Effect of hematopoietic NPC1 on gut microbiota composition

While the link between diet-induced changes in gut microbiota and lipid metabolism in metabolic syndrome (MetS) has been established, the exact contribution of non-dietary factors explaining this relation is unclear. As several findings suggested a role for the lysosomal lipid transporter Niemann-Pick type C1 (NPC1) in macrophages for disturbing lipid homeostasis in MetS, we here explored whether a hematopoietic Npc1 mutation also influences gut microbiota composition. To mimic a human plasma lipoprotein profile, low-density lipoprotein receptor knockout (Ldlr-/-) mice were fed a high-fat, high-cholesterol (HFC) diet for 12 weeks. Subsequently, they were transplanted with bone marrow from Niemann-Pick type C1 mutant (Npc1mut) mice, which are known to develop lysosomal lipid accumulation. As a control, Ldlr-/- mice were transplanted with wildtype (Npc1wt) bone marrow. Fecal samples were used to profile the microbial composition by 16s ribosomal RNA gene sequencing. The hematopoietic Npc1 mutation shifted the gut microbiota composition and increased microbial richness and diversity. Variations in plasma lipid levels correlated with microbial diversity and richness as well as with several bacterial genera. This study shows that non-dietary disturbances in lipid metabolism such as a hematopoietic Npc1 mutation affect the gut microbiome. Future research investigating the role of non-dietary factors (such as host genetics) on gut microbiota can therefore lead to identification of novel diagnostic and therapeutic targets for MetS.