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Research ArticleArticle

Gut Microbiome–Wide Search for Bacterial Azoreductases Reveals Potentially Uncharacterized Azoreductases Encoded in the Human Gut Microbiome

Domenick J. Braccia, Glory Minabou Ndjite, Ashley Weiss, Sophia Levy, Stephenie Abeysinghe, Xiaofang Jiang, Mihai Pop and Brantley Hall
Drug Metabolism and Disposition January 2023, 51 (1) 142-153; DOI: https://doi.org/10.1124/dmd.122.000898
Domenick J. Braccia
Center for Bioinformatics and Computational Biology (D.B., M.P., B.H.) and Departments of Cell Biology and Molecular Genetics (G.M.N., A.W., S.L., S.A., B.H.) and Computer Science (M.P.), University of Maryland, College Park, Maryland; and National Library of Medicine, National Institutes of Health, Bethesda, Maryland (X.J.)
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  • ORCID record for Domenick J. Braccia
Glory Minabou Ndjite
Center for Bioinformatics and Computational Biology (D.B., M.P., B.H.) and Departments of Cell Biology and Molecular Genetics (G.M.N., A.W., S.L., S.A., B.H.) and Computer Science (M.P.), University of Maryland, College Park, Maryland; and National Library of Medicine, National Institutes of Health, Bethesda, Maryland (X.J.)
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Ashley Weiss
Center for Bioinformatics and Computational Biology (D.B., M.P., B.H.) and Departments of Cell Biology and Molecular Genetics (G.M.N., A.W., S.L., S.A., B.H.) and Computer Science (M.P.), University of Maryland, College Park, Maryland; and National Library of Medicine, National Institutes of Health, Bethesda, Maryland (X.J.)
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Sophia Levy
Center for Bioinformatics and Computational Biology (D.B., M.P., B.H.) and Departments of Cell Biology and Molecular Genetics (G.M.N., A.W., S.L., S.A., B.H.) and Computer Science (M.P.), University of Maryland, College Park, Maryland; and National Library of Medicine, National Institutes of Health, Bethesda, Maryland (X.J.)
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Stephenie Abeysinghe
Center for Bioinformatics and Computational Biology (D.B., M.P., B.H.) and Departments of Cell Biology and Molecular Genetics (G.M.N., A.W., S.L., S.A., B.H.) and Computer Science (M.P.), University of Maryland, College Park, Maryland; and National Library of Medicine, National Institutes of Health, Bethesda, Maryland (X.J.)
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Xiaofang Jiang
Center for Bioinformatics and Computational Biology (D.B., M.P., B.H.) and Departments of Cell Biology and Molecular Genetics (G.M.N., A.W., S.L., S.A., B.H.) and Computer Science (M.P.), University of Maryland, College Park, Maryland; and National Library of Medicine, National Institutes of Health, Bethesda, Maryland (X.J.)
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Mihai Pop
Center for Bioinformatics and Computational Biology (D.B., M.P., B.H.) and Departments of Cell Biology and Molecular Genetics (G.M.N., A.W., S.L., S.A., B.H.) and Computer Science (M.P.), University of Maryland, College Park, Maryland; and National Library of Medicine, National Institutes of Health, Bethesda, Maryland (X.J.)
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Brantley Hall
Center for Bioinformatics and Computational Biology (D.B., M.P., B.H.) and Departments of Cell Biology and Molecular Genetics (G.M.N., A.W., S.L., S.A., B.H.) and Computer Science (M.P.), University of Maryland, College Park, Maryland; and National Library of Medicine, National Institutes of Health, Bethesda, Maryland (X.J.)
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Abstract

The human gut is home to trillions of microorganisms that are responsible for the modification of many orally administered drugs, leading to a wide range of therapeutic outcomes. Prodrugs bearing an azo bond are designed to treat inflammatory bowel disease and colorectal cancer via microbial azo reduction, allowing for topical application of therapeutic moieties to the diseased tissue in the intestines. Despite the inextricable link between microbial azo reduction and the efficacy of azo prodrugs, the prevalence, abundance, and distribution of azoreductases have not been systematically examined across the gut microbiome. Here, we curated and clustered amino acid sequences of experimentally confirmed bacterial azoreductases and conducted a hidden Markov model–driven homolog search for these enzymes across 4644 genome sequences present in the representative Unified Human Gastrointestinal Genomes collection. We identified 1958 putative azo-reducing species, corroborating previous findings that azo reduction appears to be a ubiquitous function of the gut microbiome. However, through a systematic comparison of predicted and confirmed azo-reducing strains, we hypothesize the presence of uncharacterized azoreductases in 25 prominent strains of the human gut microbiome. Finally, we confirmed the azo reduction of Acid Orange 7 by multiple strains of Fusobacterium nucleatum, Bacteroides fragilis, and Clostridium clostridioforme. Together, these results suggest the presence and activity of many uncharacterized azoreductases in the human gut microbiome and motivate future studies aimed at characterizing azoreductase genes in prominent members of the human gut microbiome.

SIGNIFICANCE STATEMENT This work systematically examined the prevalence, abundance, and distribution of azoreductases across the healthy and inflammatory bowel disease human gut microbiome, revealing potentially uncharacterized azoreductase genes. It also confirmed the reduction of Acid Orange 7 by strains of Fusobacterium nucleatum, Bacteroides fragilis, and Clostridium clostridioforme.

Footnotes

    • Received March 14, 2022.
    • Accepted August 18, 2022.
  • D.B. was supported in part by the National Science Foundation [DGE-1632976] and in part by B.H. startup funding from the University of Maryland. X.J. was supported in part by the Intramural Research Program of National Institutes of Health National Library of Medicine. M.P. was supported by National Institutes of Health [Grant R01-AI-100947]. B.H., G.M.N., A.W., S.L., and S.A. were supported by startup funding from the University of Maryland.

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • dx.doi.org/10.1124/dmd.122.000898.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Drug Metabolism and Disposition: 51 (1)
Drug Metabolism and Disposition
Vol. 51, Issue 1
1 Jan 2023
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Research ArticleArticle

Prediction of Uncharacterized Azo Reduction by the Gut Microbiome

Domenick J. Braccia, Glory Minabou Ndjite, Ashley Weiss, Sophia Levy, Stephenie Abeysinghe, Xiaofang Jiang, Mihai Pop and Brantley Hall
Drug Metabolism and Disposition January 1, 2023, 51 (1) 142-153; DOI: https://doi.org/10.1124/dmd.122.000898

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Research ArticleArticle

Prediction of Uncharacterized Azo Reduction by the Gut Microbiome

Domenick J. Braccia, Glory Minabou Ndjite, Ashley Weiss, Sophia Levy, Stephenie Abeysinghe, Xiaofang Jiang, Mihai Pop and Brantley Hall
Drug Metabolism and Disposition January 1, 2023, 51 (1) 142-153; DOI: https://doi.org/10.1124/dmd.122.000898
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