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Lysophosphatidylserines Derived from Microbiota in Crohn’s Disease Elicit Pathological Th1 Response
Hisako Kayama1, Yuriko Otake2, Hideki Iijima2, Kiyoshi Takeda11 Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
2 Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Background: Crohn’s disease (CD), the main inflammatory bowel disease (IBD) clinical phenotype, is a chronic gastrointestinal tract disorder with transmural inflammation with unknown etiology. The accumulation of T helper 1 (Th1) cells that produce pro-inflammatory cytokines, such as interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, in the intestine is associated with CD severity. Along with dysregulated host immune responses, microbial community alterations, referred to as dysbiosis, are a feature of CD. However, the mechanisms by which a dysbiotic microbiota induces IFN-gamma-producing CD4+ T cells remains unclear.
Aims: We previously reported that some lysophospholipid species were elevated in the plasma of patients with CD. Therefore, we attempted to identify the mechanism of action of dysbiosis-dependent lipid metabolites on the gut immunity in this study.
Methods: We performed lipidomic analysis and shotgun metagenomic sequencing using fecal samples from healthy individuals and patients with CD. In addition, we analyzed effects of bioactive lipid lysophosphatidylserine (LysoPS) on differentiation and activation of human and murine IFN-gamma-producing CD4+ T cells in in vivo and in vitro.
Results: Patients with CD showed elevated 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-gamma-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.
Conclusions: Our study provides evidence for the contribution of LysoPS to intestinal inflammation development or progression via perturbations of host adaptive immunity. Regulation of lipid metabolites, including leukotrienes and prostaglandins, is an emerging therapeutic approach for inflammatory disorders. Thus, the bioactive lipid LysoPS could be a putative diagnostic biomarker and a therapeutic target for CD.
This work was funded by CREST, Japan Agency for Medical Research and Development (19gm1010004) and The National Cancer Center Research and Development Fund (No. 28-A-7) ( K. Takeda), Grant-in-Aid for Scientific Research (B) (17H04159) (to H. Iijima), Scientific Research (C) (17K08881) and PRIME, Japan Agency for Medical Research and Development (19gm6210016) (to H. Kayama).
Speakers
Hisako Kayama