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

Abstract 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.