ABSTRACT

Both mast cells and microbiota play important roles in the pathogenesis of Irritable Bowel Syndrome (IBS), however the precise mechanisms are unknown. Using microbiota-humanized IBS mouse model, we show that colonic mast cells and mast cells co-localized with neurons were higher in mice colonized with IBS microbiota compared with those with healthy control (HC) microbiota. In situ hybridization showed presence of IBS, but not control microbiota, in the lamina propria and RNAscope demonstrated frequent co-localization of IBS bacteria and mast cells. TLR4 and H₄ receptor expression was higher in mice with IBS microbiota, and in peritoneal-derived and bone marrow-derived mast cells (BMMCs) stimulated with IBS bacterial supernatant, which also increased BMMCs degranulation, chemotaxis, adherence and histamine release. While both TLR4 and H₄ receptor inhibitors prevented BMMCs degranulation, only the latter attenuated their chemotaxis. We provide novel insights into the mechanisms, which contribute to gut dysfunction and visceral hypersensitivity in IBS.

摘要

肥大细胞和微生物群在肠易激综合征（IBS）的发病机制中发挥重要作用，但确切的机制尚不清楚。使用微生物群人源化 IBS 小鼠模型，我们发现与健康对照 (HC) 微生物群相比，在 IBS 微生物群定植的小鼠中，结肠肥大细胞和与神经元共定位的肥大细胞更高。原位杂交显示固有层中存在 IBS，但不存在对照微生物群，RNAscope 显示 IBS 细菌和肥大细胞频繁共定位。TLR4 和 H ₄在 IBS 微生物群的小鼠中，受体表达较高，在 IBS 细菌上清液刺激的腹膜来源和骨髓来源的肥大细胞 (BMMCs) 中，这也增加了 BMMCs 脱颗粒、趋化性、粘附和组胺释放。虽然 TLR4 和 H ₄受体抑制剂都阻止了 BMMC 脱粒，但只有后者减弱了它们的趋化性。我们对导致 IBS 中肠道功能障碍和内脏超敏反应的机制提供了新的见解。