Abstract
Obesity, insulin resistance and the metabolic syndrome are associated with changes to the gut microbiota; however, the mechanism by which modifications to the gut microbiota might lead to these conditions is unknown. Here we show that increased production of acetate by an altered gut microbiota in rodents leads to activation of the parasympathetic nervous system, which, in turn, promotes increased glucose-stimulated insulin secretion, increased ghrelin secretion, hyperphagia, obesity and related sequelae. Together, these findings identify increased acetate production resulting from a nutrient–gut microbiota interaction and subsequent parasympathetic activation as possible therapeutic targets for obesity.
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Primary accessions
European Nucleotide Archive
Data deposits
Sequence data are deposited to the European Nucleotide Archive with accession code PRJEB13505.
Change history
28 June 2016
The Reviewer Information section was included.
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Acknowledgements
We thank J. Dong, Y. Nozaki, W. Zhu, X. Zhao, J. Stack, M. Kahn, B. Lim, and Y. Kosover for technical assistance. This study was funded by grants from the National Institutes of Health (R01 DK-40936, R01 AG-23686, P30 DK-45735, U24 DK-59635, T32 DK-101019, R01 DK-92606, R01 GM-103574 and DP2 GM-105456) and the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.
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R.J.P., L.P., N.A.B., G.W.C., D.Z., and R.L.C. performed the in vivo and in vitro studies, and all authors analysed data. G.W.C., K.F.P., R.G.K., A.L.G., and G.I.S. provided critical advice for the experiments. Studies were designed and the manuscript was written by R.J.P. and G.I.S. with input from all authors.
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The authors declare no competing financial interests.
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Reviewer Information Nature thanks D. Piomelli, C. Wollheim and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
Extended Data Figure 2 HFD-fed rats exhibit increased gut acetate production.
a, Plasma triglycerides. b, HOMA-IR. c, Dietary acetate concentrations. n = 2 replicates per diet. d, Faecal acetate normalized to dry weight. e–g, Plasma propionate, whole-body propionate turnover, and faecal propionate concentrations. h–j, Plasma butyrate, whole-body butyrate turnover, and faecal butyrate concentrations. k, [13C]acetate enrichment in plasma of rats fed [13C]bicarbonate-labelled food and water. l, [U-13C]acetate from faeces incubated in [U-13C]glucose or fatty acids. m, In vitro acetate production rate from faeces incubated in [U-13C]glucose or fatty acids. n, In vitro acetate production rate in control, boiled, and UV-irradiated faecal samples. ****P < 0.0001 versus control. o, In vitro faecal acetate production following treatment with antibiotics. Unless otherwise specified, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus chow-fed rats; §§P < 0.01 versus 3-day HFD-fed rats by one-way ANOVA with Bonferroni’s multiple comparisons test. In k, data were compared by two-tailed unpaired Student’s t-test. In l–o, data are the mean ± s.e.m. of n = 4 per group, with comparisons to controls via two-tailed unpaired Student’s t-test (n). Unless otherwise specified, n = 6 replicates per group.
Extended Data Figure 3 HFD-fed rats exhibit increased GSIS driven by increased acetate turnover.
a, b, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus chow-fed rats. c, Plasma insulin area under the curve (AUC) during the hyperglycaemic clamp. d, Plasma acetate. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus 2 μmol kg−1 min−1 acetate; §§§§P < 0.0001 versus 8 μmol kg−1 min−1 acetate. e, f, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp. g, Plasma insulin AUC during the clamp. h, i, Plasma butyrate and whole-body butyrate turnover. *P < 0.05, ****P < 0.0001. j, k, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp. l, m, Plasma insulin concentrations during the hyperglycaemic clamp, and plasma insulin AUC. In all panels, data are the mean ± s.e.m. of n = 6 animals per group, with comparisons by one-way ANOVA with Bonferroni’s multiple comparisons test (a–g) or two-tailed unpaired Student’s t-test (h–m).
Extended Data Figure 4 Increasing total caloric intake leads to increased acetate turnover and GSIS via the microbiota in rats.
a, b, Plasma acetate and whole-body acetate turnover. c, d, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp. e, f, Plasma insulin and insulin AUC during the clamp. g, Caloric intake from protein, fat, and carbohydrate. In g–m, each group was compared to pair-fed, high-carbohydrate-fed rats. h, i, Plasma glucose and glucose infusion rate in the hyperglycaemic clamp. j, k, Plasma acetate and whole-body acetate turnover. l, m, Plasma insulin and insulin AUC during the hyperglycaemic clamp. n, Linear regression: whole-body acetate turnover versus total caloric intake in each diet group. o, p, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp in 4-week HFD-fed rats treated with broad-spectrum non-absorbable antibiotics. q, Plasma acetate. r, Plasma [13C]acetate enrichment following three days of feeding [13C]bicarbonate food and water. Data were compared using the two-tailed unpaired Student’s t-test. s, Insulin AUC during a hyperglycaemic clamp. In all panels, data are the mean ± s.e.m. of n = 6 rats per group, with groups compared by one-way ANOVA with Bonferroni’s multiple comparisons test, unless otherwise stated. In a–f, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus 12-h starved rats; §P < 0.05, §§P < 0.01, §§§P < 0.001, §§§§P < 0.0001 versus 48-h starved rats. In h–m, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus pair-fed rats given the high-carbohydrate diet. In o–s, ***P < 0.001, ****P < 0.0001 versus HFD-fed rats; §§§P < 0.001, §§§§P < 0.0001 versus antibiotics-treated rats.
Extended Data Figure 5 Faecal transplantation alters recipient microbiomes to resemble their donors as revealed by culture-independent 16S rRNA sequencing of faecal microbiomes from donors and recipients.
a, Relative abundance at the phylum level. Only phyla with relative abundance ≥ 0.1% in at least one group are shown. Data are the mean ± s.e.m. of n = 7–8 replicates per group; *P < 0.05 by 2-tailed unpaired Student’s t-test. b–f, Beta diversity analysis of faecal microbiomes before and after transplantation. The largest component of variation (captured by principal coordinate (PC)1) is shown in b and PC1–PC3 are shown in c–f. Rats from independent litters were randomized before diet administration or faecal transplantation. Beta diversity reflects principal coordinates analysis based on Hellinger distances; the results from unweighted, non-phylogenetic distance metrics and from phylogenetic metrics (weighted and unweighted UniFrac) are similar.
Extended Data Figure 6 The gut microbiota drive increased acetate turnover and GSIS.
a, b, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp in rats following faecal transplant replicates acetate turnover and GSIS in the donor group. c, Plasma acetate. d, Faecal acetate concentration. n = 7 (HFD to chow) or 8 (chow to chow, chow to HFD) per group. e, Plasma insulin AUC. f, Glucose-stimulated insulin release in isolated islets incubated with 400 μM acetate in a physiological buffer. n = 4 per group. g, Plasma C2 acetylcarnitine content. h, Glucose-stimulated insulin release in isolated islets incubated with 100 μM acetylcarnitine. i–m, Plasma alanine, leucine, arginine, glucagon, and GLP-1 concentrations. n, o, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp in acetate-infused rats treated with a GLP-1 inhibitor. p, q, Plasma acetate and whole-body acetate turnover. r, s, Plasma insulin and insulin AUC during the clamp. In all panels, data are mean ± s.e.m. of n = 6 per group. In a–e, ****P < 0.0001 versus chow-fed donor to chow-fed recipient transplants; §§§§P < 0.0001 versus chow-fed donor to HFD-fed recipient transplants by one-way ANOVA with Bonferroni’s multiple comparisons test. Data are the mean ± s.e.m. of n = 6 (HFD to chow) or 7 (chow to chow, chow to HFD) per group. In g–m, *P < 0.05, **P < 0.01 versus 2 μmol kg−1 min−1 acetate; §P < 0.05 versus 8 μmol kg−1 min−1 acetate by one-way ANOVA with Bonferroni’s multiple comparisons test. In g–s, data are the mean ± s.e.m. of n = 6 (unless otherwise specified) per group. In n–s, no significant differences were measured by the two-tailed unpaired Student’s t-test.
Extended Data Figure 7 Acetate drives GSIS via a CNS mechanism.
a, Body weight before and after vagotomy. b, c, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp. d, e, Plasma acetate and whole-body acetate turnover. f, Insulin AUC during the clamp. g, Plasma gastrin during the clamp. h, Plasma glucagon after 120 min of the clamp. h, i, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp in acetate-infused, atropine-treated rats. k, l, Plasma acetate and whole-body acetate turnover. m, Plasma insulin AUC during the clamp. n, Plasma glucagon. In all panels, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by the two-tailed unpaired Student’s t-test; data represent the mean ± s.e.m. of n = 6 replicates per group.
Extended Data Figure 8 Acetate drives GSIS via parasympathetic activation.
a, b, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp in rats treated with ICV acetate. c, Plasma insulin AUC. d, Plasma glucagon. e, f, Plasma acetate and whole-body acetate turnover in rats treated with systemic intra-arterial acetate and ICV methylatropine. g, h, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp. i, Plasma insulin AUC during the clamp. j, k, Plasma and brain tissue acetate in rats given an injection of acetate into the nucleus tractus solitarius. l, m, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp. n, Plasma insulin AUC during the clamp. o, Plasma glucagon. In all panels, data are the mean ± s.e.m. of n = 6 animals per group, with comparisons by one-way ANOVA with Bonferroni’s multiple comparisons test (a–i) or two-tailed unpaired Student’s t-test (j–o). In b–d, **P < 0.01, ***P < 0.001 versus controls; §§P < 0.01, §§§P < 0.001 versus ICV acetate-treated rats by one-way ANOVA with Bonferroni’s multiple comparisons test. In e–i, ***P < 0.001, ****P < 0.0001 versus controls; §§§P < 0.001, §§§§P < 0.0001 versus acetate-infused rats.
Extended Data Figure 9 Chronic intragastric acetate infusion causes hyperphagia and metabolic syndrome through parasympathetic activation.
a, b, Plasma acetate and whole-body acetate turnover. c, d, Plasma glucose and insulin concentrations during an intraperitoneal glucose tolerance test. e, Insulin AUC during the glucose tolerance test. f, g, Plasma glucose and glucose infusion rate during a hyperglycaemic clamp. h, Insulin AUC during the hyperglycaemic clamp. i, Body weight before and after the infusion study (n = 16 controls, 16 acetate-infused, and 12 acetate-infused and vagotomised rats). j, Caloric intake during the 10-day acetate infusion study. k, Homeostatic model assessment of insulin resistance (HOMA-IR). l, Plasma triglyceride concentrations. m, Plasma insulin at the 120-min time point of a hyperinsulinaemic–euglycaemic clamp. n, o, Plasma glucose and glucose infusion rate during the hyperinsulinaemic–euglycaemic clamp. p, Plasma glucagon. Unless otherwise specified, data are mean ± s.e.m. of n = 6 rats per group, with comparisons by one-way ANOVA with Bonferroni’s multiple comparisons test. In all panels, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus controls; §P < 0.05, §§P < 0.01, §§§P < 0.001, §§§§P < 0.0001 versus intragastric acetate-infused rats.
Extended Data Figure 10 Germ-free mice have negligible endogenous short-chain fatty acid production.
a, Ratio of tissue:plasma [13C]acetate in mice fed [13C]bicarbonate. b, c, Plasma and tissue propionate concentrations. d, Plasma [13C]propionate enrichment. e, f, Plasma and tissue butyrate. g, Plasma [13C]butyrate enrichment. h, i, Liver and muscle diacylglycerol concentrations. In all panels, data are the mean ± s.e.m. of n = 9 (GF) or n = 10 (CONV-D) mice per group, with comparisons by two-tailed unpaired Student’s t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus CONV-D mice on the same diet.
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Perry, R., Peng, L., Barry, N. et al. Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature 534, 213–217 (2016). https://doi.org/10.1038/nature18309
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DOI: https://doi.org/10.1038/nature18309
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