Effect of exercise and butyrate supplementation on microbiota composition and lipid metabolism

in Journal of Endocrinology
Correspondence should be addressed to L Fu: lifu@tmu.edu.cn
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The composition and activity of the gut microbiota depend on the host genome, nutrition, and lifestyle. Exercise and sodium butyrate (NaB) exert metabolic benefits in both mice and humans. However, the underlying mechanisms have not been fully elucidated. This study aimed to examine the effect of exercise training and dietary supplementation of butyrate on the composition of gut microbiota and whether the altered gut microbiota can stimulate differential production of short-chain fatty acids (SCFAs), which promote the expression of SESN2 and CRTC2 to improve metabolic health and protect against obesity. C57BL/6J mice were used to study the effect of exercise and high-fat diet (HFD) with or without NaB on gut microbiota. Bacterial communities were assayed in fecal samples using pyrosequencing of 16S rRNA gene amplicons. Western blot was performed using relevant antibodies to detect the protein expressions in liver and HepG2 cell extracts. Exercise and butyrate administration significantly reversed metabolic dysfunctions induced by HFD (P < 0.05). The number of Firmicutes and the proportion of Firmicutes to Bacteroidetes order were predominant in all HFD groups (P = 0.001). Exercise and butyrate supplementation significantly inhibited the relative abundance of lipopolysaccharide-producing phyla (P = 0.001). SESN2 and CRTC2 expression in the liver of mice were significantly increased after exercise (P < 0.05) and/or supplementation of butyrate (P < 0.05). Exercise enhances butyrate-producing fecal bacteria and increases butyrate production and consequently improves lipid metabolism through the butyrate-SESN2/CRTC2 pathway. Excess butyrate may reduce the proportion of probiotics and reverse the metabolic effects.

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  • Supplemental Fig.1 Verified the validity of different treatment. Hepa1-6 cells were transfected with SESN2 adenovirus, Sesn2-siRNA or Crtc2-siRNA. Effect of different treatment on SESN2 and CRTC2 protein expression (A-C). Hepa1-6 and THP1 cells were treated with LPS followed by butyrate, and the expression of inflammatory cytokines including IL-1β and TNF-ɑ (D-E) were determined by Western blot. * vs C, p < 0.05; # vs LPS, p < 0.05.

 

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    Effects of different interventions on mice metabolism. Body weight (A), food intake (B), energy intake (C), liver weight (D), gWAT weight (E), fat mass (F), free fat mass (G), BMI (H), TC (I), TG (J), and FFA (K) were determined. Data are shown as mean ± s.d. * vs NC, P < 0.05; # vs HC, P < 0.05.

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    Effects of different interventions on metabolic endotoxemia and systemic chronic low-grade inflammation. Fasting plasma lipopolysaccharide (LPS) levels (A), cytokine concentrations in plasma (B, C and D). Butyrate in plasma and feces (E and F). Data are means ± s.d. * vs NC, P < 0.05; # vs HC, P < 0.05.

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    Effects of different interventions on gut microbiota composition. Anosim analysis confirmed the effectiveness of intervention on intestinal microbiota (A). Principal coordinate analysis (PCoA) and histogram for microbiota composition among groups (B and C). Heatmap of microbiota abundance (D). A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0122.

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    Linear discriminant analysis (LDA) score showing the most differentially significant abundant taxa enriched in microbiota from different groups. LDA score derived from LEfSe analysis, showing the biomarker taxa (LDA score of >2 and a significance of P < 0.05 determined by the Wilcoxon signed-rank test). A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0122.

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    Effects of 8-week HFD and butyrate supplementation on lipid metabolism in mouse liver with/without aerobic exercise. Effects on Sestrin2 and CRTC2 expression (A and B). Effects on lipid synthesis proteins (C, D and E) and lipolysis proteins (F, G and H). Data are shown as mean ± s.d. * vs NC, P < 0.05; # vs HC, P < 0.05.

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    Effects of LPS and butyrate sodium on Sestrin2/CRTC2 signaling pathway in HepG2 cell line. HepG2 cells were incubated with vehicle, LPS (100 µg/ml) or LPS (100 µg/ml) + sodium butyrate (But, 5 mM/L) for 24 h. Inflammatory cytokines IL-1β (A), TNF-α (B), lipid synthesis protein (C and D), lipolysis protein (E and F), and protein SESN2, CRTC2 were determined by Western blot. Data are shown as mean ± s.d. * vs NC, P < 0.05; # vs HC, P < 0.05.

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    Butyrate improved lipid metabolism via regulating SESN2/CRTC2 pathway. Hepa1-6 cells were treated with LPS or LPS + NaB followed by transfecting with SESN2 adenovirus, Sesn2-siRNA, or Crtc2-siRNA for 24 hours. SESN2, CRTC2 protein (A, B and G, H), lipid synthesis protein (C, D and I, J) and lipolysis protein (E, F and K, L) were determined by Western blot. * vs LPS, P < 0.05; # vs LPS + NaB, # vs LPS + Ad-SESN2, P < 0.05.

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