Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) can cause significant small bowel injuries. The role of gut microbiota in this NSAID-induced enteropathy is poorly understood. We studied the dynamic changes in gut microbiota following indomethacin administration in mice, and investigated the effects of these adaptive changes on subsequent NSAID-induced enteropathy. The changes in gut microbiota were studied using 16S rRNA sequencing, and the effects of such changes were investigated using antibiotics and a faecal transplantation model. After indomethacin treatment, significant adaptive changes in gut microbiota were observed, including increased abundance of Firmicutes and decreased abundance in that of Bacteroidetes. Depletion of gut microbiota with antibiotics led to a higher mortality (P = 0.0021) in mice compared to controls. Mice pre-transplanted with adaptively changed microbiota showed less small bowel injury and lower levels of pro-inflammatory cytokines when exposed to indomethacin. In summary, this study identifies adaptive changes in the gut microbiota upon indomethacin administration, which can in turn ameliorate further NSAID-induced injury. The heightened mortality with antibiotic depletion of the adaptively changed microbiota suggests its important role in protecting against such injury. This study provides insight for future efforts to target the microbiota as a therapeutic strategy.

Highlights

  • The pathogenesis of Non-steroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy is complex

  • Antibiotic depletion of gut microbiota resulted in an increased mortality in indomethacin treated mice

  • Post-mortem examination showed that mice died in antibiotics group suffered from severe peritonitis and small intestinal perforation, where the only deceased mouse in the control group died from small intestinal bleeding (Supplementary Fig. S1)

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Summary

Introduction

The pathogenesis of NSAID-induced enteropathy is complex. Commensal microbiota has been implicated in the pathogenesis of NSAIDs enteropathy. Germ-free mice are resistant to indomethacin-induced small bowel injuries, but would become susceptible when colonized with commensal microbiota[4,5]. The use of antibiotics has been shown to reduce indomethacin-induced small bowel injuries in rats[6,7]. Gut commensal microbiota has been shown to change rapidly after NSAID administration in animal models[8,9]. The effects of these adaptive changes in gut microbiota in response to NSAIDs is not clear. We studied how the dynamic changed gut microbiota could influence pathogenesis of indomethacin-induced enteropathy

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