GPR31-dependent dendrite protrusion of intestinal CX3CR1+ cells by bacterial metabolites

Small intestinal mononuclear cells that express CX3CR1 (CX3CR1(+) cells) regulate immune responses(1-5). CX3CR1(+) cells take up luminal antigens by protruding their dendrites into the lumen(1-4,6). However, it remains unclear how dendrite protrusion by CX3CR1(+) cells is induced in the intestine. Here we show in mice that the bacterial metabolites pyruvic acid and lactic acid induce dendrite protrusion via GPR31 in CX3CR1(+) cells. Mice that lack GPR31, which was highly and selectively expressed in intestinal CX3CR1(+) cells, showed defective dendrite protrusions of CX3CR1(+) cells in the small intestine. A methanol-soluble fraction of the small intestinal contents of specific-pathogen-free mice, but not germ-free mice, induced dendrite extension of intestinal CX3CR1(+) cells in vitro. We purified a GPR31-activating fraction, and identified lactic acid. Both lactic acid and pyruvic acid induced dendrite extension of CX3CR1(+) cells of wild-type mice, but not of Gpr31b(-/-) mice. Oral administration of lactate and pyruvate enhanced dendrite protrusion of CX3CR1(+) cells in the small intestine of wild-type mice, but not in that of Gpr31b(-/-) mice. Furthermore, wild-type mice treated with lactate or pyruvate showed an enhanced immune response and high resistance to intestinal Salmonella infection. These findings demonstrate that lactate and 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.