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 D 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 indomethacininduced shift of the microbiota.

Microbiota‐derived tryptophan indoles increase after gastric bypass surgery and reduce intestinal permeability in vitro and in vivo

“…At 40‐fold higher concentration (10 mmol L −1 for 24 hours) in HCT‐8 cells, indole increased TEER . In mice with small intestinal enteropathy, indole (20 mg kg −1 ) reduced infiltrating neutrophils and reversed the upregulation of inflammatory genes (including IL‐1α, IL1‐β, TNF‐α, and IL‐6) induced by indomethacin . Local indole exposure levels may be higher in vivo, than we were able to replicate in vitro, eg, human feces have high μmol L −1 to low mmol L −1 indole levels .…”

“…24 In mice with small intestinal enteropathy, indole (20 mg kg −1 ) reduced infiltrating neutrophils and reversed the upregulation of inflammatory genes (including IL-1α, IL1β, TNFα, and IL-6) induced by indomethacin. 32 Local indole exposure levels may be higher in vivo, than we were able to replicate in vitro, eg, human feces have high μmol L −1 to low mmol L −1 indole levels. 25 Tryptamine (bacterially derived, as described above) was an indole derivative that LGR5 VILL1 OLCN TJP1 SLC2A5 SLC51B SLC10A SLC25A SLC5A1 BCAT2 BCKDHA CCBL1 TPH1 IDO1 TNF IL6 TRIL IL22 IL1b TLR3 FOXA1 FOXA2 FFAR2 PDX11 HDAC3 HDAC5 HNF4a HNF1a GATA4 REG3a GPBAR1 TMPRSS GCG SPLC1 GLS ACLY CS MDH2 MDH1 PCK1 G6PC 0 1 2 3 4 5 10 30 10 000 20 000…”

The gut microbiota metabolite indole alleviates liver inflammation in mice

“…This metabolite and related bacterial compounds (indole-3-aldehyde, indole-3-lactate, and indole-3-propionate) were previously shown to reduce intestinal inflammation and to prevent gut barrier dysfunction (19, 25, 26, 35–38). In the present study, we show for the first time that indole alleviates inflammation in the liver, away from the gut.…”

Effect of selective versus nonselective cyclooxygenase inhibitors on gastric ulceration scores and intestinal inflammation in horses

“…This theory may be an oversimplification of the mechanisms involved and explain why COX‐2‐selective NSAID did not reduce the incidence of NSAID enteropathy in several studies of human patients . The conflicting findings would instead support a complex pathophysiology of NSAID enteropathy, involving many factors beyond COX inhibition, such as the microbiota, direct epithelial damage to the intestine, and idiosyncratic responses to these drugs . Variability in some or all of these individual factors (eg, microbiota composition, idiosyncratic responses) likely explains the variation in fecal MPO among horses within the same treatment group in our study .…”