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Changes in the Type 2 diabetes gut mycobiome associate with metformin treatment across populations.

ABSTRACT: The human gut teems with a diverse ecosystem of microbes, yet non-bacterial portions of that community are overlooked in studies of metabolic diseases firmly linked to gut bacteria. Type 2 diabetes mellitus (T2D) associates with compositional shifts in the gut bacterial microbiome and fungal mycobiome, but whether T2D and/or pharmaceutical treatments underpin the community change is unresolved. To differentiate these effects, we curated a gut mycobiome cohort to-date spanning 1,000 human samples across 5 countries and a murine experimental model. We use Bayesian multinomial logistic normal models to show that metformin and T2D both associate with shifts in the relative abundance of distinct gut fungi. T2D associates with shifts in the Saccharomycetes and Sordariomycetes fungal classes, while the genera Fusarium and Tetrapisipora most consistently associate with metformin treatment. We confirmed the impact of metformin on individual gut fungi by administering metformin to healthy mice. Thus, metformin and T2D account for subtle, but significant and distinct variation in the gut mycobiome across human populations. This work highlights for the first time that oral pharmaceuticals can confound associations of gut fungi with T2D and warrants the need to consider pharmaceutical interventions in investigations of linkages between metabolic diseases and gut microbial inhabitants.

SUBMITTER: Van Syoc E

PROVIDER: S-EPMC10312434 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Changes in the Type 2 diabetes gut mycobiome associate with metformin treatment across populations.

Van Syoc Emily E Nixon Michelle Pistner MP Silverman Justin D JD Luo Yuhong Y Gonzalez Frank J FJ Elbere Ilze I Klovins Janis J Patterson Andrew D AD Rogers Connie J CJ Ganda Erika E

bioRxiv : the preprint server for biology 20231103

The human gut teems with a diverse ecosystem of microbes, yet non-bacterial portions of that community are overlooked in studies of metabolic diseases firmly linked to gut bacteria. Type 2 diabetes mellitus (T2D) associates with compositional shifts in the gut bacterial microbiome and fungal mycobiome, but whether T2D and/or pharmaceutical treatments underpin the community change is unresolved. To differentiate these effects, we curated a gut mycobiome cohort to-date spanning 1,000 human samples ...[more]

PMID: 37398234

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Project description:UnlabelledMetformin, a biguanide derivate, has pleiotropic effects beyond glucose reduction, including improvement of lipid profiles and lowering microvascular and macrovascular complications associated with type 2 diabetes mellitus (T2DM). These effects have been ascribed to adenosine monophosphate-activated protein kinase (AMPK) activation in the liver and skeletal muscle. However, metformin effects are not attenuated when AMPK is knocked out and intravenous metformin is less effective than oral medication, raising the possibility of important gut pharmacology. We hypothesized that the pharmacology of metformin includes alteration of bile acid recirculation and gut microbiota resulting in enhanced enteroendocrine hormone secretion. In this study we evaluated T2DM subjects on and off metformin monotherapy to characterize the gut-based mechanisms of metformin. Subjects were studied at 4 time points: (i) at baseline on metformin, (ii) 7 days after stopping metformin, (iii) when fasting blood glucose (FBG) had risen by 25% after stopping metformin, and (iv) when FBG returned to baseline levels after restarting the metformin. At these timepoints we profiled glucose, insulin, gut hormones (glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and glucose-dependent insulinotropic peptide (GIP) and bile acids in blood, as well as duodenal and faecal bile acids and gut microbiota. We found that metformin withdrawal was associated with a reduction of active and total GLP-1 and elevation of serum bile acids, especially cholic acid and its conjugates. These effects reversed when metformin was restarted. Effects on circulating PYY were more modest, while GIP changes were negligible. Microbiota abundance of the phylum Firmicutes was positively correlated with changes in cholic acid and conjugates, while Bacteroidetes abundance was negatively correlated. Firmicutes and Bacteroidetes representation were also correlated with levels of serum PYY. Our study suggests that metformin has complex effects due to gut-based pharmacology which might provide insights into novel therapeutic approaches to treat T2DM and associated metabolic diseases.Trial registrationwww.ClinicalTrials.gov NCT01357876.

Project description:Aim Gastrointestinal discomfort is the most common adverse event in metformin treatment for type 2 diabetes. The mechanism of action of metformin is associated with gut microbiota. However, the gut microbial community structure related to metformin-induced gastrointestinal adverse events remains unclear. This study aimed to investigate it. Methods 50 patients with newly diagnosed diabetes were treated with metformin 1500mg/d for 12 weeks. The patients were divided into two groups according to whether gastrointestinal adverse events occurred (group B) or did not occur (group A) after treatment. The fecal bacterial communities and short-chain fatty acids (SCFAs) were sequenced and compared. 70 diabetes mice were randomly divided into 8 groups and treated with metformin (Met), clindamycin (Clin) and/or SCFA, which were the Met+/Clin+, Met+/Clin-, Met-/Clin+, Met-/Clin-, Met+/SCFA+, Met+/SCFA-, Met-/SCFA+ and Met-/SCFA- group. After 4 weeks of metformin treatment, blood glucose, food intake, fecal SCFAs, gut microbiota and gut hormones were measured. Results Metformin increased the abundance of Phascolarctobacterium, Intestinimonas and Clostridium III. Functional prediction analysis showed that the propanoate metabolism pathway was significantly up-regulated. The concentrations of acetic acid and propanoic acid in feces were significantly increased. The abundance of Clostridium sensu stricto, Streptococcus and Akkermansia induced by metformin in group B was higher than that in group A. The propanoate metabolism pathway and propanoic acid in feces were significantly up-regulated in group B. In the animal experiments, the food intake decreased and glucose control increased in metformin groups compared with those in the control groups. The total GLP-1 level in the Met+/Clin- group was significantly higher than that in the Met-/Clin- group, while there was no statistical difference between the Met-/Clin- and Met+/Clin+ group. The total GLP-1 level in the Met-/SCFA+ group was significantly higher than that in the Met-/SCFA-group, while the levels of total GLP-1 and active GLP-1 in the Met+/SCFA- group and the Met+/SCFA+ group were significantly higher than those in the Met-/SCFA-group. Conclusions Our data suggest that metformin promotes the secretion of intestinal hormones such as GLP-1 by increasing the abundance of SCFA-producing bacteria, which not only plays an anti-diabetic role, but also may causes gastrointestinal adverse events.

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Changes in the Type 2 diabetes gut mycobiome associate with metformin treatment across populations.

Publications

Changes in the Type 2 diabetes gut mycobiome associate with metformin treatment across populations.

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