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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.
Abbreviations
| ANOSIM | = | Analysis of similarity |
| CXCL | = | Chemokine (C-X-C motif) |
| DMSO | = | Dimethylysulfoxide |
| ELISA | = | Enzyme-linked immunosorbent assay |
| FDR | = | False discovery rate |
| GI | = | Gastrointestinal |
| IL | = | Interleukin |
| LPS | = | Lipopolysaccharide |
| MLN | = | Mesenteric lymph node |
| NF-κB | = | Nuclear factor kappa-light-chain-enhancer of activated B cells |
| NSAID | = | Non-steroidal anti-inflammatory drug |
| OTU – | = | Operational taxonomic unit |
| PBS | = | Phosphate buffered saline |
| PCA | = | Principal component analysis |
| PICRUSt | = | Phylogenetic investigation of communities by reconstruction of unobserved states |
| QIIME | = | Quantitative insights into microbial ecology |
| RNA-Seq | = | RNA sequencing |
| SIMPER | = | Similarity percentage analysis |
| TLR | = | Toll-like receptor |
| TNF | = | Tumor necrosis factor |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Funding
This work was supported by grants from the Department of Large Animal Clinical Sciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America and a post-doctoral trainee grant from the College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America. Additional support was provided by the Link Equine Research Endowment at Texas A&M University and the Center for Translational Environmental Health Research (NIH P30ES023512). Dr. Chapkin is supported by a grant from the National Institutes of Health (NIH R35CA197707).