APC Microbiome Ireland, University College Cork, Cork, Ireland.
Department of Medicine, School of Medicine, University College Cork, Cork, Ireland.
Gut Microbes. 2023 Jan-Dec;15(1):2163838. doi: 10.1080/19490976.2022.2163838.
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 (AIEC)], might explain this inconsistent NSAIDs/IBD correlation. Using 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 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.
关于非甾体抗炎药 (NSAIDs) 的使用与炎症性肠病 (IBD) 症状恶化之间的关联存在相互矛盾的证据。我们假设，条件致病菌 [例如粘附侵袭性 (AIEC)] 的不同流行率可能解释了这种不一致的 NSAIDs/IBD 相关性。我们使用小鼠发现，NSAID 会加重 AIEC 定植动物的结肠炎。这伴随着 NLRP3 炎性体、Caspase-8、细胞凋亡和细胞焦亡的激活，这些特征在单独暴露于 AIEC 或 NSAID 的小鼠中没有出现，揭示了 AIEC/NSAID 的协同作用。抑制 NLRP3 或 Caspase-8 的活性可改善结肠炎，减少 NLRP3 炎性体的激活、细胞死亡标志物、活化的 T 细胞和巨噬细胞，改善组织学，并增加 XIVa 簇物种的丰度。我们的研究结果提供了新的见解，即 NSAIDs 和机会性肠道条件致病菌如何协同作用以加重 IBD 症状。针对 NLRP3 炎性体或 Caspase-8 可能是 NSAIDs 加重肠道炎症的 IBD 患者的一种潜在治疗策略。
