Nonmicrobicidal Small Molecule Inhibition of Polysaccharide Metabolism in Human Gut Microbes: A Potential Therapeutic Avenue

Santilli, Anthony; Dawson, Elizabeth M.; Whitehead, Kristi J.; Whitehead, Daniel C.

doi:10.1021/acschembio.8b00309

Cited by 27 publications

(20 citation statements)

References 81 publications

(110 reference statements)

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“…This is in contrast to the degradation of many complex plant polysaccharides and host mucosal glycans, both of which are more of a specialty food source for select gut bacteria (58, 59). However, because acarbose is minimally absorbed by the host, it transits the distal gut, where it could inhibit starch processing by gut bacteria (60). Therefore, the diet consumed with acarbose greatly influences the possible changes in community structure, as we observed.…”

Section: Discussionmentioning

confidence: 99%

The Glucoamylase Inhibitor Acarbose Has a Diet-Dependent and Reversible Effect on the Murine Gut Microbiome

Baxter

Lesniak

Sinani

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

The Glucoamylase Inhibitor Acarbose Has a Diet-Dependent and Reversible Effect on the Murine Gut Microbiome

Baxter

Lesniak

Sinani

et al. 2019

mSphere

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“…While it is unsurprising that an increased flux of starch to the large intestine affected the gut microbiota and their fermentation products, the specific impacts could not be easily predicted, especially since ACA can also inhibit bacterial enzymes, and this can be variable across taxa [24]. The increased relative abundance in ACA-treated mice of the dominant OTU—OTU-1 at UM and TJL and OTU-4 at UT—was dramatic: one or the other was increased approximately 4-fold at all three sites and in multiple samples more than half of sequences belonged to these OTUs.…”

Section: Discussionmentioning

confidence: 99%

Changes in the gut microbiome and fermentation products concurrent with enhanced longevity in acarbose-treated mice

et al. 2019

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Background: Treatment 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. Results: Microbial 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. Conclusion: We 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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“…In the homeostatic state, a healthy GIT has a normal and stable commensal intestinal microbiota. This provides the host with nutrition and energy through the production of vitamins [ 25 , 26 , 27 ], aids in the maintenance of intestinal epithelial barrier integrity, aids in resistance to pathogens, and plays a role in the metabolic and immune systems [ 28 , 29 , 30 ]. Furthermore, the idea that the interplay between the gut and brain can modulate behavior is emerging as an exciting concept in health and disease.…”

Section: The Intestinal Microbiota and Homeostasismentioning

confidence: 99%

Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer’s Disease

et al. 2018

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The bidirectional communication between the central nervous system (CNS) and the gut microbiota plays a pivotal role in human health. Increasing numbers of studies suggest that the gut microbiota can influence the brain and behavior of patients. Various metabolites secreted by the gut microbiota can affect the cognitive ability of patients diagnosed with neurodegenerative diseases. Nearly one in every ten Korean senior citizens suffers from Alzheimer’s disease (AD), the most common form of dementia. This review highlights the impact of metabolites from the gut microbiota on communication pathways between the brain and gut, as well as the neuroinflammatory roles they may have in AD patients. The objectives of this review are as follows: (1) to examine the role of the intestinal microbiota in homeostatic communication between the gut microbiota and the brain, termed the microbiota–gut–brain (MGB) axis; (2) to determine the underlying mechanisms of signal dysfunction; and (3) to assess the impact of signal dysfunction induced by the microbiota on AD. This review will aid in understanding the microbiota of elderly people and the neuroinflammatory roles they may have in AD.

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Nonmicrobicidal Small Molecule Inhibition of Polysaccharide Metabolism in Human Gut Microbes: A Potential Therapeutic Avenue

Cited by 27 publications

References 81 publications

The Glucoamylase Inhibitor Acarbose Has a Diet-Dependent and Reversible Effect on the Murine Gut Microbiome

The Glucoamylase Inhibitor Acarbose Has a Diet-Dependent and Reversible Effect on the Murine Gut Microbiome

Changes in the gut microbiome and fermentation products concurrent with enhanced longevity in acarbose-treated mice

Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer’s Disease

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