Trim27 deficiency triggers irritable bowel syndrome by inhibiting Wnt/beta-catenin signaling in intestinal stem cells

Gastrointestinal disorders severely impair the quality of life of patients and impose a considerable burden on the global economy. Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are two of the most common gastrointestinal disorders, which usually share overlapping symptoms. The pathogenesis of IBD has been elucidated, but the pathogenesis of IBS remains poorly understood, which largely limits the diagnosis and treatment of IBS. Here we identify that Trim27 is a critical host factor for inhibiting IBS, which promotes the activation of Wnt signaling pathway in intestinal stem cells (ISCs) by stabilizing beta-catenin, thus promoting the self-renewal and differentiation of ISCs to maintain intestinal homeostasis. We found that Trim27-knockout (Trim27-/-) mice exhibited elevated levels of pro-inflammatory cytokines, chemokines, 5-HT and disorders of gut microbiota, which phenotypes are consistent with the symptoms of IBS patients. Moreover, complementary expression of Trim27 or beta-catenin can rescue the disruption of organoid formation in mice that Trim27 is specifically knockout in Lgr5-positive ISCs (trim27[Lgr5]). Furthermore, beta-catenin degradation inhibitor or probiotic treatment can ameliorate IBS symptoms in trim27[Lgr5] mice. Collectively, our study reveals the key host regulatory factors and potential pathogenesis of IBS, thus providing novel strategies for the diagnosis and treatment of IBS.

胃肠道疾病会严重损害患者的生活质量，并给全球经济带来沉重负担。炎症性肠病（Inflammatory Bowel Disease，IBD）与肠易激综合征（Irritable Bowel Syndrome，IBS）是两类最为常见的胃肠道疾病，二者通常存在症状重叠的情况。目前炎症性肠病的发病机制已得到阐明，但肠易激综合征的发病机制仍不甚明晰，这在很大程度上限制了其诊疗工作的开展。本研究发现Trim27是抑制肠易激综合征的关键宿主因子，其可通过稳定β-连环蛋白（beta-catenin），激活肠干细胞（Intestinal Stem Cells，ISCs）中的Wnt信号通路（Wnt signaling pathway），进而促进肠干细胞的自我更新与分化，以维持肠道稳态。我们观察到，Trim27基因敲除（Trim27-/-）小鼠体内的促炎细胞因子、趋化因子、5-羟色胺（5-HT）水平升高，且肠道菌群（gut microbiota）结构紊乱，这些表型与肠易激综合征患者的症状高度相符。此外，在Lgr5阳性肠干细胞（Lgr5-positive Intestinal Stem Cells）中特异性敲除Trim27的小鼠（trim27[Lgr5]）中，若补充表达Trim27或β-连环蛋白，可挽救其类器官（organoid）形成受损的表型。进一步研究发现，β-连环蛋白降解抑制剂或益生菌（probiotic）干预可改善trim27[Lgr5]小鼠的肠易激综合征症状。综上，本研究揭示了肠易激综合征的关键宿主调控因子与潜在发病机制，为肠易激综合征的诊疗提供了全新的策略。