{
  "abstract": "Background Inflammatory bowel diseases (IBDs) are characterised by dysbiosis and a leaky gut. The NADPH oxidase dual oxidase 2 (DUOX2) is upregulated in patients with IBD, yet its role in driving the disease remains unclear.Objective We interrogated the functional consequences of epithelial DUOX2 activity for the host and microbiome.Design DUOX2 function was studied in mice with epithelial-specific DUOX2 overactivation (vTLR4), inactivation (vTLR4 DUOXA IEC-KO) and wild-type controls. We assessed the effect of dysbiosis on DUOX2 signalling and intestinal permeability (FITC-dextran, serum zonulin, bacterial translocation) with germ-free (GF) mice engrafted with IBD or healthy microbiota. RNA sequencing of colonic mucosa and microbiota and faecal metabolomics were used to characterise the host–microbe interface. Mechanistic studies were conducted in mouse colonoids, IBD biopsies and patient serum samples.Results DUOX2 activity increased permeability and bacterial translocation and induced subclinical inflammation in vTLR4 mice. GF vTLR4 mice had increased DUOX2 activity and permeability but no subclinical inflammation. In patients with IBD, DUOX2 expression was positively associated with plasma zonulin levels and negatively associated with ZO-1 expression. Engraftment of GF mice with IBD stool increased DUOX2 activity and triggered low-grade inflammation and permeability defects in mice. DUOX2 activity functionally altered the microbiome, reduced butyrate metabolism and promoted proinflammatory and pro-oncogenic bacterial metabolites. Butyrate and histone deacetylase (HDAC) inhibitors blocked DUOX2 activation and reversed its effects.Conclusions Elevated DUOX2 signalling contributes to epithelial barrier dysfunction, microbiome alterations and subclinical inflammation. Butyrate and HDAC inhibitors reversed these effects, indicating that DUOX2 may be a therapeutic target in IBD.",
  "authors": [
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA",
        "F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA"
      ],
      "name": "Hajar Hazime"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Gloria Michelle Ducasa"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Ana M Santander"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Nivis Brito"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Eddy Ernesto Gonzalez-Horta"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA",
        "F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA"
      ],
      "name": "Maria A Quintero"
    },
    {
      "affiliations": [
        "Department of Pharmacology and Toxicology, The University of Alabama Heersink School of Medicine, Birmingham, Alabama, USA"
      ],
      "name": "Stephen Barnes"
    },
    {
      "affiliations": [
        "Department of Pharmacology and Toxicology, The University of Alabama Heersink School of Medicine, Birmingham, Alabama, USA"
      ],
      "name": "Landon Wilson"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, Florida, USA"
      ],
      "name": "Yanping Zhang"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, Florida, USA"
      ],
      "name": "Fahong Yu"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Florida, Gainesville, Florida, USA"
      ],
      "name": "Raad Z Gharaibeh"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida, USA"
      ],
      "name": "Christian Jobin"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA",
        "F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA"
      ],
      "name": "Katerina M Faust"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Oriana M Damas"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Amar Deshpande"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "David H Kerman"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Siobhan Proksell"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Judith Pignac-Kobinger"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA",
        "F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA"
      ],
      "name": "Irina Fernández"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA"
      ],
      "name": "Juan F Burgueño"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA",
        "F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA"
      ],
      "name": "Maria T Abreu"
    }
  ],
  "title": "DUOX2 activation drives bacterial translocation and subclinical inflammation in IBD-associated dysbiosis",
  "uid": "f67e0e66-3b7e-513e-8612-a68ee0be9fb5"
}