Wang Shouli, Kuang Junliang, Zhang Hongwei, Chen Wenlian, Zheng Xiaojiao, Wang Jieyi, Huang Fengjie, Ge Kun, Li Mengci, Zhao Mingliang, Rajani Cynthia, Zhu Jinshui, Zhao Aihua, Jia Wei
Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Department of Metabolic and Bariatric Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Adv Sci (Weinh). 2022 May;9(16):e2200263. doi: 10.1002/advs.202200263. Epub 2022 Mar 14.
Bile reflux gastritis (BRG) is associated with the development of gastric cancer (GC), but the specific mechanism remains elusive. Here, a comprehensive study is conducted to explore the roles of refluxed bile acids (BAs) and microbiome in gastric carcinogenesis. The results show that conjugated BAs, interleukin 6 (IL-6), lipopolysaccharide (LPS), and the relative abundance of LPS-producing bacteria are increased significantly in the gastric juice of both BRG and GC patients. A secondary BA, taurodeoxycholic acid (TDCA), is significantly and positively correlated with the LPS-producing bacteria in the gastric juice of these patients. TDCA promotes the proliferation of normal gastric epithelial cells (GES-1) through activation of the IL-6/JAK1/STAT3 pathway. These results are further verified in two mouse models, one by gavage of TDCA, LPS, and LPS-producing bacteria (Prevotella melaninogenica), respectively, and the other by bile reflux (BR) surgery, mimicking clinical bile refluxing. Moreover, the bile reflux induced gastric precancerous lesions observed in the post BR surgery mice can be prevented by treatment with cryptotanshinone, a plant-derived STAT3 inhibitor. These results reveal an important underlying mechanism by which bile reflux promotes gastric carcinogenesis and provide an alternative strategy for the prevention of GC associated with BRG.
胆汁反流性胃炎（BRG）与胃癌（GC）的发生有关，但其具体机制仍不清楚。在此，进行了一项全面研究，以探讨反流胆汁酸（BAs）和微生物群在胃癌发生中的作用。结果显示，在BRG和GC患者的胃液中，结合型BAs、白细胞介素6（IL-6）、脂多糖（LPS）以及产LPS细菌的相对丰度均显著增加。次级胆汁酸牛磺脱氧胆酸（TDCA）与这些患者胃液中产LPS细菌显著正相关。TDCA通过激活IL-6/JAK1/STAT3通路促进正常胃上皮细胞（GES-1）的增殖。这些结果在两种小鼠模型中得到进一步验证，一种分别通过灌胃TDCA、LPS和产LPS细菌（产黑素普雷沃菌），另一种通过胆汁反流（BR）手术模拟临床胆汁反流。此外，在BR手术后小鼠中观察到的胆汁反流诱导的胃癌前病变可通过用隐丹参酮（一种植物源性STAT3抑制剂）治疗来预防。这些结果揭示了胆汁反流促进胃癌发生的一个重要潜在机制，并为预防与BRG相关的GC提供了一种替代策略。
