Gut Microbiota Regulate Lipid Metabolism via the Bile Acid Pathway: Resistance to Hypoxia in Gansu Zokor (<i>Eospalax cansus</i>)

The Gansu zokor (Eospalax cansus), a subterranean rodent endemic to the Loess Plateau of China, exhibits remarkable adaptability to hypoxic environments. While gut microbiota are known to regulate lipid metabolism through bile acid (BA) pathways, this phenomenon has not been investigated in subterranean rodents exposed to hypoxia. This study employed 16SrRNA sequencing, targeted analysis of BA metabolites in colonic contents, and assessments of BA and lipid metabolites alongside molecular analyses in the liver and ileum under conditions of acute and chronic hypoxia in Gansu zokors. The results revealed that hypoxia altered the composition of gut microbiota and BA pools in Gansu zokors. Hypoxia-induced changes increased the abundance of gut microbiota associated with BA metabolism, thereby modulating lipid metabolism via farnesoid X receptor (FXR) signaling in the distal ileum and liver cells. Under acute hypoxia, FXR upregulated lipid synthesis and suppressed fatty acid β-oxidation by downregulating the carnitine palmitoyl-transferase1A (CPT1A) expression. Conversely, during chronic hypoxia, particularly under long-term exposure, FXR reduced lipid synthesis and enhanced fatty acid β-oxidation by upregulating acyl-CoA oxidase (ACOX1) expression. In both hypoxic conditions, FXR facilitated lipoprotein metabolism. In summary, this study elucidates that gut microbiota-mediated BA metabolic pathways contribute to the Gansu zokor's ability to maintain lipid metabolic homeostasis and adaptation to hypoxia.