Early-life Microbiome-Derived HCA Enhances Type 3 Immunity via FXR-dependent m⁶A RNA methylation

The gut microbiome plays a crucial role in the development of intestinal immunity during early life, but the underlying mechanisms remain largely unknown. Here, we found oxygen consumption in neonatal rats by S. boulardii accelerated the colonization of the microbiome and the development of type 3 immunity, which protected against S. typhimurium . Microbiome maturation increased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and elevated the levels of Hyocholic acid (HCA). HCA promotes the development of γδT and type 3 innate lymphoid cell (ILC3) by sustaining the stability of Rorc mRNA via the FXR-WTAP- N6-methyl-adenosine (m 6 A) axis. L. reuteri , a bacterium encoding BSH, was enriched by oxygen consumption in the intestine and promoted intestinal type 3 immunity. However, inhibition of BSH blocks the L. reuteri- induced development of intestinal type 3 immunity. These results reveal the role of microbiome-derived HCA in the regulation of intestinal type 3 immunity during early life.