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Microbiota‐derived Purines Support Intestinal Proliferation and Mucus Barrier Integrity
Author(s) -
Lee J. Scott,
Wang Ruth,
Goldberg Matthew,
Kao Daniel,
Colgan Sean
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06657
Subject(s) - mucus , purine metabolism , intestinal mucosa , biology , purine , metabolite , metabolomics , microbiology and biotechnology , chemistry , biochemistry , bioinformatics , medicine , enzyme , ecology
The gastrointestinal mucosa forms a dynamic physical and biochemical barrier to isolate the host immune system from potentially pathogenic microorganisms. A dysfunctional barrier allows bacterial contact with and translocation across the epithelium. Recent studies have appreciated that epithelial barrier formation and maintenance is energetically demanding, yet the colonic epithelium exists in a rather energetically‐depleted state of physiological hypoxia. Moreover, the intestinal mucosa is short lived, undergoing turnover every 3 – 5 days, incurring a substantial need for nucleotide genesis to preserve the epithelial cell population and provide ATP for energy balance. In the present work, we demonstrate that large quantities of purines are made and released by the gut microbiota and that such microbiota‐derived purines (MDP) are available to the intestinal mucosa. Through a series of experiments in which MDP production was depleted by antibiotic treatment, and purines reconstituted by supplementation and colonization with purine‐producing bacteria, the contribution of MDP to colonic proliferation and energetics during DSS‐induced colitis was delineated. Through HPLC‐based metabolite analyses, exogenously supplied purines showed incorporation into the murine colonic purine metabolite pool, were utilized for nucleotide genesis, and promoted energy balance. Immunofluorescent and metabolite analyses revealed that DSS‐insulted colon tissue lacking MDP substrates were proliferatively stunted, with notable energetic and endoplasmic reticulum (ER) stress, to the detriment of mucus barrier integrity. Upon purine reconstitution, the energetic state of the tissue was improved and ER stress alleviated, with concomitant reclamation of proliferative capacity and mucus barrier sterility. Together, this work establishes MDP as a critical substrate for colonic tissue metabolism and facilitates mucosal homeostasis and inflammatory resolution. Support or Funding Information This work was supported by NIH grants F32DK122741, DK1047893, DK50189, DK095491, DK103712 and by the Veterans Administration Merit Award BX002182.