Regulation of gut microbiome by extracellular phospholipases

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22483
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Murakami Makoto 東京大学, 大学院医学系研究科(医学部), 教授 (60276607)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: 脂質 / 酵素 / 腸内細菌叢 / アレルギー / メタボローム

Outline of Final Research Achievements

Besides modifying inflammation by mobilizing lipid mediators, secreted phospholipase A2 (sPLA2) prevents bacterial infection by degrading bacterial membranes. In this study, we found that despite the restricted intestinal expression of sPLA2-IIA and -X, their genetic deletions altered the susceptibility to cancer, allergy or obesity in distal skin and adipose tissue. Metagenome, transcriptome and metabolome analyses revealed that the deficiency of these sPLA2s altered the gut microbiota, accompanied by notable changes in various blood metabolites and fecal bacterial lipids. The phenotypes in distal tissues were lost when the knockout mice were co-housed with littermate wild-type mice, or when they were housed in a more stringent pathogen-free facility. Thus, our results highlight a new aspect of the sPLA2 family as a modulator of gut microbiota, perturbation of which affects host responses in distal tissues.

Free Research Field

生物系薬学

Academic Significance and Societal Importance of the Research Achievements

近年、腸内細菌叢の組成変化が腸疾患だけでなく遠隔組織の病態にも波及することが注目されている。したがって、腸内細菌叢が宿主に及ぼす影響とそのメカニズムを解明することは、国民のQOL向上を目指す上で学術的にも社会的にも重要である。本研究は細胞外リン脂質代謝酵素sPLA2の動作原理に関する概念を大きく転換させるものであり、脂質や腸内細菌叢の研究領域への学術的貢献度は高い。また社会的には、将来的にsPLA2の機能介入を通じて腸内細菌叢と宿主の相互作用をプレバイオティクスやプロバイオティクスにより人為的に調節できれば、新しい機序に基づく健康食品・医薬品の開発に結びつくことも期待される。