Obeticholic acid attenuates the intestinal barrier disruption in a rat model of short bowel syndrome.

Background: Short bowel syndrome (SBS) features nutrients malabsorption and impaired intestinal barrier. Patients with SBS are prone to sepsis, intestinal flora dysbiosis and intestinal failure associated liver disease. Protecting intestinal barrier and preventing complications are potential strategies for SBS treatment. This study aims to investigate the effects of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), have on intestinal barrier and ecological environment in SBS. Methods and results: Through testing the small intestine and serum samples of patients with SBS, impaired intestinal barrier was verified, as evidenced by reduced expressions of intestinal tight junction proteins (TJPs), increased levels of apoptosis and epithelial cell damage. The intestinal expressions of FXR and related downstream molecules were decreased in SBS patients. Then, global FXR activator OCA was used to further dissect the potential role of the FXR in a rat model of SBS. Low expressions of FXR-related molecules were observed on the small intestine of SBS rats, along with increased proinflammatory factors and damaged barrier function. Furthermore, SBS rats possessed significantly decreased body weight and elevated death rate. Supplementation with OCA mitigated the damaged intestinal barrier and increased proinflammatory factors in SBS rats, accompanied by activated FXR-related molecules. Using 16S rDNA sequencing, the regulatory role of OCA on gut microbiota in SBS rats was witnessed. LPS stimulation to Caco-2 cells induced apoptosis and overexpression of proinflammatory factors in vitro. OCA incubation of LPS-pretreated Caco-2 cells activated FXR-related molecules, increased the expressions of TJPs, ameliorated apoptosis and inhibited overexpression of proinflammatory factors. Conclusion: OCA supplementation could effectively ameliorate the intestinal barrier disruption and inhibit overexpression of proinflammatory factors in a rat model of SBS and LPS-pretreated Caco-2 cells. As a selective activator of FXR, OCA might realize its protective function through FXR activation.背景：短肠综合征（SBS）以营养吸收不良与肠屏障功能受损为主要特征，此类患者易并发脓毒症、肠道菌群失调及肠衰竭相关性肝病。保护肠屏障、防控并发症是短肠综合征治疗的潜在策略。本研究旨在探究法尼醇X受体（FXR）激动剂奥贝胆酸（OCA）对短肠综合征患者肠屏障及肠道微生态环境的影响。方法与结果：本研究通过检测短肠综合征患者的小肠组织与血清样本，证实其存在肠屏障功能受损，具体表现为肠紧密连接蛋白（TJPs）表达下调、细胞凋亡水平升高及上皮细胞损伤加重；且短肠综合征患者小肠组织中FXR及其相关下游分子的表达水平均显著降低。随后，本研究选用广谱FXR激动剂奥贝胆酸，在短肠综合征大鼠模型中进一步解析FXR的潜在作用。结果显示，短肠综合征大鼠小肠组织中FXR相关分子表达低下，同时伴随促炎因子水平升高与屏障功能受损；此外，短肠综合征大鼠体重显著降低，死亡率升高。给予奥贝胆酸干预可改善短肠综合征大鼠的肠屏障损伤，降低促炎因子水平，同时激活FXR相关分子通路。通过16S rDNA测序，本研究证实奥贝胆酸可调控短肠综合征大鼠的肠道菌群结构。体外实验中，脂多糖（LPS）刺激Caco-2细胞可诱导细胞凋亡及促炎因子过度表达；对脂多糖预处理后的Caco-2细胞给予奥贝胆酸孵育，可激活FXR相关分子通路，提升紧密连接蛋白表达，减轻细胞凋亡并抑制促炎因子的过度表达。结论：奥贝胆酸干预可有效改善短肠综合征大鼠模型及脂多糖预处理Caco-2细胞中的肠屏障破坏，并抑制促炎因子的过度表达。作为选择性FXR激动剂，奥贝胆酸或可通过激活FXR通路发挥肠道保护作用。