Disruption of hindgut microbiome homeostasis promotes postpartum energy metabolism disorders in dairy ruminants by inhibiting acetate-mediated hepatic AMPK-PPARA axis.

BACKGROUND: Postpartum energy metabolism disorders pose a significant challenge to the health and productivity of dairy ruminants, yet their underlying pathogenesis remains poorly understood. The critical role of the gut microbiota in regulating host metabolic processes via the "gut-liver axis" has garnered increasing attention, but its specific mechanisms in dairy ruminant energy metabolism disorders are still unclear. This study uses dairy cows as a model and employs a large-scale case-control analysis to systematically investigate the pathophysiological basis of postpartum energy metabolism disorders through the lens of the "gut-liver axis." RESULTS: Postpartum energy metabolism disorders in dairy cows are characterized by elevated blood β-hydroxybutyrate (BHB) and aspartate aminotransferase (AST) levels, and hepatic steatosis. A random forest model based on gut microbiota effectively predicts disease occurrence (AUC = 0.74). Multi-omics (metagenomics, metabolomics, and transcriptomics) analysis further identified key microbes, including Faecousia species (sp017465625 and sp017380435), Methanosphaera species (sp016282985), and Bifidobacterium globosum. These microbes regulate acetate concentration in the gut, which is significantly correlated with key genes in the hepatic PPAR and PI3K-AKT pathways, as well as with blood BHB levels. Primary hepatocyte culture experiments further confirmed that sodium acetate effectively inhibits hepatic fat deposition induced by mixed fatty acids through the hepatic AMPK-PPARA axis and reduces the production of BHB in the culture medium. CONCLUSION: This study demonstrates that key gut microbes and their metabolic product (acetate) inhibit the occurrence of metabolic disorders through the hepatic AMPK-PPARA axis. These findings provide new insights and potential therapeutic targets for understanding and mitigating postpartum metabolic disorders in dairy ruminants. Video Abstract.