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Changes in the gut microbiota and fermentation products associated with enhanced longevity in acarbose-treated mice

View ORCID ProfileByron J Smith, Richard A Miller, View ORCID ProfileAaron C Ericsson, David C Harrison, Randy Strong, Thomas M Schmidt
doi: https://doi.org/10.1101/311456
Byron J Smith
1Department of Ecology & Evolutionary Biology, University of Michigan, 48109 Ann Arbor, MI, USA.
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  • ORCID record for Byron J Smith
Richard A Miller
2Department of Pathology and Geriatrics Center, University of Michigan, 48109 Ann Arbor, MI, USA.
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Aaron C Ericsson
3University of Missouri Metagenomics Center, University of Missouri, 65201 Columbia, MO USA.
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David C Harrison
4The Jackson Laboratory, 04609 Bar Harbor, ME USA.
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Randy Strong
5Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 78229 San Antonio, TX USA.
6Barshop Institute for Longevity and Aging Studies, 78245 San Antonio, TX USA.
7Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, 78229 San Antonio, TX USA.
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Thomas M Schmidt
1Department of Ecology & Evolutionary Biology, University of Michigan, 48109 Ann Arbor, MI, USA.
8Department of Internal Medicine, University of Michigan, 48109 Ann Arbor, MI, USA.
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  • For correspondence: schmidti@umich.edu
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Abstract

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. Total SCFA concentrations in feces were increased in treated mice, with increased butyrate and propionate in particular. 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 have demonstrated 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 microbiota illustrates 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, and to test a causal role of SCFAs in the observed effects of acarbose.

  • List of Abbreviations

    ACA
    : Acarbose
    SCFA
    : Short-chain fatty acid
    ITP
    : Interventions Testing Program
    TJL
    : The Jackson Laboratory
    UM
    : The University of Michigan
    UT
    : The University of Texas Health Science Center at San Antonio
    OTU
    : Operational taxonomic unit
    HPLC
    : High-performance liquid chromatography
    LASSO
    : Least absolute shrinkage and selection operation
    S. alaskensis
    : Sphingopyxis alaskensis
    FDR
    : False-discovery rate
    PBS
    : Phosphate-buffered saline
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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    Posted April 30, 2018.
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    Changes in the gut microbiota and fermentation products associated with enhanced longevity in acarbose-treated mice
    Byron J Smith, Richard A Miller, Aaron C Ericsson, David C Harrison, Randy Strong, Thomas M Schmidt
    bioRxiv 311456; doi: https://doi.org/10.1101/311456
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    Changes in the gut microbiota and fermentation products associated with enhanced longevity in acarbose-treated mice
    Byron J Smith, Richard A Miller, Aaron C Ericsson, David C Harrison, Randy Strong, Thomas M Schmidt
    bioRxiv 311456; doi: https://doi.org/10.1101/311456

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