Commensal microbes in the gut maintain the mucosal immune system by regulating the differentiation and expansion of several types of T cells. Clostridia, a dominant class of commensal microbes, induce colonic regulatory T (Treg) cells that play a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms underlying the induction of colonic Treg cells by commensal microbes are unclear. One of the most important features of commensal bacteria is their metabolic activity. Intestinal bacteria actively consume indigestible materials and produce small-molecule metabolites that are used by host cells. Therefore, it was hypothesized that bacterial metabolites were responsible for the induction of colonic Treg cells. To test this hypothesis, a comparative metabolome analysis was performed. It revealed that luminal concentrations of short-chain fatty acids, which are produced by commensal bacteria through fermentation, positively correlated with the number of colonic Treg cells. Of the short-chain fatty acids present in the colon, butyrate induced the differentiation of colonic Treg cells both in vitro and in vivo and ameliorated the development of experimental colitis. Treatment of naive T cells with butyrate under Treg cell-polarizing conditions enhanced histone H3 acetylation in the promoter and conserved the non-coding sequences of Foxp3, suggesting that microbial-derived butyrate regulates the differentiation of colonic Treg cells through epigenetic modification. Next, the molecular entity responsible for the expansion and maturation of colonic Treg cells was elucidated. Germ-free mice colonized with gut microbiota upregulated the expression of DNA methylation adaptor Uhrf1 in colonic Treg cells. Mice with T cell-specific deficiency of Uhrf1 (Uhrf1-cKO mice) showed defective proliferation and functional maturation of colonic Treg cells. Global gene expression and DNA methylation analyses showed that Uhrf1 deficiency suppressed the expression of Cdkn1a (encoding cyclin-dependent kinase inhibitor 1A; also known as p21) through the hypomethylation of its promoter region, resulting in the cell cycle arrest of Treg cells. Consequently, Uhrf1-cKO mice spontaneously developed severe colitis. These results suggested that epigenetic silencing of Cdkn1a by Uhrf1 is required for the maintenance of immune homeostasis in the gut. Based on the above observations, it was concluded that colonization of the gut by commensal bacteria induces the differentiation, expansion, and functional maturation of colonic Treg cells, which in turn maintain immune homeostasis in the gut through epigenetic modification of helper T cells.
Gut microbiota play an important roles in host patho-physiological functions; however, whether or not they can affect brain function has not been extensively studied so far. Several recent works, including ours have shown that gut microbiota can affect the stress responses and behavioral phenotypes of the host. We here reviewed recent advances in this knowledge concerning, i.e. the interaction between gut microbiota and brain function, based on our series of experimental data series.
Colonization of gut microbiota of offspring occurs on the basis of maternal resident flora during the perinatal periods. The maternal gut microbiota links the relationship between mother and offspring, and an adequate relationship between mother and offspring is essential for the development of offspring. Many lines of evidences have shown that various environmental factors including maternal infection, maternal stress, and maternal high fat diet-induced obesity during the perinatal periods can influence the colonization of the gut microbiota of offspring, resulting in disturbance in the development of the brains of offspring. We performed an experiment in which the gut microbiota of pregnant mice was perturbed by the administration of non-absorbable antibiotics. The results showed that the disturbance of the maternal gut microbiota altered the behavior of the offspring. In this review, I discuss the possible function of maternal gut microbiota during the perinatal periods in the development of the brains of offspring.