دورية أكاديمية
أعرض في EDS

Diverse but desolate landscape of gut microbial azoreductases: A rationale for idiopathic IBD drug response.

التفاصيل البيبلوغرافية
العنوان: Diverse but desolate landscape of gut microbial azoreductases: A rationale for idiopathic IBD drug response.
المؤلفون: Simpson JB; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Sekela JJ; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Carry BS; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Beaty V; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Patel S; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Redinbo MR; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Biochemistry and Biophysics, Department of Microbiology and Immunology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
المصدر: Gut microbes [Gut Microbes] 2023 Jan-Dec; Vol. 15 (1), pp. 2203963.
نوع المنشور: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101495343 Publication Model: Print Cited Medium: Internet ISSN: 1949-0984 (Electronic) Linking ISSN: 19490976 NLM ISO Abbreviation: Gut Microbes Subsets: MEDLINE
أسماء مطبوعة: Publication: 2015- : Philadelphia, PA : Taylor & Francis
Original Publication: Austin, Tex. : Landes Bioscience
مواضيع طبية MeSH: Gastrointestinal Microbiome* , Prodrugs* , Amlodipine Besylate, Olmesartan Medoxomil Drug Combination* , Crohn Disease* , Colitis, Ulcerative* , Inflammatory Bowel Diseases*/drug therapy, Humans ; Mesalamine/therapeutic use
مستخلص: Prodrugs reliant on microbial activation are widely used but exhibit a range of efficacies that remain poorly understood. The anti-inflammatory compound 5-aminosalicylic acid (5-ASA), which is packaged in a variety of azo-linked prodrugs provided to most Ulcerative Colitis (UC) patients, shows confounding inter-individual variabilities in response. Such prodrugs must be activated by azo-bond reduction to form 5-ASA, a process that has been attributed to both enzymatic and non-enzymatic catalysis. Gut microbial azoreductases (AzoRs) are the first catalysts shown to activate azo-linked drugs and to metabolize toxic azo-chemicals. Here, we chart the scope of the structural and functional diversity of AzoRs in health and in patients with the inflammatory bowel diseases (IBDs) UC and Crohn's Disease (CD). Using structural metagenomics, we define the landscape of gut microbial AzoRs in 413 healthy donor and 1059 IBD patient fecal samples. Firmicutes encode a significantly higher number of unique AzoRs compared to other phyla. However, structural and biochemical analyses of distinct AzoRs from the human microbiome reveal significant differences between prevalent orthologs in the processing of toxic azo-dyes, and their generally poor activation of IBD prodrugs. Furthermore, while individuals with IBD show higher abundances of AzoR-encoding gut microbial taxa than healthy controls, the overall abundance of AzoR-encoding microbes is markedly low in both disease and health. Together, these results establish that gut microbial AzoRs are functionally diverse but sparse in both health and disease, factors that may contribute to non-optimal processing of azo-linked prodrugs and idiopathic IBD drug responses.
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معلومات مُعتمدة: P30 CA016086 United States CA NCI NIH HHS; R01 GM135218 United States GM NIGMS NIH HHS; R01 GM137286 United States GM NIGMS NIH HHS
فهرسة مساهمة: Keywords: Azoreductase; Irritable Bowel Disease; Multi-omics; Structural Biology; Structural Metagenomics; Sulfasalazine; metagenomics; microbial metabolism
المشرفين على المادة: EC 1.7.1.17 (azoreductase)
0 (Prodrugs)
0 (Amlodipine Besylate, Olmesartan Medoxomil Drug Combination)
4Q81I59GXC (Mesalamine)
تواريخ الأحداث: Date Created: 20230430 Date Completed: 20230502 Latest Revision: 20231101
رمز التحديث: 20231101
مُعرف محوري في PubMed: PMC10132220
DOI: 10.1080/19490976.2023.2203963
PMID: 37122075
قاعدة البيانات: MEDLINE
الوصف
تدمد:1949-0984
DOI:10.1080/19490976.2023.2203963