Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation

Center for Genome Sciences and Department of Medicine, Washington University School of Medicine, St. Louis, MO 63108, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2009; 106(27):11276-81. DOI: 10.1073/pnas.0902366106
Source: PubMed


Studies in mice indicate that the gut microbiota promotes energy harvest and storage from components of the diet when these components are plentiful. Here we examine how the microbiota shapes host metabolic and physiologic adaptations to periods of nutrient deprivation. Germ-free (GF) mice and mice who had received a gut microbiota transplant from conventionally raised donors were compared in the fed and fasted states by using functional genomic, biochemical, and physiologic assays. A 24-h fast produces a marked change in gut microbial ecology. Short-chain fatty acids generated from microbial fermentation of available glycans are maintained at higher levels compared with GF controls. During fasting, a microbiota-dependent, Ppar alpha-regulated increase in hepatic ketogenesis occurs, and myocardial metabolism is directed to ketone body utilization. Analyses of heart rate, hydraulic work, and output, mitochondrial morphology, number, and respiration, plus ketone body, fatty acid, and glucose oxidation in isolated perfused working hearts from GF and colonized animals (combined with in vivo assessments of myocardial physiology) revealed that the fasted GF heart is able to sustain its performance by increasing glucose utilization, but heart weight, measured echocardiographically or as wet mass and normalized to tibial length or lean body weight, is significantly reduced in both fasted and fed mice. This myocardial-mass phenotype is completely reversed in GF mice by consumption of a ketogenic diet. Together, these results illustrate benefits provided by the gut microbiota during periods of nutrient deprivation, and emphasize the importance of further exploring the relationship between gut microbes and cardiovascular health.

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    • "In mice, for example, starvation is known to alter the gut microbiota in a way that it confers health benefits to its host (Zhang et al., 2013). Furthermore, the gut microbiota is known to positively influence physiological responses of the host to starvation (Crawford et al., 2009). As strong fluctuations in food availability commonly occur in natural populations (Müller-Navarra & Lampert, 1996), this factor might be an important driver of host–microbiota interactions and can thus be highly relevant from an ecological perspective. "
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    • "One potential mechanism for the dysbiosis observed during cachexia in mice might be the associated reduction in food intake observed at the late stage of the disease. Food intake has been reported to influence the composition of the gut microbiota (Crawford et al., 2009), and it may be considered that this reduced food intake constitutes a confounding factor in this mouse model. However, one must consider that anorexia is a fully fledged hallmark of cachexia, and thus, it should be integrated into experimental models. "

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    • ". From the 18 , 177 OTUs generated for the full dataset ( 397 , 144 amplicons ; Supplemental Table 1 ) , representative sequences were chosen for classification by the RDP Classifier at 80% confidence intervals using QIIME ( Wang et al . , 2007 ) . Alpha - diversity was calculated in QIIME to generate rarefaction curves ( Supplemental Figure 3 ) ( Crawford et al . , 2009 ; Caporaso et al . , 2010 ) and Shannon diversity ( H ' ) and Chao1 indices were calculated in the computer program R using the package phyloseq ( version 1 . 10 . 0 ) ( McMurdie and Holmes , 2013 ) . Higher numbers for both indices indicate greater OTU - level richness . All OTUs shared between samples were compared for presence / abse"
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