Male microbiota-associated metabolites restore macrophage apoptotic cell clearance function in female lupus-prone mice

Abstract

Abstract Systemic lupus erythematosus (SLE) has been linked to microbiota dysbiosis. We have previously shown that lupus-prone female and non-lupus-prone male BWF1 mice have significantly different gut microbiota compositions and metabolomic profiles. Transferring microbiota from male into female BWF1 mice suppresses disease. This protective phenotype is androgen dependent, as microbiota from castrated male BWF1 mice (i.e., lupus-prone) fails to protect against disease. This protection could be mediated via differential metabolite production. Metabolomic analyses of female, and castrated and intact male BWF1 feces identified >100 differentially produced metabolites including phytol and phytanic acid, byproducts of chlorophyll degradation that can act as RXR agonists. These metabolites were produced at higher levels in non-lupus-prone male mice than in lupus-prone female and castrated male mice. Their presence in male BWF1 mice correlated with higher levels of a bacterial family, Lachnospiraceae, which contains species that express chlorophyll-degrading enzymes. Feeding phytanic acid to female mice delayed kidney disease onset. This male microbiota metabolite may confer protection, in part, by improving splenic macrophage phagocytosis of apoptotic cells. Macrophage clearance of apoptotic debris (efferocytosis) is defective in SLE patients, and this is thought to drive disease progression. We found lupus-prone female and castrated male BWF1 mice also have defective macrophage efferocytosis and this defect could be corrected in vitro by phytanic acid treatment. Taken together, our data indicate that BWF1 male microbiota produce metabolites that enhance macrophage efferocytosis and protect against disease.