Identification of microbiota-derived metabolites that regulate the host immunity

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H04028
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Osaka University
• Principal Investigator: Takeda Kiyoshi 大阪大学, 医学系研究科, 教授 (20309446)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 粘膜免疫

Outline of Final Research Achievements

Small intestinal mononuclear cells expressing CX3CR1 (CX3CR1+ cells) uptake luminal antigens by protruding their dendrites into the lumen. Mice lacking GPR31, which was highly and selectively expressed in intestinal CX3CR1+ cells, showed defective dendrite protrusions of CX3CR1+ cells in the small intestine. We purified a GPR31-activating fraction of intestinal content. Both lactic acid and pyruvic acid induced dendrite extension of CX3CR1+ cells of wild-type mice, but not GPR31-deficient mice. Oral administration of lactate/pyruvate enhanced dendrite protrusion of CX3CR1+ cells in the intestine of wild-type mice, but not GPR31-deficient mice. Lactate/pyruvate-treated wild-type mice showed enhanced immune response and high resistance to intestinal Salmonella infection. Thus, lactate/pyruvate, which are produced in the intestinal lumen in a bacteria-dependent manner, contribute to enhanced immune responses by inducing GPR31-mediated dendrite protrusion of intestinal CX3CR1+ cells.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

近年腸内細菌叢が我々宿主の生理機能に重要な役割を担っていることが明らかになってきた。しかしながら、消化管腔という体外で、腸管上皮のバリア機能により宿主細胞に接することなく棲息する腸内細菌叢が、宿主に作用するメカニズムは明らかになっていなかった。本研究で、腸内細菌叢が消化管腔で産生する代謝産物を介して宿主に作用していることが明らかになった。さらに、乳酸・ピルビン酸の経口投与が、消化管免疫系の強化につながることを明らかにしたことは、今後経口免疫強化剤の開発に資する成果と考えられる。