Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome

doi:10.1038/nature18309

. 2016 Jun 9;534(7606):213-7.

doi: 10.1038/nature18309.

Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome

Rachel J Perry¹, Liang Peng¹, Natasha A Barry^{2

3}, Gary W Cline¹, Dongyan Zhang⁴, Rebecca L Cardone¹, Kitt Falk Petersen^{1

5}, Richard G Kibbey^{1

6}, Andrew L Goodman^{2

3}, Gerald I Shulman^{1

4

5

6}

Affiliations

¹ Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
² Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
³ Microbial Sciences Institute, Yale University School of Medicine, New Haven, Connecticut 06516, USA.
⁴ Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06519, USA.
⁵ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark.
⁶ Department of Cellular &Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

PMID: 27279214
PMCID: PMC4922538
DOI: 10.1038/nature18309

Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome

Rachel J Perry et al. Nature. 2016.

. 2016 Jun 9;534(7606):213-7.

doi: 10.1038/nature18309.

Authors

Affiliations

¹ Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
² Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
³ Microbial Sciences Institute, Yale University School of Medicine, New Haven, Connecticut 06516, USA.
⁴ Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06519, USA.
⁵ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark.
⁶ Department of Cellular &Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

PMID: 27279214
PMCID: PMC4922538
DOI: 10.1038/nature18309

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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Conflict of interest statement

The authors declare no competing financial interests.

Figures

**Extended Data Fig. 1**
Mechanism by which a diet-microbiota interaction drives obesity and the metabolic syndrome.

**Extended Data Fig. 2**
HFD rats exhibit increased gut acetate production. (a) Plasma triglycerides. In all panels, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. chow fed rats; §§P<0.01 vs. 3 day HFD rats. (b) HOMA-IR. (c) Dietary acetate concentrations. n=2 replicates per diet. In panels (c) and (k), data were compared by the 2-tailed unpaired Student’s t-test. (d) Fecal acetate normalized to dry weight. (e)–(g) Plasma propionate, whole-body propionate turnover, and fecal propionate concentrations. (h)–(j) Plasma butyrate, whole-body butyrate turnover, and fecal butyrate concentrations. (k) ¹³C acetate enrichment in plasma of rats fed ¹³C bicarbonate labeled food and water. (l) [U-¹³C] acetate from feces incubated in [U-¹³C] glucose or fatty acids. In panels (l)–(o), data are the mean ± S.E.M. of n=4 per group, with comparisons to controls (n) via the 2-tailed unpaired Student’s t-test. (m) *In vitro* acetate production rate from feces incubated in [U-¹³C] glucose or fatty acids. (n) *In vitro* acetate production rate in control, boiled, and UV irradiated fecal samples. ****P<0.0001 vs. control. (o) *In vitro* fecal acetate production following treatment with antibiotics. Unless otherwise specified, n=6 replicates per group.

**Extended Data Fig. 3**
HFD rats exhibit increased GSIS driven by increased acetate turnover. (a), (b) Plasma glucose and glucose infusion rate during a hyperglycemic clamp. In all panels, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. chow fed rats. (c) Plasma insulin area under the curve (AUC) during the hyperglycemic clamp. (d) Plasma acetate. In all panels, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. 2 μmol/(kg-min) acetate; §§§§P<0.0001 vs. 8 μmol/(kg-min) acetate. (e), (f) Plasma glucose and glucose infusion rate during a hyperglycemic clamp. (g) Plasma insulin AUC during the clamp. (a), (b) Plasma butyrate and whole-body butyrate turnover. *P<0.05, ****P<0.0001. (c), (d) Plasma glucose and glucose infusion rate during a hyperglycemic clamp. (e), (f) Plasma insulin concentrations during the hyperglycemic 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 [panels (a)–(g)] or by the 2-tailed unpaired Student’s t-test [panels (h)–(m)].

**Extended Data Fig. 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. In panels (a)–(f), *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. 12 hour fasted rats; §P<0.05, §§P<0.01, §§§P<0.001, §§§§P<0.0001 vs. 48 hour fasted rats. (c), (d) Plasma glucose and glucose infusion rate during a hyperglycemic clamp. (e), (f) Plasma insulin and insulin AUC during the clamp. (g) Caloric intake from protein, fat, and carbohydrate. In panels (g)–(m), each group was compared to pair fed, high carbohydrate fed rats. (h), (i) Plasma glucose and glucose infusion rate in the hyperglycemic clamp. In all panels, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. pair fed rats given the high CHO diet. (j), (k) Plasma acetate and whole-body acetate turnover. (l), (m) Plasma insulin and insulin AUC during the hyperglycemic clamp. (n) Linear regression: whole-body acetate turnover vs. total caloric intake in each diet group. (o), (p) Plasma glucose and glucose infusion rate during a hyperglycemic clamp in 4 week HFD rats treated with broad-spectrum non-absorbable antibiotics. In panels (o)–(r), ***P<0.001, ****P<0.0001 vs. HFD rats; §§§P<0.001, §§§§P<0.0001 vs. antibiotics-treated rats. (q) Plasma acetate. (r) Plasma ¹³C acetate enrichment following three days of feeding ¹³C bicarbonate food and water. Data were compared using the 2-tailed unpaired Student’s t-test. (s) Insulin AUC during a hyperglycemic clamp. Data are mean ± S.E.M. of n=6 per group. 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.

**Extended Data Fig. 5**
Fecal transplantation alters recipient microbiomes to resemble their donors as revealed by culture-independent 16S rRNA sequencing of fecal 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 the 2-tailed unpaired Student’s t-test. (b)–(f) Comparison of fecal microbiomes before and after transplantation (beta diversity analysis) as measured by PC1 (b) or in a three-dimensional representation (c)–(f). Rats from independent litters were randomized prior to diet administration or fecal 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 Fig. 6**
The gut microbiota drive increased acetate turnover and GSIS. (a), (b) Plasma glucose and glucose infusion rate during a hyperglycemic clamp in rats following fecal transplant replicates acetate turnover and GSIS in the donor group. In panels (a)–(c) and (e), ****P<0.0001 vs. chow (donor) to chow (recipient) transplants; §§§§P<0.0001 vs. chow (donor) to HFD (recipient) transplants. Data are the mean ± S.E.M. of n=6 (HFD to chow) or 7 (chow to chow, chow to HFD) per group. (c) Plasma acetate. (d) Fecal 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 physiologic buffer. n=4 per group. (g) Plasma C2 acetylcarnitine content. In panels (g)–(m), *P<0.05, **P<0.01 vs. 2 μmol/(kg-min) acetate; §P<0.05 vs. 8 μmol/(kg-min) acetate by one-way ANOVA with Bonferroni’s multiple comparisons test. In panels (g)–(s), data are the mean ± S.E.M. of n=6 (unless otherwise specified) per group. (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 hyperglycemic clamp in acetate-infused rats treated with a GLP-1 inhibitor. In panels (n)–(s), no significant differences were measured by the two-tailed unpaired Student’s t-test. (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.

**Extended Data Fig. 7**
Acetate drives GSIS via parasympathetic activation. (a) Body weight before and after vagotomy. (b), (c) Plasma glucose and glucose infusion rate during a hyperglycemic clamp. In all panels, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 by the 2-tailed unpaired Student’s t-test. (d), (e) Plasma acetate and whole-body acetate turnover. (f) Insulin AUC during the clamp. (g) Plasma gastrin during the clamp. (h) Plasma glucagon at 120 min of the clamp. (h), (i) Plasma glucose and glucose infusion rate during a hyperglycemic clamp in acetate-infused, atropine-treated rats. (k), (l) Plasma acetate and whole-body acetate turnover. (m) Plasma insulin area under the curve during the clamp. (n) Plasma glucagon. In all panels, data represent the mean ± S.E.M. of n=6 replicates per group, with comparisons by the two-tailed unpaired Student’s t-test.

**Extended Data Fig. 8**
Acetate drives GSIS via parasympathetic activation. (a), (b) Plasma glucose and glucose infusion rate during a hyperglycemic clamp in rats treated with ICV acetate. In panels (b)–(d), **P<0.01, ***P<0.001 vs. controls; §§P<0.01, §§§P<0.001 vs. ICV acetate treated rats by one-way ANOVA with Bonferroni’s multiple comparisons test. (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. In panels (e)–(i), ***P<0.001, ****P<0.0001 vs. controls; §§§P<0.001, §§§§P<0.0001 vs. acetate-infused rats. (g), (h) Plasma glucose and glucose infusion rate during a hyperglycemic clamp. (i) Plasma insulin AUC during the clamp. (j), (k) Plasma and brain tissue acetate in rats given an injection of acetate into the NTS. (l), (m) Plasma glucose and glucose infusion rate during a hyperglycemic clamp. (n) Plasma insulin area under the curve 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 [panels (a)–(i)], or by the 2-tailed unpaired Student’s t-test [panels (j)–(o)].

**Extended Data Fig. 9**
Chronic intragastric acetate infusion causes hyperphagia and metabolic syndrome through parasympathetic activation. (a), (b) Plasma acetate and whole-body acetate turnover. In all panels, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. controls; §P<0.05, §§P<0.01, §§§P<0.001, §§§§P<0.0001 vs. intragastric acetate infused rats. (c), (d) Plasma glucose and insulin concentrations during an intraperitoneal glucose tolerance test. (e) Insulin area under the curve during the glucose tolerance test. (f), (g) Plasma glucose and glucose infusion rate during a hyperglycemic clamp. (h) Insulin area under the curve during the hyperglycemic clamp. (i) Body weight before and after the infusion study (n=16 controls, 16 acetate infused, and 12 acetate infused + vagotomy). (j) Caloric intake during the 10-day acetate infusion study. (k) HOMA-IR. (l) Plasma triglyceride concentrations. (m) Plasma insulin at the 120 min time point of a hyperinsulinemic-euglycemic clamp. (n), (o) Plasma glucose and glucose infusion rate during the hyperinsulinemic-euglycemic clamp. (p) Plasma glucagon. Unless otherwise specified, data are presented as the mean ± S.E.M. of n=6 rats per group, with comparisons by one-way ANOVA with Bonferroni’s multiple comparisons test.

**Extended Data Fig. 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. In all panels, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. CONV-D mice on the same diet. (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 the two-tailed unpaired Student’s t-test.

**Fig. 1**
High fat fed rats exhibit increased whole-body acetate turnover. (a), (b) Plasma acetate concentrations and whole-body acetate turnover in chow, 3 day, and 4 week HFD rats. (c) Acetate content in the entire cecum and colon lumen. (d) Tissue acetate concentrations. In all panels, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. chow fed rats; §§§P<0.001, §§§§P<0.0001 vs. 3 day HFD rats. Data are the mean ± S.E.M. of n=6 animals per group.

**Fig. 2**
The contents of the colonic lumen are the primary source of acetate in high fat fed rats. (a) Tissue/plasma ¹³C acetate enrichment in rats infused with ¹³C acetate. (b) Whole-body acetate turnover before and after washout of the gut. **P<0.01, ***P<0.001 vs. before washout. (c) Whole-body acetate turnover in HFD rats before and after portal vein ligation. (d), (e) Whole-body acetate turnover, and acetate in the entire cecum and colon lumen. (f) Whole-body acetate turnover in HFD rats before and after acute colectomy. In all panels, ***P<0.001, ****P<0.0001. Data are the mean ± S.E.M. of n=6 replicates per group.

**Fig. 3**
Acetate turnover drives GSIS. (a) Plasma insulin in a hyperglycemic clamp. *P<0.05, **P<0.01, ***P<0.001 vs. chow; §P<0.05 vs. 3 day HFD. (b), (c) Acetate turnover and GSIS in rats given acute acetate. *P<0.05, **P<0.01, ****P<0.0001 vs. 2 μmol/(kg-min); §P<0.05, §§P<0.01, §§§§P<0.0001 vs. 8 μmol/(kg-min). (d), (e) Acetate turnover, GSIS. *P<0.05, **P<0.01, ****P<0.0001 vs. controls; §P<0.05, §§P<0.01, §§§P<0.001, §§§§P<0.0001 vs. antibiotics. (f), (g) Whole-body acetate turnover, GSIS. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. chow donor/chow recipient; §§P<0.01, §§§P<0.001, §§§§P<0.0001 vs. chow donor/HFD recipient. (h) GSIS in isolated islets (KRB buffer; n=4 replicates per group). Unless otherwise specified, n=6 replicates per group.

**Fig. 4**
Acetate drives increased GSIS via parasympathetic activation. (a) Plasma gastrin. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. 2 μmol/(kg-min); §P<0.05 vs. 8 μmol/(kg-min) acetate. (b) Tissue acetate. In (b)–(d), (i), and (j), *P<0.05, **P<0.01, ***P<0.001, and ****P<0.0001. (c), (d) GSIS. (e), (f) Plasma acetate and GSIS. *P<0.05, **P<0.01, ***P<0.001 vs. controls; §P<0.05, §§P<0.01, §§§P<0.001 vs. ICV acetate. (g), (h) Plasma gastrin (120 min) and GSIS. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. controls; §P<0.05, §§P<0.01, §§§P<0.001, §§§§P<0.0001 vs. acetate. (i), (j) Plasma gastrin (120 min) and GSIS following NTS acetate injection. Data are the mean ± S.E.M. of n=6 animals per group.

**Fig. 5**
Chronic increases in whole-body acetate turnover promote hyperphagia, obesity, and metabolic syndrome. (a) Plasma insulin during a hyperglycemic clamp. In all panels, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. controls; §P<0.05, §§P<0.01, §§§P<0.001, §§§§P<0.0001 vs. acetate treated. n=6 replicates unless otherwise stated. (b), (c) Plasma gastrin and ghrelin at time 0 of the hyperglycemic clamp. (d) Weight change during the ten-day infusion (n=16 controls, 16 acetate, and 12 acetate + vagotomy). (e), (f) Liver and skeletal muscle triglyceride content. (g) Endogenous glucose production during a hyperinsulinemic-euglycemic clamp. (h) Glucose disposal rate during the clamp. All data are the mean ± S.E.M.

**Fig. 6**
Gut bacteria are responsible for the majority of acetate production *in vivo*, and for the increase in HFD rodents. (a), (b) Plasma and cecal/colon lumen acetate concentrations in germ-free (GF) and ex-GF conventionalized (CONV-D) mice. In all panels, *P<0.05 and ****P<0.0001. (c) Tissue acetate concentrations. (d) Plasma ¹³C acetate enrichment in mice fed water containing ¹³C bicarbonate for 3 days. (e), (f) Plasma gastrin and ghrelin concentrations. (g), (h) Liver and skeletal muscle triglyceride content. In all panels, data are the mean ± S.E.M. of n=9 GF mice and 10 CONV-D mice per diet.

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Comment in

Physiology: Microbial signals to the brain control weight.
Trajkovski M, Wollheim CB. Trajkovski M, et al. Nature. 2016 Jun 9;534(7606):185-7. doi: 10.1038/534185a. Nature. 2016. PMID: 27279209 No abstract available.
Metabolism: Acetate promotes obesity via a gut-brain-β-cell axis.
Ridler C. Ridler C. Nat Rev Endocrinol. 2016 Aug;12(8):436. doi: 10.1038/nrendo.2016.93. Epub 2016 Jun 10. Nat Rev Endocrinol. 2016. PMID: 27282448 No abstract available.
Microbially Produced Acetate: A "Missing Link" in Understanding Obesity?
Trent CM, Blaser MJ. Trent CM, et al. Cell Metab. 2016 Jul 12;24(1):9-10. doi: 10.1016/j.cmet.2016.06.023. Cell Metab. 2016. PMID: 27411005

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References

1. Rahat-Rozenbloom S, Fernandes J, Gloor GB, Wolever TM. Evidence for greater production of colonic short-chain fatty acids in overweight than lean humans. International journal of obesity. 2014;38:1525–1531. doi: 10.1038/ijo.2014.46. - DOI - PMC - PubMed
1. Shepherd ML, Ponder MA, Burk AO, Milton SC, Swecker WS., Jr Fibre digestibility, abundance of faecal bacteria and plasma acetate concentrations in overweight adult mares. Journal of nutritional science. 2014;3:e10. doi: 10.1017/jns.2014.8. - DOI - PMC - PubMed
1. Turnbaugh PJ, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031. doi: 10.1038/nature05414. - DOI - PubMed
1. Fernandes J, Su W, Rahat-Rozenbloom S, Wolever TM, Comelli EM. Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans. Nutrition & diabetes. 2014;4:e121. doi: 10.1038/nutd.2014.23. - DOI - PMC - PubMed
1. Li M, et al. Gut carbohydrate metabolism instead of fat metabolism regulated by gut microbes mediates high-fat diet-induced obesity. Beneficial microbes. 2014;5:335–344. doi: 10.3920/BM2013.0071. - DOI - PubMed

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[1] Rahat-Rozenbloom S, Fernandes J, Gloor GB, Wolever TM. Evidence for greater production of colonic short-chain fatty acids in overweight than lean humans. International journal of obesity. 2014;38:1525–1531. doi: 10.1038/ijo.2014.46. - DOI - PMC - PubMed

[2] Rahat-Rozenbloom S, Fernandes J, Gloor GB, Wolever TM. Evidence for greater production of colonic short-chain fatty acids in overweight than lean humans. International journal of obesity. 2014;38:1525–1531. doi: 10.1038/ijo.2014.46. - DOI - PMC - PubMed

[3] Shepherd ML, Ponder MA, Burk AO, Milton SC, Swecker WS., Jr Fibre digestibility, abundance of faecal bacteria and plasma acetate concentrations in overweight adult mares. Journal of nutritional science. 2014;3:e10. doi: 10.1017/jns.2014.8. - DOI - PMC - PubMed

[4] Shepherd ML, Ponder MA, Burk AO, Milton SC, Swecker WS., Jr Fibre digestibility, abundance of faecal bacteria and plasma acetate concentrations in overweight adult mares. Journal of nutritional science. 2014;3:e10. doi: 10.1017/jns.2014.8. - DOI - PMC - PubMed

[5] Turnbaugh PJ, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031. doi: 10.1038/nature05414. - DOI - PubMed

[6] Turnbaugh PJ, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031. doi: 10.1038/nature05414. - DOI - PubMed

[7] Fernandes J, Su W, Rahat-Rozenbloom S, Wolever TM, Comelli EM. Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans. Nutrition & diabetes. 2014;4:e121. doi: 10.1038/nutd.2014.23. - DOI - PMC - PubMed

[8] Fernandes J, Su W, Rahat-Rozenbloom S, Wolever TM, Comelli EM. Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans. Nutrition & diabetes. 2014;4:e121. doi: 10.1038/nutd.2014.23. - DOI - PMC - PubMed

[9] Li M, et al. Gut carbohydrate metabolism instead of fat metabolism regulated by gut microbes mediates high-fat diet-induced obesity. Beneficial microbes. 2014;5:335–344. doi: 10.3920/BM2013.0071. - DOI - PubMed

[10] Li M, et al. Gut carbohydrate metabolism instead of fat metabolism regulated by gut microbes mediates high-fat diet-induced obesity. Beneficial microbes. 2014;5:335–344. doi: 10.3920/BM2013.0071. - DOI - PubMed

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Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome

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Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome

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