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Inhibition of DPP9 has recently been shown to activate the nucleotide-binding domain leucine-rich repeat 1 (NLRP1) inflammasome. NLRP1 is known to bind nucleic acids with high affinity and directly interact with double stranded RNA, which plays a key role in viral replication. DPP9 has also recently emerged as a key gene related to lung-inflammation in critical SARS-CoV-2 infection. Importantly, DPP9 activity is strongly dependent on the oxidative status. Here, we explored the potential role of DPP9 in the gastrointestinal tract. We performed transcriptomics analyses of colon (microarray, n = 37) and jejunal (RNA sequencing, n = 31) biopsies from two independent cohorts as well as plasma metabolomics analyses in two independent cohorts (n = 37 and n = 795). The expression of DPP9 in the jejunum, colon, and blood was significantly associated with circulating biomarkers of oxidative stress (uric acid, bilirubin). It was also associated positively with the expression of transcription factors (NRF-2) and genes (SOD, CAT, GPX) encoding for antioxidant enzymes, but negatively with that of genes (XDH, NOX) and transcription factors (NF-KB) involved in ROS-generating enzymes. Gene co-expression patterns associated with DPP9 identified several genes participating in antiviral pathways in both tissues. Notably, DPP9 expression in the colon and plasma was strongly positively associated with several circulating nucleotide catabolites (hypoxanthine, uric acid, 3-ureidopropionic acid) with important roles in the generation of ROS and viral infection, as well as other metabolites related to oxidative stress (Resolvin D1, glutamate-containing dipeptides). Gene-drug enrichment analyses identified artenimol, puromycin, anisomycin, 3-phenyllactic acid, and linezolid as the most promising drugs targeting these DPP9-associated genes. We have identified a novel potential pathogenic mechanism of viral infection in the digestive tract and promising existing drugs that can be repositioned against viral infection.<\/jats:p>","DOI":"10.3390\/antiox11112177","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T03:28:10Z","timestamp":1667532490000},"page":"2177","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["DPP9 as a Potential Novel Mediator in Gastrointestinal Virus Infection"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0140-1418","authenticated-orcid":false,"given":"\u00c1ngela","family":"del Castillo-Izquierdo","sequence":"first","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, 17007 Girona, Spain"},{"name":"Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2883-511X","authenticated-orcid":false,"given":"Jos\u00e9 Mar\u00eda","family":"Moreno-Navarrete","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, 17007 Girona, Spain"},{"name":"Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Medical Sciences, School of Medicine, University of Girona, 17004 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7603-1458","authenticated-orcid":false,"given":"Jessica","family":"Latorre","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, 17007 Girona, Spain"},{"name":"Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Arnoriaga-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, 17007 Girona, Spain"},{"name":"Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Medical Sciences, School of Medicine, University of Girona, 17004 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Ballanti","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"Center for Atherosclerosis, Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1339-9076","authenticated-orcid":false,"given":"Giovanni","family":"Monteleone","sequence":"additional","affiliation":[{"name":"Center for Atherosclerosis, Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omero","family":"Alessandro Paoluzi","sequence":"additional","affiliation":[{"name":"Center for Atherosclerosis, Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geltrude","family":"Mingrone","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Catholic University, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Diabetes and Nutritional Sciences, Hodgkin Building, Guy\u2019s Campus, King\u2019s College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2791-6599","authenticated-orcid":false,"given":"Josep","family":"Puig","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, 17007 Girona, Spain"},{"name":"Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain"},{"name":"Department of Medical Sciences, School of Medicine, University of Girona, 17004 Girona, Spain"},{"name":"Department of Radiology (IDI), Hospital Universitari de Girona Dr. Josep Trueta, 17007 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Ramos","sequence":"additional","affiliation":[{"name":"Department of Diabetes, 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25198 Lleida, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1424-8958","authenticated-orcid":false,"given":"Joaquim","family":"Sol","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Lleida-Lleida Biomedical Research Institute (UdL-IRBLleida), 25198 Lleida, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9366-5129","authenticated-orcid":false,"given":"Philippe","family":"Lefebvre","sequence":"additional","affiliation":[{"name":"Institut Pasteur de Lille, Universit\u00e9 Lille, Inserm, CHU Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3784-1503","authenticated-orcid":false,"given":"Bart","family":"Staels","sequence":"additional","affiliation":[{"name":"Institut Pasteur de Lille, Universit\u00e9 Lille, Inserm, CHU Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Federici","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"Center for Atherosclerosis, Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7442-9323","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Fern\u00e1ndez-Real","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, 17007 Girona, Spain"},{"name":"Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Medical Sciences, School of Medicine, University of Girona, 17004 Girona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3788-3815","authenticated-orcid":false,"given":"Jordi","family":"Mayneris-Perxachs","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, 17007 Girona, Spain"},{"name":"Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"aaf6395","DOI":"10.1126\/science.aaf6395","article-title":"Intracellular Innate Immune Surveillance Devices in Plants and 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Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eaay2002","DOI":"10.1126\/science.aay2002","article-title":"Enteroviral 3C Protease Activates the Human NLRP1 Inflammasome in Airway Epithelia","volume":"370","author":"Robinson","year":"2020","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"eabd0811","DOI":"10.1126\/science.abd0811","article-title":"Human NLRP1 Is a Sensor for Double-Stranded RNA","volume":"371","author":"Bauernfried","year":"2021","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"387","DOI":"10.3389\/fimmu.2015.00387","article-title":"The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis","volume":"6","author":"Waumans","year":"2015","journal-title":"Front. 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