Myeloid-specific NLRP12 is a checkpoint of colonic inflammation by promoting taurine-driven microbiota 2309979

Abstract Introduction Inflammatory bowel diseases (IBD) exhibit a global disease burden, with pathogenesis driven by the dynamic interplay of genetic susceptibility, gut microbial dysbiosis, and immune dysregulation. We studied the tissue-specific regulatory role of Nlrp12 in gut microbial dysbiosis and colonic inflammation and revealed a complex regulatory link of myeloid-specific NLRP12 and the promotion of taurine to induce colitis-mitigating bacteria while restraining bacterial species that exacerbate gut inflammation. Methods We generated Nlrp12flox/flox (Nlrp12fl/fl) mice and created both myeloids-specific cre and epithelial-specific cre mouse. We used both conventional mouse and germ-free mouse model. For acute colitis induction, we used DSS for 5 days and then regular drinking water. DSS-AOM was used for colorectal cancer model. ELISA and western blot were used to study cytokine production and signaling pathways. Fecal microbiome profiling was done by 16s rRNA sequencing. We also have human fecal sample and qPCR was used to quantify specific strains. Fecal microbiome transfer was used to study the causality between genetics, microbial species and colitis. Results Myeloid-specific , but not epithelial-specifc expression of NLRP12 is protective against colitis. Deficiency of Nlrp12 in myeloid cells has minimal effects on colorectal cancer. Myeloid-specific NLRP12 does not result in inflammasome activation in the colitis model. Deficiency of Nlrp12 in myeloid cells promotes microbial dysbiosis. Fecal microbiota transplantation from WT mice attenuates colonic inflammation in Nlrp12ΔMye mice. Allobaculum exacerbate DSS-induced colitis in GF mice. Human IBD patient samples demonstrate similar microbial signatures. Fecal metabolomic analysis reveals alterations in taurine and bile acid metabolism in Nlrp12ΔMye mice. Conclusion This work reveals the profound effect of a host innate immune checkpoint that functions in a cell-specific fashion to protect against metabolomics changes and dysbiosis. that leads to colitis. Funding Source NIH Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)