title: The microbiota-derived metabolite indole decreases mucosal inflammation and injury in a murine model of NSAID enteropathy.
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently used classes of medications in the world. Unfortunately, NSAIDs induce an enteropathy associated with high morbidity and mortality. Although the pathophysiology of this condition involves the interaction of the gut epithelium, microbiota, and NSAIDs, the precise mechanisms by which microbiota influence NSAID enteropathy are unclear. One possible mechanism is that the microbiota may attenuate the severity of disease by specific metabolite-mediated regulation of host inflammation and injury. The microbiota-derived tryptophan-metabolite indole is abundant in the healthy mammalian gut and positively influences intestinal health. We thus examined the effects of indole administration on NSAID enteropathy. Mice (n = 5 per group) were treated once daily for 7 days with an NSAID (indomethacin; 5 mg/kg), indole (20 mg/kg), indomethacin plus indole, or vehicle only (control). Outcomes compared among groups included: microscopic pathology; fecal calprotectin concentration; proportion of neutrophils in the spleen and mesenteric lymph nodes; fecal microbiota composition and diversity; small intestinal mucosal transcriptome; and, fecal tryptophan metabolites. Co-administration of indole with indomethacin: significantly reduced mucosal pathology scores, fecal calprotectin concentrations, and neutrophilic infiltration of the spleen and mesenteric lymph nodes induced by indomethacin; modulated NSAID-induced perturbation of the microbiota, fecal metabolites, and inferred metagenome; and, abrogated a pro-inflammatory gene expression profile in the small intestinal mucosa induced by indomethacin. The microbiota-derived metabolite indole attenuated multiple deleterious effects of NSAID enteropathy, including modulating inflammation mediated by innate immune responses and altering indomethacin-induced shift of the microbiota.
authors.affiliation: a Department of Large Animal Clinical Sciences , College of Veterinary Medicine & Biomedical Sciences, Texas A&M University , College Station , Texas , USA.
authors.forename: Canaan M
authors.initials: CM
authors.lastname: Whitfield-Cargile
authors.affiliation: a Department of Large Animal Clinical Sciences , College of Veterinary Medicine & Biomedical Sciences, Texas A&M University , College Station , Texas , USA.
authors.forename: Noah D
authors.initials: ND
authors.lastname: Cohen
authors.affiliation: b Department of Nutrition and Food Science , College of Agriculture and Life Sciences, Texas A&M University , College Station , Texas , USA.|d Department of Microbial Pathogenesis and Immunology , College of Medicine, Texas A&M Health Science Center, Texas A&M University , College Station , Texas , USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chapkin
authors.affiliation: c Department of Veterinary Pathobiology , College of Veterinary Medicine & Biomedical Sciences, Texas A&M University , College Station , Texas , USA.
authors.forename: Brad R
authors.initials: BR
authors.lastname: Weeks
authors.affiliation: b Department of Nutrition and Food Science , College of Agriculture and Life Sciences, Texas A&M University , College Station , Texas , USA.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Davidson
authors.affiliation: b Department of Nutrition and Food Science , College of Agriculture and Life Sciences, Texas A&M University , College Station , Texas , USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Goldsby
authors.affiliation: d Department of Microbial Pathogenesis and Immunology , College of Medicine, Texas A&M Health Science Center, Texas A&M University , College Station , Texas , USA.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Hunt
authors.affiliation: d Department of Microbial Pathogenesis and Immunology , College of Medicine, Texas A&M Health Science Center, Texas A&M University , College Station , Texas , USA.
authors.forename: Shelby H
authors.initials: SH
authors.lastname: Steinmeyer
authors.affiliation: e Department of Chemical Engineering , College of Engineering, Texas A&M University , College Station , Texas , USA.
authors.forename: Rani
authors.initials: R
authors.lastname: Menon
authors.affiliation: f Department of Small Animal Clinical Sciences , College of Veterinary Medicine & Biomedical Sciences, Texas A&M University , College Station , Texas , USA.
authors.forename: Jan S
authors.initials: JS
authors.lastname: Suchodolski
authors.affiliation: e Department of Chemical Engineering , College of Engineering, Texas A&M University , College Station , Texas , USA.
authors.forename: Arul
authors.initials: A
authors.lastname: Jayaraman
authors.affiliation: d Department of Microbial Pathogenesis and Immunology , College of Medicine, Texas A&M Health Science Center, Texas A&M University , College Station , Texas , USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Alaniz
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D001419:Bacteria / Q000145:classification / Q000302:isolation & purification; D058448:Biota; D004195:Disease Models, Animal; D004751:Enteritis / Q000139:chemically induced / Q000188:drug therapy*; D005243:Feces / Q000737:chemistry / Q000382:microbiology; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006651:Histocytochemistry; D007211:Indoles / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology*; D039841:Leukocyte L1 Antigen Complex / Q000032:analysis; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D009504:Neutrophils / Q000276:immunology; D013154:Spleen / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005765:Gastrointestinal Agents; D007211:Indoles; D039841:Leukocyte L1 Antigen Complex; C030374:indole
keywords: dysbiosis; indole; microbial metabolites; microbiota; non-steroidal antiinflammatory drugs (NSAIDs); transcriptome