title: Gut Microbiota Conversion of Dietary Ellagic Acid into Bioactive Phytoceutical Urolithin A Inhibits Heme Peroxidases.
abstract: Numerous studies signify that diets rich in phytochemicals offer many beneficial functions specifically during pathologic conditions, yet their effects are often not uniform due to inter-individual variation. The host indigenous gut microbiota and their modifications of dietary phytochemicals have emerged as factors that greatly influence the efficacy of phytoceutical-based intervention. Here, we investigated the biological activities of one such active microbial metabolite, Urolithin A (UA or 3,8-dihydroxybenzo[c]chromen-6-one), which is derived from the ellagic acid (EA). Our study demonstrates that UA potently inhibits heme peroxidases i.e. myeloperoxidase (MPO) and lactoperoxidase (LPO) when compared to the parent compound EA. In addition, chrome azurol S (CAS) assay suggests that EA, but not UA, is capable of binding to Fe3+, due to its catechol-like structure, although its modest heme peroxidase inhibitory activity is abrogated upon Fe3+-binding. Interestingly, UA-mediated MPO and LPO inhibition can be prevented by innate immune protein human NGAL or its murine ortholog lipocalin 2 (Lcn2), implying the complex nature of host innate immunity-microbiota interactions. Spectral analysis indicates that UA inhibits heme peroxidase-catalyzed reaction by reverting the peroxidase back to its inactive native state. In support of these in vitro results, UA significantly reduced phorbol myristate acetate (PMA)-induced superoxide generation in neutrophils, however, EA failed to block the superoxide generation. Treatment with UA significantly reduced PMA-induced mouse ear edema and MPO activity compared to EA treated mice. Collectively, our results demonstrate that microbiota-mediated conversion of EA to UA is advantageous to both host and microbiota i.e. UA-mediated inhibition of pro-oxidant enzymes reduce tissue inflammation, mitigate non-specific killing of gut bacteria, and abrogate iron-binding property of EA, thus providing a competitive edge to the microbiota in acquiring limiting nutrient iron and thrive in the gut.
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Piu
authors.initials: P
authors.lastname: Saha
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Beng San
authors.initials: BS
authors.lastname: Yeoh
authors.affiliation: Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Rajbir
authors.initials: R
authors.lastname: Singh
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (inStem), UAS-GKVK Campus, Bellary Road, Bangalore, Karnataka, India.
authors.forename: Bhargavi
authors.initials: B
authors.lastname: Chandrasekar
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (inStem), UAS-GKVK Campus, Bellary Road, Bangalore, Karnataka, India.|Ramalingaswami ReEntry Fellow, Dept. of Biotechnology, Govt. of India.
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Vemula
authors.affiliation: Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Bodduluri
authors.initials: B
authors.lastname: Haribabu
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Medicine, The Pennsylvania State University Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
authors.affiliation: Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Venkatakrishna R
authors.initials: VR
authors.lastname: Jala
mesh_terms: D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology; D003374:Coumarins / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D004032:Diet; D004487:Edema / Q000473:pathology; D004610:Ellagic Acid / Q000378:metabolism*; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D006418:Heme / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007501:Iron / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D007784:Lactoperoxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071068:Lipocalin-2 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
chemical_list: D003374:Coumarins; D007502:Iron Chelating Agents; D000071068:Lipocalin-2; D017382:Reactive Oxygen Species; C026423:3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one; D004610:Ellagic Acid; D006418:Heme; D007501:Iron; D007784:Lactoperoxidase; D009195:Peroxidase; D013755:Tetradecanoylphorbol Acetate