GSE169006
Lysophosphatidylserines derived from microbiota in Crohn's disease elicit pathological Th1 response
Microbiota alteration and IFN-?-producing CD4+ T cell overactivation are implicated in Crohn's disease (CD) pathogenesis. However, it remains unclear how dysbiosis enhances Th1 responses, leading to intestinal inflammation. Here, we identified key metabolites that are derived from dysbiotic microbiota and induce enhanced Th1 responses and severe colitis in mouse models. Patients with CD showed elevated lysophosphatidylserine (LysoPS) concentration in their feces, accompanied with a higher relative abundance of microbiota possessing a gene encoding the phospholipid-hydrolyzing enzyme phospholipase A. LysoPS induced metabolic reprograming, thereby eliciting aberrant effector responses in both human and mouse IFN-?-producing CD4+ T cells. Administration of LysoPS into T cell-dependent mouse colitis models induced severe inflammation. LysoPS-induced aggravation of colitis was impaired in mice lacking P2ry10 and P2ry10b, and their CD4+ T cells were hypo-responsive to LysoPS. Thus, our findings elaborate on the mechanism by which metabolites elevated in patients with CD harboring dysbiotic microbiota induce intestinal pathology. Overall design: RNA sequencing was performed on Illumina NovaSeq 6000 for naive_T_cells and HiSeq 2500 platforms for PMA_Iono_LysoPS cells and in 101 and 75-base single-end mode, respectively. Colonic CD4+ T cells, such as naive T cells, effector T cells, and regulatory T cells were performed RNA sequence analysis.