The study investigates the role of short-chain fatty acids (SCFAs) produced by commensal bacteria in promoting the generation of regulatory T (Treg) cells. The authors found that butyrate, a SCFA produced during starch fermentation, enhances the differentiation of extrathyMIC Treg cells. This effect is dependent on the intronic enhancer CNS1, which is essential for extrathyMIC but not thymic Treg cell differentiation. Propionate, another SCFA, also potentiates Treg cell generation, while acetate does not. The study demonstrates that SCFAs mediate communication between the commensal microbiota and the immune system, influencing the balance between pro- and anti-inflammatory responses. In vivo experiments show that butyrate administration to antibiotic-treated mice increases peripheral Treg cell numbers, particularly in the spleen and lymph nodes, without affecting colonic Treg cells. Butyrate promotes Treg cell generation by enhancing Foxp3 protein acetylation, which stabilizes and enhances Foxp3 function. Additionally, butyrate-pretreated dendritic cells (DCs) have a superior ability to induce Foxp3 expression in naïve CD4+ T cells. The study concludes that SCFAs produced by commensal bacteria play a crucial role in regulating Treg cell generation and immune homeostasis.The study investigates the role of short-chain fatty acids (SCFAs) produced by commensal bacteria in promoting the generation of regulatory T (Treg) cells. The authors found that butyrate, a SCFA produced during starch fermentation, enhances the differentiation of extrathyMIC Treg cells. This effect is dependent on the intronic enhancer CNS1, which is essential for extrathyMIC but not thymic Treg cell differentiation. Propionate, another SCFA, also potentiates Treg cell generation, while acetate does not. The study demonstrates that SCFAs mediate communication between the commensal microbiota and the immune system, influencing the balance between pro- and anti-inflammatory responses. In vivo experiments show that butyrate administration to antibiotic-treated mice increases peripheral Treg cell numbers, particularly in the spleen and lymph nodes, without affecting colonic Treg cells. Butyrate promotes Treg cell generation by enhancing Foxp3 protein acetylation, which stabilizes and enhances Foxp3 function. Additionally, butyrate-pretreated dendritic cells (DCs) have a superior ability to induce Foxp3 expression in naïve CD4+ T cells. The study concludes that SCFAs produced by commensal bacteria play a crucial role in regulating Treg cell generation and immune homeostasis.