Investigating the Role of the Gut Microbiome in the Systemic Fasting Metabolic Response

Abstract

With the increasing prevalence of metabolic disease globally, fasting has been identified as a potential tool to effectively improve metabolic health. Fasting drives pleiotropic effects across all organ systems, including altered metabolome profiles and gut microbiome composition. Both of these changes on their own can significantly impact metabolic health. Changes in metabolomics and microbiome composition are complex, as the host metabolome shapes microbiome composition via nutrient inputs, and the microbiome can affect the host metabolome via bacterial outputs. However, the interaction between these two areas in fasting has not been studied. Thus, this study sought to investigate potential causal roles of the gut microbiome in the systemic metabolic response to fasting. To carry out this task, we subjected mice with an intact or antibiotic-depleted microbiome to 48 hours of water-only fasting, followed by metabolomic profiling of multiple tissues and serum. We identified fasting-induced increases of fatty acids and acylcarnitines in intestinal content, with microbiome depletion-mediated blunting or exacerbation of the fasting effect. We also found significant changes in microbiome composition and gene expression related to fatty acid and acylcarnitine metabolism, suggesting possible mechanisms for the microbiome-mediated fasting effect. Finally, we found evidence suggesting that our observed murine patterns of fatty acid and acylcarnitine metabolism are relevant for human metabolism. Overall, these results suggest that the gut microbiome plays an important causal role in regulating fatty acid and acylcarnitine metabolism during fasting. This work serves to improve our understanding of how the diet and the microbiome of an individual interact to regulate the metabolic activity of the host.