Microbiota Metabolite TDCA Sustains Intestinal ILC Residency via P2Y10

In a new Science Advances study, Xu et al. report a critical microbiota metabolite-GPCR pathway that anchors ILCs within the intestine (1). Using germ-free and antibiotic-treated mice, the authors revealed that normal microbiota are required for maintenance of ILC tissue residency and that microbiota disruption leads to ILC egress. Transcriptomic profiling identified P2Y10, a purinergic GPCR enriched on intestinal ILCs, and the microbiota-derived bile acid taurodeoxycholic acid (TDCA) as its ligand. TDCA–P2Y10 signaling activates Ca²⁺ and RhoA pathways, which induced Zfp414 transcription and subsequently promoted CD69 and integrin αE expression to tether ILCs in the mucosa. Genetic loss of P2ry10, Zfp414, or Itgae disrupted ILC residency and exacerbated colitis and bacterial infection in mouse models, whereas TDCA supplementation restored residency and improved protection. Consistent with this, the authors confirmed low expression of P2Y10 in samples from people with Crohn’s disease (CD) and referenced previous findings about decreased levels of TDCA in the guts of these patients.  

Together, this study identifies the TDCA–P2Y10–ZFP414 axis as a central regulator of ILC tissue residency and introduces TDCA administration as a potential therapeutic avenue for inflammatory bowel disease.