The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic T _reg Cell Homeostasis

Abstract

Regulatory T cells (Tregs) 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 Treg 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 Tregs. We determined that short chain fatty acids (SCFA), gut microbiota-derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2(GPR43)-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota co-adaptation and promotes colonic homeostasis and health.

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

“…Interestingly, Foxp3 þ RORgt þ T cells also showed increased expression of Gpr15 and Ffar2, the two receptors with fundamental roles especially in colonic Treg homeostasis. 28,29 To directly assess the tissue-homing capacity of Foxp3 þ RORgt þ T cells, we performed short-term homing assays using adoptive transfer of radiolabeled T cells into wild-type recipient mice. 30 Although Foxp3 þ RORgt þ T cells showed a slight tendency toward enhanced homing into mucosal tissues, overall the migration behavior was comparable to Foxp3 þ Tregs (Supplementary Figure S4).…”

Western lifestyle and immunopathology of multiple sclerosis

“…SCFAs were recently found to ameliorate EAE, as well as other autoimmune diseases, such as type 1 diabetes, by expanding lamina propria–derived T reg cells through suppression of the JNK1 and p38 pathway 98, 125. In line with these studies, SFCAs also increase the number of colonic T reg cells in an experimental model of inflammatory bowel disease 126, 127. In addition to controlling JNK1 and p38 signaling, SCFA may also function as histone deacetylase inhibitors, thereby potentially controlling the acetylation of T reg ‐associated genes 128…”

Impact of environmental factors on alloimmunity and transplant fate

“…For instance, bile acids were recently reported to reduce inflammation and metabolic syndrome by inhibiting the NLRP3 inflammasome (147). SCFAs induced the differentiation of colonic Tregs and maintained gut Treg homeostasis (148,149). A reduction in SCFA butyrate was observed after bone marrow transplantation (BMT), and its administration, or that of butyrate-producing Clostridia, improved intestinal epithelial cell junctional integrity and reduced GVHD (150).…”