Life science
Medical & healthcare, Drug development

Development of therapeutic strategy for Crohn’s diseaseby targeting microbiota-derived metabolites
Institute for Advanced Co-Creation Studies
Associate Professor Hisako Kayama

https://researchmap.jp/0425Kayama_Hisako?lang=en

Department of Microbiology and Immunology, Graduate School of Medicine
Professor Kiyoshi Takeda					https://researchmap.jp/read0118278?lang=en

Life science

Abstract
The number of patients with inflammatory bowel diseases (IBD),
such as Crohn’s disease (CD), has been increasing worldwide.
IBD patients are shown to harbor dysbiotic microbial communities
associated with alterations of intestinal metabolite concentrations.
The enzymes phospholipase A generates lysoglycerophospholipids and release free fatty acids by hydrolyzing cell membrane glycerophospholipid. Among lysoglycerophospholipids, concentrationsof lysophosphatidylserine (LysoPS) and lysophosphatidylcholine
are elevated in the stool and blood of patients with CD. However,
the roles of lysoglycerophospholipids in the pathogenesis of CDremains poorly understood. We found that LysoPS promotes Th1
responses by the P2Y10 receptor-mediated promotion of glycolysis, thereby exaggerating intestinal pathology. These results reveal
the mechanism exacerbating Th1-meditaed intestinal pathology
through modulation of Th1 cell metabolism and may serve to identify therapeutic targets for CD.

accumulation of dysbiotic microbiota-derived LysoPS to intestinal
inflammation progression via perturbations of host Th1 immunity
through promoting glycolysis. Modulation of glycolysis in lymphocytes and myeloid cells by small molecule dimethyl fumarate abrogates chemically induced colitis in mice. Thus, LysoPS, P2Y10
receptor, and glycolysis could be a putative therapeutic target forCD.

▍ Background & Results
Dysbiosis-mediated alterations of intestinal metbolites andIFN-γ-producing CD4 + T cell overactivation are implicated in
Crohn’s disease (CD) pathogenesis. However, it remains unclear
how dysbiotic microbiota-derived metabolites enhance Th1 responses, leading to intestinal inflammation. We previously reported that some lysophospholipid species, including LysoPS, wereelevated in the plasma of patients with CD. However, much less isknown about how lysophospholipids are generated in the intestine
and whether they modulate intestinal immune reposes.
Patients with CD showed elevated concentrations of 18:0 LysoPS
and 18:1 LysoPS in their feces compared with those in healthy controls, accompanied by a higher relative abundance of microbiota
possessing a gene encoding the phospholipid-hydrolyzing enzyme
phospholipase A. LysoPS induced metabolic reprogramming (promotion of glycolysis), thereby eliciting aberrant effector responses
in both human and mouse IFN-γ-producing CD4+ T (Th1) cells. We
found that activation level of glycolysis in effector memory CD4+T cells from the blood positively correlated with fecal18:1 LysoPS
concentration in patients with CD, suggesting that dysbiotic microbiota-derived LysoPS promotes glycolysis in effector memory T cells.
Administration of 18:1 LysoPS into mouse colitis models promoted large intestinal inflammation. LysoPS-induced aggravation ofcolitis was impaired in mice lacking P2ry10 and P2ry10b, and theirCD4+ T cells were hyporesponsive to LysoPS. Thus, our findings
elaborate on the mechanism by which metabolites elevated in patients with CD harboring dysbiotic microbiota promote Th1-mediated intestinal pathology.

▍ Significance of the research and Future perspective

Figure 1: LysoPS-mediated promotion of glycolytic activity in Tcells from patients with CD.
Basal and maximum levels of the extracellular acidification
rate (ECAR: glycolytic activity index) in effector memory CD4+
T cells positively correlated with fecal LysoPS concentration.

Figure 2: Dysbiotic microbiota-derived LysoPS progresses Crohn’s disease.
Lysophosphatidylserines (LysoPS) generated by E. coli possessing
ECSF_3660 gene encoding phospholipase A elicit immunopathologicalTh1 cell response through P2Y10 receptor-mediated modulation of glycolysis, thereby leading to progression of Crohn’s disease.

Our study provides evidence for the contribution of excessive

P a t e n t
Tr e a t i s e

Otake-Kasamoto, Yuriko; Kayama, Hisako; Takeda, Kiyoshi et al. Lysophosphatidylserines derived from microbiota in Crohn’s disease elicit pathologicalTh1 response. J Exp Med. 2022, 219(7), e20211291. doi: 10.1084/jem.20211291

URL
K e y w o r d Crohn’s disease, P2Y10 receptor, lysophosphatidylserine, Th1 cell, glycolysis