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. 2009 Jul 7;106(27):11276-81.
doi: 10.1073/pnas.0902366106. Epub 2009 Jun 22.

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

Peter A Crawford  1 , Jan R Crowley, Nandakumar Sambandam, Brian D Muegge, Elizabeth K Costello, Micah Hamady, Rob Knight, Jeffrey I Gordon
Affiliations

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

Peter A Crawford et al. Proc Natl Acad Sci U S A. .

Abstract

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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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Hepatic ketogenesis is enhanced during a 24-h fast by the gut microbiota. (A) Serum β-hydroxybutyrate levels in GF and CONV-D mice fed a standard CARB diet or after a 24-h fast. ***, P < 0.001; NS, not significant; n = 10 animals per condition. (B) Steady-state β-hydroxybutyrate levels in liver extracts. ***, P < 0.001; n = 6 animals per condition. (C–E) qRT-PCR assays of liver Pparα, Fgf21, and Hmgcs2 mRNA levels that are expressed relative to fed GF controls. *, P < 0.05; ***, P < 0.001 (n = 5–10 mice per condition; 2-way ANOVA with Bonferroni posthoc testing). Note that the difference in Fgf21 mRNA levels observed between GF- and CONV-D-fed animals does not reach statistical significance by ANOVA test.
Fig. 2.
Fig. 2.
Influence of the gut microbiota on myocardial substrate selection. Hearts from fasted WT GF or CONV-D animals were perfused for 60 min in the working mode by using Krebs–Henseleit buffer containing 1.7 mM β-hydroxybutyrate, 5 mM glucose, and 1.2 mM palmitate. (A) Oxidation of d-[14C(U)]-glucose; n = 5 animals per group. (B) Oxidation of [9,10]-3H-palmitate; n = 8 animals per group. (C) Oxidation of d-[14C(U)]-glucose in the absence of added β-hydroxybutyrate, n = 5 animals per group. *, P < 0.05; **, P < 0.01 (Student's t test).
Fig. 3.
Fig. 3.
Influence of the presence or absence of the gut microbiota on myocardial mass. (A) Echocardiographic measurement of left ventricular mass (LVM) in the fasting state normalized to tibial length (TL) in mm (n = 5 animals per group). (B and C). The reduction in myocardial mass [heart weight (HW)] normalized to tibial length (B), or to lean body mass [fat-free mass (FFM), as defined by MRI] (C), that is observed in GF mice fasted for 24 h after being maintained on a CARB diet, is abrogated in GF animals maintained on a ketogenic diet. *, P < 0.05; **, P < 0.01; ***, P < 0.001 (n = 8 animals in each fasting and ketogenic diet group, and 6 animals in each CARB-fed group; 2-way ANOVA with Bonferroni posthoc testing).
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