Microbiota metabolite taurodeoxycholic acid maintains intestinal tissue residency of innate lymphoid cells via engagement with P2Y10 receptor

Innate lymphoid cells (ILCs) play critical roles in innate immunity, epithelial barrier protection, and tissue homeostasis. However, the maintenance machinery of intestinal tissue residency of ILCs remains elusive. Here, we show that gut microbiota is necessary for the maintenance of intestinal tissue residency of ILCs. Microbiota metabolite taurodeoxycholic acid (TDCA) binds to P2Y10 receptor on ILCs to initiate downstream Ca²⁺ and RhoA signaling pathways. TDCA-P2Y10 engagement induces <i>Zfp414</i> transcription to prime expression of CD69 and integrin αE on ILCs, leading to intestinal residency of ILCs. Moreover, decreased levels of TDCA or P2Y10 deficiency abrogates the intestinal residency of ILCs, resulting in severer intestinal inflammation. Of note, TDCA administration can enhance intestinal tissue residency of ILCs and promote protection against intestinal inflammation. Thus, TDCA might be used as a potential drug to treat patients with inflammatory bowel disease.