Abstract

While the link between diet-induced changes in gut microbiota and lipid metabolism in metabolic syndrome (MetS) has been established, the contribution of host genetics is rather unexplored. As several findings suggested a role for the lysosomal lipid transporter Niemann-Pick type C1 (NPC1) in macrophages during MetS, we here explored whether a hematopoietic Npc1 mutation, induced via bone marrow transplantation, influences gut microbiota composition in low-density lipoprotein receptor knockout (Ldlr−/−) mice fed a high-fat, high-cholesterol (HFC) diet for 12 weeks. Ldlr−/− mice fed a HFC diet mimic a human plasma lipoprotein profile and show features of MetS, providing a model to explore the role of host genetics on gut microbiota under MetS conditions. Fecal samples were used to profile the microbial composition by 16 s 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 suggests that host genetic influences on lipid metabolism affect the gut microbiome under MetS conditions. Future research investigating the role of host genetics on gut microbiota might therefore lead to identification of diagnostic and therapeutic targets for MetS.

Highlights

  • While the link between diet-induced changes in gut microbiota and lipid metabolism in metabolic syndrome (MetS) has been established, the contribution of host genetics is rather unexplored

  • The current study investigated whether a hematopoietic Npc[1] mutation influences the gut microbiota in low-density lipoprotein receptor knockout (Ldlr−/−) mice fed a high-fat, high-cholesterol (HFC) diet for 12 weeks

  • Subjecting Niemann-Pick type C1 mutant (Npc1mut)-tp Ldlr−/− mice to a HFC diet for 12 weeks resulted in a strong increase in hepatic cholesterol levels, while a reduction was observed for hepatic triglyceride levels (Table 1)

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Summary

Introduction

While the link between diet-induced changes in gut microbiota and lipid metabolism in metabolic syndrome (MetS) has been established, the contribution of host genetics is rather unexplored. As several findings suggested a role for the lysosomal lipid transporter Niemann-Pick type C1 (NPC1) in macrophages during MetS, we here explored whether a hematopoietic Npc[1] mutation, induced via bone marrow transplantation, influences gut microbiota composition in low-density lipoprotein receptor knockout (Ldlr−/−) mice fed a high-fat, high-cholesterol (HFC) diet for 12 weeks. While mutations in the gene encoding for the lysosomal membrane protein Niemann-Pick type C1 (NPC1) are well-known to induce a rare lysosomal storage disease, recent findings have linked a dysfunctional NPC1 protein to the development of obesity and MetS5,6. Low-grade inflammatory response in non-alcoholic steatohepatitis[14,15] and atherosclerosis[12,16,17,18] These findings imply a role for macrophage NPC1 in disturbing lipid homeostasis in MetS. Gaining knowledge into the exact interactions between environment and host genetics on gut microbiota and associated pathophysiological processes is essential to improve our diagnostic and therapeutic approaches to tackle metabolic pathologies

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