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.

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.