Dysbiotic Gut Microbiota-Derived Metabolites and Their Role in Non-Communicable Diseases.

Dysbiosis, generally defined as the disruption to gut microbiota composition or function, is observed in most diseases, including allergies, cancer, metabolic diseases, neurological disorders and diseases associated with autoimmunity. Dysbiosis is commonly associated with reduced levels of beneficial gut microbiota-derived metabolites such as short-chain fatty acids (SCFA) and indoles. Supplementation with these beneficial metabolites, or interventions to increase their microbial production, has been shown to ameliorate a variety of inflammatory diseases. Conversely, the production of gut 'dysbiotic' metabolites or by-products by the gut microbiota may contribute to disease development. This review summarizes the various 'dysbiotic' gut-derived products observed in cardiovascular diseases, cancer, inflammatory bowel disease, metabolic diseases including non-alcoholic steatohepatitis and autoimmune disorders such as multiple sclerosis. The increased production of dysbiotic gut microbial products, including trimethylamine, hydrogen sulphide, products of amino acid metabolism such as p-Cresyl sulphate and phenylacetic acid, and secondary bile acids such as deoxycholic acid, is commonly observed across multiple diseases. The simultaneous increased production of dysbiotic metabolites with the impaired production of beneficial metabolites, commonly associated with a modern lifestyle, may partially explain the high prevalence of inflammatory diseases in western countries.

GPR109A expressed on medullary thymic epithelial cells affects thymic Treg development.

Regulatory T cells (Treg) maintain immune homeostasis due to their anti-inflammatory functions. They can be generated either centrally in the thymus or in peripheral organs. Metabolites such as short-chain fatty acids produced by intestinal microbiota can induce peripheral Treg differentiation, by activating G-protein-coupled-receptors like GPR109A. In this study, we identified a novel role for GPR109A in thymic Treg development. We found that Gpr109a-/- mice had increased Treg under basal conditions in multiple organs compared with WT mice. GPR109A was not expressed on T cells but on medullary thymic epithelial cells (mTECs), as revealed by single-cell RNA sequencing in both mice and humans and confirmed by flow cytometry in mice. mTECs isolated from Gpr109a-/- mice had higher expression of autoimmune regulator (AIRE), the key regulator of Treg development, while the subset of mTECs that did not express Gpr109a in the WT displayed increased Aire expression and also enhanced signaling related to mTEC functionality. Increased thymic Treg in Gpr109a-/- mice was associated with protection from experimental autoimmune encephalomyelitis, with ameliorated clinical signs and reduced inflammation. This work identifies a novel role for GPR109A and possibly the gut microbiota, on thymic Treg development via its regulation of mTECs.

Diet, commensal microbiota-derived extracellular vesicles, and host immunity.

The gut microbiota has co-evolved with its host, and commensal bacteria can influence both the host's immune development and function. Recently, a role has emerged for bacterial extracellular vesicles (BEVs) as potent immune modulators. BEVs are nanosized membrane vesicles produced by all bacteria, possessing the membrane characteristics of the originating bacterium and carrying an internal cargo that may include nucleic acid, proteins, lipids, and metabolites. Thus, BEVs possess multiple avenues for regulating immune processes, and have been implicated in allergic, autoimmune, and metabolic diseases. BEVs are biodistributed locally in the gut, and also systemically, and thus have the potential to affect both the local and systemic immune responses. The production of gut microbiota-derived BEVs is regulated by host factors such as diet and antibiotic usage. Specifically, all aspects of nutrition, including macronutrients (protein, carbohydrates, and fat), micronutrients (vitamins and minerals), and food additives (the antimicrobial sodium benzoate), can regulate BEV production. This review summarizes current knowledge of the powerful links between nutrition, antibiotics, gut microbiota-derived BEV, and their effects on immunity and disease development. It highlights the potential of targeting or utilizing gut microbiota-derived BEV as a therapeutic intervention.

Dysbiosis in imiquimod-induced psoriasis alters gut immunity and exacerbates colitis development.

Psoriasis has long been associated with inflammatory bowel disease (IBD); however, a causal link is yet to be established. Here, we demonstrate that imiquimod-induced psoriasis (IMQ-pso) in mice disrupts gut homeostasis, characterized by increased proportions of colonic CX3CR1hi macrophages, altered cytokine production, and bacterial dysbiosis. Gut microbiota from these mice produce higher levels of succinate, which induce de novo proliferation of CX3CR1hi macrophages ex vivo, while disrupted gut homeostasis primes IMQ-pso mice for more severe colitis with dextran sulfate sodium (DSS) challenge. These results demonstrate that changes in the gut environment in psoriasis lead to greater susceptibility to IBD in mice, suggesting a two-hit requirement, that is, psoriasis-induced altered gut homeostasis and a secondary environmental challenge. This may explain the increased prevalence of IBD in patients with psoriasis.

Dietary protein increases T-cell-independent sIgA production through changes in gut microbiota-derived extracellular vesicles.

Secretory IgA is a key mucosal component ensuring host-microbiota mutualism. Here we use nutritional geometry modelling in mice fed 10 different macronutrient-defined, isocaloric diets, and identify dietary protein as the major driver of secretory IgA production. Protein-driven secretory IgA induction is not mediated by T-cell-dependent pathways or changes in gut microbiota composition. Instead, the microbiota of high protein fed mice produces significantly higher quantities of extracellular vesicles, compared to those of mice fed high-carbohydrate or high-fat diets. These extracellular vesicles activate Toll-like receptor 4 to increase the epithelial expression of IgA-inducing cytokine, APRIL, B cell chemokine, CCL28, and the IgA transporter, PIGR. We show that succinate, produced in high concentrations by microbiota of high protein fed animals, increases generation of reactive oxygen species by bacteria, which in turn promotes extracellular vesicles production. Here we establish a link between dietary macronutrient composition, gut microbial extracellular vesicles release and host secretory IgA response.

Your Regulatory T Cells Are What You Eat: How Diet and Gut Microbiota Affect Regulatory T Cell Development.

Modern industrial practices have transformed the human diet over the last century, increasing the consumption of processed foods. Dietary imbalance of macro- and micro-nutrients and excessive caloric intake represent significant risk factors for various inflammatory disorders. Increased ingestion of food additives, residual contaminants from agricultural practices, food processing, and packaging can also contribute deleteriously to disease development. One common hallmark of inflammatory disorders, such as autoimmunity and allergies, is the defect in anti-inflammatory regulatory T cell (Treg) development and/or function. Treg represent a highly heterogeneous population of immunosuppressive immune cells contributing to peripheral tolerance. Tregs either develop in the thymus from autoreactive thymocytes, or in the periphery, from naïve CD4+ T cells, in response to environmental antigens and cues. Accumulating evidence demonstrates that various dietary factors can directly regulate Treg development. These dietary factors can also indirectly modulate Treg differentiation by altering the gut microbiota composition and thus the production of bacterial metabolites. This review provides an overview of Treg ontogeny, both thymic and peripherally differentiated, and highlights how diet and gut microbiota can regulate Treg development and function.

Dietary carbohydrate, particularly glucose, drives B cell lymphopoiesis and function.

While diet modulates immunity, its impact on B cell ontogeny remains unclear. Using mixture modeling, a large-scale isocaloric dietary cohort mouse study identified carbohydrate as a major driver of B cell development and function. Increasing dietary carbohydrate increased B cell proportions in spleen, mesenteric lymph node and Peyer's patches, and increased antigen-specific immunoglobulin G production after immunization. This was linked to increased B lymphopoiesis in the bone marrow. Glucose promoted early B lymphopoiesis and higher total B lymphocyte numbers than fructose. It drove B cell development through glycolysis and oxidative phosphorylation, independently of fatty acid oxidation in vitro and reduced B cell apoptosis in early development via mTOR activation, independently of interleukin-7. Ours is the first comprehensive study showing the impact of macronutrients on B cell development and function. It shows the quantitative and qualitative interplay between dietary carbohydrate and B cells and argues for dietary modulation in B cell-targeting strategies.