Gut Microbiota‐Derived Hyocholic Acid Enhances Type 3 Immunity and Protects Against <i>Salmonella enterica</i> Serovar Typhimurium in Neonatal Rats

This study investigates how microbiome colonization influences the development of intestinal type 3 immunity in neonates. The results showed that reduced oxygen levels in the small intestine of neonatal rats induced by Saccharomyces boulardii accelerated microbiome colonization and type 3 immunity development, which protected against Salmonella enterica serovar Typhimurium infection. Microbiome maturation increased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and hyocholic acid (HCA) levels. Furthermore, reducing oxygen levels in the intestine increased the abundance of Limosilactobacillus reuteri, a bacterium encoding BSH, and promoted intestinal type 3 immunity. However, inhibition of BSH blocked the L. reuteri-induced development of intestinal type 3 immunity. Mechanistically, HCA promoted the development of gamma-delta T cells and type 3 innate lymphoid cells by stabilizing the mRNA expression of RAR-related orphan receptor C via the farnesoid X receptor-WT1-associated protein-N6-methyl-adenosine axis. These results reveal that gut microbiota-derived HCA plays a crucial role in promoting the development of intestinal type 3 immunity in neonates. This discovery introduces potential therapeutic avenues for strengthening intestinal immunity in early life or treating bacterial infections by targeting microbial metabolites.