ABSTRACTMetabolic maladaptation in dairy cows after calving can lead to long-term elevation of ketones, such as β-hydroxybutyrate (BHB), representing the condition known as hyperketonemia, which greatly influences the health and production performance of cows during the lactation period. Although the gut microbiota is known to alter in dairy cows with hyperketonemia, the association of microbial metabolites with development of hyperketonemia remains unknown. In this study, we performed a multi-omics analysis to investigate the associations between fecal microbial community, fecal/plasma metabolites, and serum markers in hyperketonemic dairy cows during the transition period. Dynamic changes in the abundance of the phyla Verrucomicrobiota and Proteobacteria were detected in the gut microbiota of dairy cows, representing an adaptation to enhanced lipolysis and abnormal glucose metabolism after calving. Random forest and univariate analyses indicated that Frisingicoccus is a key bacterial genus in the gut of cows during the development of hyperketonemia, and its abundance was positively correlated with circulating branched-chain amino acid levels and the ketogenesis pathway. Taurodeoxycholic acid, belonging to the microbial metabolite, was strongly correlated with an increase in blood BHB level, and the levels of other secondary bile acid in the feces and plasma were altered in dairy cows prior to the diagnosis of hyperketonemia, which link the gut microbiota and hyperketonemia. Our results suggest that alterations in the gut microbiota and its metabolites contribute to excessive lipolysis and insulin insensitivity during the development of hyperketonemia, providing fundamental knowledge about manipulation of gut microbiome to improve metabolic adaptability in transition dairy cows.IMPORTANCEAccumulating evidence is pointing to an important association between gut microbiota-derived metabolites and metabolic disorders in humans and animals; however, this association in dairy cows from late gestation to early lactation is poorly understood. To address this gap, we integrated longitudinal gut microbial (feces) and metabolic (feces and plasma) profiles to characterize the phenotypic differences between healthy and hyperketonemic dairy cows from late gestation to early lactation. Our results demonstrate that cows underwent excessive lipid mobilization and insulin insensitivity before hyperketonemia was evident. The bile acids are functional readouts that link gut microbiota and host phenotypes in the development of hyperketonemia. Thus, this work provides new insight into the mechanisms involved in metabolic adaptation during the transition period to adjust to the high energy and metabolic demands after calving and during lactation, which can offer new strategies for livestock management involving intervention of the gut microbiome to facilitate metabolic adaptation.
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