{
  "abstract": "Background Both host and microbe metabolism of tryptophan (Trp) is altered in diabetes; however, the molecular mechanisms are incompletely understood.Objective We used strategies to increase either angiotensin converting enzyme-2 (ACE-2) dependent or independent Trp absorption in a model of type 2 diabetes, db/db mice, and tested whether the strategies could prevent development of diabetic retinopathy (DR), the most common microvascular complication of diabetes. Additionally, we investigated levels of Trp metabolites in humans with and without DR.Design Enhanced ACE-2 dependent Trp absorption was achieved with gavage of genetically modified bacteria that preserved intestinal ACE2:sodium coupled neutral amino acid transporter expression. ACE-2 independent Trp absorption was achieved by gavage of the Trp dipeptide (Isoleucine-Trp; IW) absorbed via solute carrier family 15 member 1. Both strategies were used either as a prevention (6 months treatment) or intervention (3 months treatment) and at the conclusion, intestinal, metabolic and retinal studies were performed including spatial mass spectroscopy (MS). Plasma Trp metabolites and gut permeability markers were measured in individuals with T2D with (n=30) and without (n=40) DR and compared with healthy controls (n=35).Results Lactobacillus paracasei-ACE2 or IW treatment prevented DR, corrected dysbiosis, enriched Trp-metabolising bacteria, improved gut barrier integrity, boosted incretin secretion and restored glucose homeostasis in db/db mice. Spatial MS identified indole propionic acid (IPA) as a metabolite in the retinal pigment epithelial layer protecting the posterior blood retinal barrier. T2D individuals with DR demonstrated elevated serum markers of endotoxemia and intestinal barrier disruption while showing reduced levels of the beneficial metabolite IPA and elevated levels of the toxic metabolite indole sulfate.Conclusion Nutraceutical strategies that restore Trp metabolism or IPA serve as both a biomarker and a treatment for DR.",
  "authors": [
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Ram Prasad"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Yvonne Adu-Rutledge"
    },
    {
      "affiliations": [
        "Department of Biochemistry & Molecular Biology and Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA"
      ],
      "name": "Borhane Ziani"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Jason L Floyd"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Edgar L Ready"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Sarbodeep Paul"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Fadeela Sheini"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Rati Sharma"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Robert F Rosencrans"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Sergio Li Calzi"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Micheli Severo Sielski"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Nicholas G Medawar"
    },
    {
      "affiliations": [
        "Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Roshan Dutta"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Emory Brennis Johnson"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Xiaoping Qi"
    },
    {
      "affiliations": [
        "Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Mohit Bansal"
    },
    {
      "affiliations": [
        "Wright Labs LLC, Huntingdon, Pennsylvania, USA"
      ],
      "name": "Regina Lamendella"
    },
    {
      "affiliations": [
        "Biology, Juniata College, Huntingdon, Pennsylvania, USA"
      ],
      "name": "Justin R Wright"
    },
    {
      "affiliations": [
        "Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Suresh Kumar Verma"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Michael E Boulton"
    },
    {
      "affiliations": [
        "Physiology & Functional Genomics, University of Florida College of Medicine, Gainesville, Florida, USA"
      ],
      "name": "Bruce R Stevens"
    },
    {
      "affiliations": [
        "Department of Biochemistry & Molecular Biology and Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA"
      ],
      "name": "Craig W Vander Kooi"
    },
    {
      "affiliations": [
        "Department of Biochemistry & Molecular Biology and Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida, USA"
      ],
      "name": "Ramon C Sun"
    },
    {
      "affiliations": [
        "Department of Medicine, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada"
      ],
      "name": "Gavin Y Oudit"
    },
    {
      "affiliations": [
        "Department of Ophthalmology, University of Florida, Gainesville, Florida, USA"
      ],
      "name": "Qiuhong Li"
    },
    {
      "affiliations": [
        "Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USA"
      ],
      "name": "Maria B Grant"
    }
  ],
  "title": "Indole-3-propionic acid links gut dysfunction to diabetic retinopathy: a biomarker and novel therapeutic approach",
  "uid": "ae4a783a-d026-5639-9139-87aa13bcef39"
}