Regulatory T cells are induced by gut microbiota through differentially regulating costimulatory molecules of enteric glial cells.

Probiotics have been proven to be effective in inducing and maintaining remission of inflammatory bowel disease (IBD). However, their precise mechanisms remain unclear. Interactions between the gut microbiota and enteric glial cells (EGCs) have gained increasing attention. We aimed to investigate whether and how Bifidobacterium longum (B.l), as a typical probiotic, exerts anti-inflammatory effects by acting on EGCs. Herein, we demonstrate that EGCs possess bacterial phagocytosis and antigen-presenting functions, and their costimulatory molecule expression is differentially regulated by bacteria. Specifically, B.l significantly upregulates EGC expression of programmed death-ligand 1 (PD-L1), while enterohemorrhagic Escherichia coli (EHEC) markedly increases CD86 expression. B.l ameliorates dextran sulfate sodium (DSS)-induced experimental colitis by activating the p38 MAPK signaling pathway, upregulating PD-L1 expression in EGCs, and inducing the conversion of CD4+ cells into regulatory T (Treg) cells through the PD-L1/PD-1 pathway. This process promotes Treg cell expansion, inhibits pathogenic T-helper type 17 (Th17) cells, increasing IL-10 production, and reduces TNF-α and IL-1β production. Notably, ablation of EGCs significantly diminishes the efficacy of B.l in alleviating experimental colitis. In conclusion, our findings suggest that B.l induces the conversion of CD4+ cells into Treg cells by acting on EGCs and alleviating intestinal inflammation. These findings support the notion that EGCs are not only neural cells but also potential immune cells, which exert immune regulatory functions depending on the type of bacteria and which signaling molecules are being expressed. This study provides new data for elucidating the mechanisms of probiotics in the treatment of IBD.NEW & NOTEWORTHY The interactions between gut microbiota and enteric glial cells (EGCs) are increasingly recognized. This study reveals that EGCs possess bacterial phagocytosis and antigen-presentation functions, which are modulated differently by various bacteria. Specifically, Bifidobacterium longum (B.l) relieves DSS-induced colitis by enhancing PD-L1 expression on EGCs and promoting Treg cell differentiation through EGC-mediated immune regulation. Understanding the dual role of EGCs as both neural and immune cells expands our comprehension of gut microbiota-neural-immune interaction in intestinal health.