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Short-chain fatty acids (SCFAs), the end products of dietary fiber, influence the immune system. Moreover, during pregnancy the maternal microbiome has a great impact on the development of the offspring's immune system. However, the exact mechanisms by which maternal SCFAs during pregnancy and lactation influence the immune system of offspring are not fully understood. We investigated the molecular mechanisms underlying regulatory T cell (T reg ) differentiation in offspring regulated by a maternal high fiber diet (HFD). Plasma levels of SCFAs in offspring from HFD-fed mice were higher than in those from no fiber diet-fed mice. Consequently, the offspring from HFD-fed mice had higher frequencies of thymic T reg (tT reg ) and peripheral T regs We found that the offspring of HFD-fed mice exhibited higher autoimmune regulator (Aire) expression, a transcription factor expressed in the thymic microenvironment, suggesting SCFAs promote tT reg differentiation through increased Aire expression. Notably, the receptor for butyrate, G protein-coupled receptor 41 (GPR41), is highly expressed in the thymic microenvironment and Aire expression is not increased by stimulation with butyrate in GPR41-deficient mice. Our studies highlight the significance of SCFAs produced by a maternal HFD for T reg differentiation in the thymus of offspring. Given that Aire expression is associated with the induction of tT regs , the maternal microbiome influences T reg differentiation in the thymus of offspring through GPR41-mediated Aire expression.

Maternal High Fiber Diet during Pregnancy and Lactation Influences Regulatory T Cell Differentiation in Offspring in Mice