An IBD-associated pathobiont synergises with NSAID to promote colitis which is blocked by NLRP3 inflammasome and Caspase-8 inhibitors

Conflicting evidence exists on the association between consumption of non-steroidal anti-inflammatory drugs (NSAIDs) and symptomatic worsening of inflammatory bowel disease (IBD). We hypothesise that the heterogeneous prevalence of pathobionts [e.g., adherent-invasive Escherichia coli (AIEC)], might explain this inconsistent NSAIDs/IBD correlation. Using IL10 -/- mice, we show aggravation of colitis in AIEC-colonised animals fed NSAID. This is accompanied by activation of the NLRP3 inflammasome, Caspase-8, apoptosis and pyroptosis; features not seen in mice exposed to AIEC or NSAID alone, revealing an AIEC/NSAID synergistic effect. Inhibition of NLRP3 or Caspase-8 activity ameliorated colitis, with reduction in NLRP3 inflammasome activation, cell death markers and activated T-cells and macrophages, improved histology and increased abundance of Clostridium cluster XIVa species. Our findings provide mechanistic insights into how NSAID and an opportunistic gut-pathobiont can synergise to worsen IBD symptoms. Thus, targeting the NLRP3 inflammasome and Caspase-8 could be a potential therapeutic strategy in patients with NSAID-worsened inflammation.