within a complex community and can be used to parse microbiota-dependent phenotypes into component fractions., How bacterial strains within a complex human microbiota collectively shape intestinal T cell homeostasis is not well understood. Methods that quickly identify effector strains or species that drive specific mucosal T cell phenotypes are needed to define general principles for how the microbiota modulates host immunity. We colonize germ-free mice with defined communities of cultured strains and profile antigen-specific responses directed toward individual strains ex vivo. We find that lamina propria T cells are specific to bacterial strains at the species level and can discriminate between strains of the same species. Ex vivo restimulations consistently identify the strains within complex communities that induce Th17 responses in vivo, providing the potential to shape baseline immune tone via community composition. Using an adoptive transfer model of colitis, we find that lamina propria T cells respond to different bacterial strains in conditions of inflammation versus homeostasis. Collectively, our approach represents a unique method for efficiently predicting the relative impact of individual bacterial strains within a complex community and for parsing microbiota-dependent phenotypes into component fractions.
Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation
In mice, provision of butyrate—a short-chain fatty acid produced by commensal microorganisms during starch fermentation—facilitates extrathymic generation and differentiation of Foxp3+ regulatory T cells, demonstrating that metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells.
Scientists bust myth that our bodies have more bacteria than human cells
Decades-old assumption about microbiota revisited.
The gut-bone axis: how bacterial metabolites bridge the distance
1Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
Gut microbiome atlas maps how bacteria establish themselves and shift in inflammatory bowel disease
Researchers created a microbiome-wide atlas mapping more than seven million colonization factor genes across 4,716 human gut microbial species, revealing three putative strategies linked to metabolism, stress resistance, and microbial communication. Applying the framework to inflammatory bowel disease showed that colonization-factor profiles can provide a compact, biologically interpretable view of disease-associated microbiome changes.
A challenge if anyone wants to take it up. Here is a recent review in the BMJ on the "Evidence for clinical interventions targeting the gut microbiome in cardiometabolic disease". There is not a single effect estimate reported in this review, or either supplemental file bmj.com/content/383/bmj-2023-075180
Evidence for clinical interventions targeting the gut microbiome in cardiometabolic disease
www.bmj.com