Mice deficient in intestinal epithelial TLR9 develop small intestinal Paneth cell hyperplasia and higher Paneth cell IL‐17A levels. Since small intestinal Paneth cells and IL‐17A play critical roles in hepatic ischemia reperfusion (IR) injury, we tested whether mice lacking intestinal TLR9 have increased hepatic IR injury. Mice lacking intestinal TLR9 had profoundly increased liver injury after hepatic IR compared to WT mice with exacerbated hepatocyte necrosis, apoptosis, neutrophil infiltration, and inflammatory cytokine generation. Moreover, we observed increased small intestinal inflammation and apoptosis after hepatic IR in intestinal TLR9 deficient mice. As a potential explanation for increased hepatic IR injury, fecal short‐chain fatty acids butyrate and propionate levels were lower in intestinal TLR9 deficient mice. Suggesting a potential therapy for hepatic IR, exogenous administration of butyrate or propionate protected against hepatic IR injury in intestinal TLR9 deficient mice. Mechanistically, butyrate induced small intestinal IL‐10 expression and downregulated the claudin‐2 expression. Finally, IL‐10 neutralization abolished the protective effects of butyrate against hepatic IR injury. Our studies show intestinal TLR9 deficiency results in exacerbated hepatic IR injury with increased small intestinal apoptosis and inflammation. Furthermore, short‐chain fatty acids butyrate and propionate protect against hepatic IR injury and intestinal apoptosis/inflammation in intestinal TLR9 deficient mice.

中文翻译：

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肠道 TLR9 缺乏通过改变肠道炎症和短链脂肪酸合成加剧肝脏 IR 损伤

肠上皮 TLR9 缺陷的小鼠会出现小肠潘氏细胞增生和较高的潘氏细胞 IL-17A 水平。由于小肠 Paneth 细胞和 IL-17A 在肝缺血再灌注 (IR) 损伤中起关键作用，我们测试了缺乏肠道 TLR9 的小鼠是否增加了肝脏 IR 损伤。与肝细胞坏死、凋亡、中性粒细胞浸润和炎性细胞因子生成加剧的 WT 小鼠相比，缺乏肠道 TLR9 的小鼠在肝脏 IR 后肝损伤显着增加。此外，我们观察到肠道 TLR9 缺陷小鼠肝脏 IR 后小肠炎症和细胞凋亡增加。作为肝脏 IR 损伤增加的潜在解释，肠道 TLR9 缺陷小鼠的粪便短链脂肪酸丁酸和丙酸水平较低。建议一种潜在的肝脏 IR 疗法，丁酸盐或丙酸盐的外源性给药可保护肠道 TLR9 缺陷小鼠免受肝脏 IR 损伤。从机制上讲，丁酸盐诱导小肠 IL-10 表达并下调 claudin-2 表达。最后，IL-10 中和消除了丁酸盐对肝脏 IR 损伤的保护作用。我们的研究表明，肠道 TLR9 缺乏导致肝脏 IR 损伤加剧，小肠细胞凋亡和炎症增加。此外，短链脂肪酸丁酸和丙酸可防止肠道 TLR9 缺陷小鼠的肝脏 IR 损伤和肠道凋亡/炎症。丁酸盐诱导小肠 IL-10 表达并下调 claudin-2 表达。最后，IL-10 中和消除了丁酸盐对肝脏 IR 损伤的保护作用。我们的研究表明，肠道 TLR9 缺乏导致肝脏 IR 损伤加剧，小肠细胞凋亡和炎症增加。此外，短链脂肪酸丁酸和丙酸可防止肠道 TLR9 缺陷小鼠的肝脏 IR 损伤和肠道凋亡/炎症。丁酸盐诱导小肠 IL-10 表达并下调 claudin-2 表达。最后，IL-10 中和消除了丁酸盐对肝脏 IR 损伤的保护作用。我们的研究表明，肠道 TLR9 缺乏导致肝脏 IR 损伤加剧，小肠细胞凋亡和炎症增加。此外，短链脂肪酸丁酸和丙酸可防止肠道 TLR9 缺陷小鼠的肝脏 IR 损伤和肠道凋亡/炎症。