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

Raminder Singh; Valerio Rossini; Stephen R Stockdale; Gonzalo Saiz-Gonzalo; Naomi Hanrahan; Tanya D' Souza; Adam Clooney; Lorraine A Draper; Colin Hill; Ken Nally; Fergus Shanahan; Stefan Andersson-Engels; Silvia Melgar

doi:10.1080/19490976.2022.2163838

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

Gut Microbes. 2023 Jan-Dec;15(1):2163838. doi: 10.1080/19490976.2022.2163838.

Authors

Raminder Singh^{1

2}, Valerio Rossini¹, Stephen R Stockdale¹, Gonzalo Saiz-Gonzalo^{1

2

3}, Naomi Hanrahan^{1

2

3}, Tanya D' Souza¹, Adam Clooney¹, Lorraine A Draper¹, Colin Hill^{1

4}, Ken Nally^{1

3}, Fergus Shanahan¹, Stefan Andersson-Engels^{5

6}, Silvia Melgar¹

Affiliations

¹ APC Microbiome Ireland, University College Cork, Cork, Ireland.
² Department of Medicine, School of Medicine, University College Cork, Cork, Ireland.
³ School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
⁴ School of Microbiology, University College Cork, Cork, Ireland.
⁵ Irish Photonics Integration Centre, Tyndall National Institute, Cork, Ireland.
⁶ Department of Physics, University College Cork, Cork, Ireland.

Abstract

Conflicting evidence exists on the association between consumption of non-steroidal anti-inflammatory drugs (NSAIDs) and symptomatic worsening of inflammatory bowel disease (IBD). We hypothesized that the heterogeneous prevalence of pathobionts [e.g., adherent-invasive Escherichia coli (AIEC)], might explain this inconsistent NSAIDs/IBD correlation. Using IL10^-/- mice, we found that NSAID aggravated colitis in AIEC-colonized animals. This was 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, activated T-cells and macrophages, improved histology, and increased abundance of Clostridium cluster XIVa species. Our findings provide new insights into how NSAIDs and an opportunistic gut-pathobiont can synergize to worsen IBD symptoms. Targeting the NLRP3 inflammasome or Caspase-8 could be a potential therapeutic strategy in IBD patients with gut inflammation, which is worsened by NSAIDs.

Keywords: AIEC; IL10−/− mice; cell death; inflammasome; inflammatory bowel disease; piroxicam.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal* / adverse effects
Caspase 8 / metabolism
Caspase Inhibitors / pharmacology
Colitis* / chemically induced
Colitis* / drug therapy
Colitis* / microbiology
Escherichia coli / pathogenicity
Gastrointestinal Microbiome*
Inflammasomes
Inflammatory Bowel Diseases* / drug therapy
Inflammatory Bowel Diseases* / microbiology
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism

Substances

Anti-Inflammatory Agents, Non-Steroidal
Caspase 8
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Caspase Inhibitors

Grants and funding

This work and the authors were supported by the Science Foundation Ireland (SFI) Research Centre awards SFI/12/RC/2273-P1 and SFI/12/RC/2273-P2 to APC Microbiome Ireland and SFI Professor award grant number SFI/15/RP/2828 to SA-E. GS-G is a recipient of a Government of Ireland Postgraduate Scholarship (grant GOIPG/2019/4528).