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The human microbiome encodes resistance to the antidiabetic drug acarbose.

ABSTRACT: The human microbiome encodes a large repertoire of biochemical enzymes and pathways, most of which remain uncharacterized. Here, using a metagenomics-based search strategy, we discovered that bacterial members of the human gut and oral microbiome encode enzymes that selectively phosphorylate a clinically used antidiabetic drug, acarbose^1,2, resulting in its inactivation. Acarbose is an inhibitor of both human and bacterial α-glucosidases³, limiting the ability of the target organism to metabolize complex carbohydrates. Using biochemical assays, X-ray crystallography and metagenomic analyses, we show that microbiome-derived acarbose kinases are specific for acarbose, provide their harbouring organism with a protective advantage against the activity of acarbose, and are widespread in the microbiomes of western and non-western human populations. These results provide an example of widespread microbiome resistance to a non-antibiotic drug, and suggest that acarbose resistance has disseminated in the human microbiome as a defensive strategy against a potential endogenous producer of a closely related molecule.

SUBMITTER: Balaich J

PROVIDER: S-EPMC10258454 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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The human microbiome encodes resistance to the antidiabetic drug acarbose.

Balaich Jared J Estrella Michael M Wu Guojun G Jeffrey Philip D PD Biswas Abhishek A Zhao Liping L Korennykh Alexei A Donia Mohamed S MS

Nature 20211124 7887

The human microbiome encodes a large repertoire of biochemical enzymes and pathways, most of which remain uncharacterized. Here, using a metagenomics-based search strategy, we discovered that bacterial members of the human gut and oral microbiome encode enzymes that selectively phosphorylate a clinically used antidiabetic drug, acarbose<sup>1,2</sup>, resulting in its inactivation. Acarbose is an inhibitor of both human and bacterial α-glucosidases<sup>3</sup>, limiting the ability of the target ...[more]

PMID: 34819672

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Project description:Acarbose is a safe and effective medication for type 2 diabetes that inhibits host glucoamylases to prevent starch digestion in the small intestines and thus decrease postprandial blood glucose levels. This results in an increase in dietary starch in the distal intestine, where it becomes food for the gut bacterial community. Here, we examined the effect of acarbose therapy on the gut community structure in mice fed either a high-starch (HS) or high-fiber diet rich in plant polysaccharides (PP). The fecal microbiota of animals consuming a low dose of acarbose (25 ppm) was not significantly different from that of control animals that did not receive acarbose. However, a high dose of acarbose (400 ppm) with the HS diet resulted in a substantial change to the microbiota structure. Most notably, the HS diet with a high dose of acarbose lead to an expansion of the Bacteroidaceae and Bifidobacteriaceae and a decrease in the Verrucomicrobiaceae (such as Akkermansia muciniphila) and the Bacteroidales S24-7. Once acarbose treatment ceased, the community composition quickly reverted to mirror that of the control group, suggesting that acarbose does not irreversibly alter the gut community. The high dose of acarbose in the PP diet resulted in a distinct community structure with increased representation of Bifidobacteriaceae and Lachnospiraceae Short-chain fatty acids (SCFAs) measured from stool samples were increased, especially butyrate, as a result of acarbose treatment in both diets. These data demonstrate the potential of acarbose to change the gut community structure and increase beneficial SCFA output in a diet-dependent manner.IMPORTANCE The gut microbial community has a profound influence on host physiology in both health and disease. In diabetic individuals, the gut microbiota can affect the course of disease, and some medications for diabetes, including metformin, seem to elicit some of their benefits via an interaction with the microbiota. Here, we report that acarbose, a glucoamylase inhibitor for type 2 diabetes, changes the murine gut bacterial community structure in a reversible and diet-dependent manner. In both high-starch and high-fiber diet backgrounds, acarbose treatment results in increased short-chain fatty acids, particularly butyrate, as measured in stool samples. As we learn more about how human disease is affected by the intestinal bacterial community, the interplay between medications such as acarbose and the diet will become increasingly important to evaluate.

Project description:BackgroundTreatment with the α-glucosidase inhibitor acarbose increases median lifespan by approximately 20% in male mice and 5% in females. This longevity extension differs from dietary restriction based on a number of features, including the relatively small effects on weight and the sex-specificity of the lifespan effect. By inhibiting host digestion, acarbose increases the flux of starch to the lower digestive system, resulting in changes to the gut microbiota and their fermentation products. Given the documented health benefits of short-chain fatty acids (SCFAs), the dominant products of starch fermentation by gut bacteria, this secondary effect of acarbose could contribute to increased longevity in mice. To explore this hypothesis, we compared the fecal microbiome of mice treated with acarbose to control mice at three independent study sites.ResultsMicrobial communities and the concentrations of SCFAs in the feces of mice treated with acarbose were notably different from those of control mice. At all three study sites, the bloom of a single bacterial taxon was the most obvious response to acarbose treatment. The blooming populations were classified to the largely uncultured Bacteroidales family Muribaculaceae and were the same taxonomic unit at two of the three sites. Propionate concentrations in feces were consistently elevated in treated mice, while the concentrations of acetate and butyrate reflected a dependence on study site. Across all samples, Muribaculaceae abundance was strongly correlated with propionate and community composition was an important predictor of SCFA concentrations. Cox proportional hazards regression showed that the fecal concentrations of acetate, butyrate, and propionate were, together, predictive of mouse longevity even while controlling for sex, site, and acarbose.ConclusionWe observed a correlation between fecal SCFAs and lifespan in mice, suggesting a role of the gut microbiota in the longevity-enhancing properties of acarbose. Treatment modulated the taxonomic composition and fermentation products of the gut microbiome, while the site-dependence of the responses illustrate the challenges facing reproducibility and interpretation in microbiome studies. These results motivate future studies exploring manipulation of the gut microbial community and its fermentation products for increased longevity, testing causal roles of SCFAs in the observed effects of acarbose.

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The human microbiome encodes resistance to the antidiabetic drug acarbose.

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The human microbiome encodes resistance to the antidiabetic drug acarbose.

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