Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
Dig Liver Dis. 2022 Oct;54(10):1392-1402. doi: 10.1016/j.dld.2022.04.012. Epub 2022 May 3.
Although gut-derived lipopolysaccharide (LPS) affects the progression of non-alcoholic steatohepatitis (NASH) pathogenesis, few studies have focused on this relationship to develop treatments for NASH.
To explore the effects of combination with rifaximin and lubiprostone on NASH liver fibrosis through the modulation of gut barrier function.
To induce steatohepatitis, F344 rats were fed a choline-deficient l-amino acid-defined (CDAA) diet for 12 weeks and received oral administration of rifaximin and/or lubiprostone. Histological, molecular, and fecal microbial analyses were performed. Barrier function in Caco-2 cells were assessed by in vitro assays.
Combination rifaximin/lubiprostone treatment significantly suppressed macrophage expansion, proinflammatory responses, and liver fibrosis in CDAA-fed rats by blocking hepatic translocation of LPS and activation of toll-like receptor 4 signaling. Rifaximin and lubiprostone improved intestinal permeability via restoring tight junction proteins (TJPs) with the intestinal activation of pregnane X receptor and chloride channel-2, respectively. Moreover, this combination increased the abundance of Bacteroides, Lactobacillus, and Faecalibacterium as well as decreased that of Veillonella resulting in an increase of fecal short-chain fatty acids and a decrease of intestinal sialidase activity. Both agents also directly suppressed the LPS-induced barrier dysfunction and depletion of TJPs in Caco-2 cells.
The combination of rifaximin and lubiprostone may provide a novel strategy for treating NASH-related fibrosis.
尽管肠道来源的脂多糖（LPS）会影响非酒精性脂肪性肝炎（NASH）的发病进程，但很少有研究关注这种关系以开发 NASH 的治疗方法。
通过调节肠道屏障功能，探索利福昔明和鲁比前列酮联合治疗对 NASH 肝纤维化的影响。
为了诱导脂肪性肝炎，F344 大鼠喂食胆碱缺乏 l-氨基酸定义（CDAA）饮食 12 周，并接受利福昔明和/或鲁比前列酮的口服给药。进行组织学、分子和粪便微生物分析。通过体外测定评估 Caco-2 细胞的屏障功能。
利福昔明/鲁比前列酮联合治疗通过阻断 LPS 肝内易位和 Toll 样受体 4 信号转导，显著抑制 CDAA 喂养大鼠的巨噬细胞扩张、促炎反应和肝纤维化。利福昔明和鲁比前列酮通过分别恢复紧密连接蛋白（TJPs）和激活孕烷 X 受体和氯离子通道-2 来改善肠道通透性。此外，这种联合用药增加了拟杆菌、乳杆菌和粪杆菌的丰度，降低了韦荣球菌的丰度，导致粪便短链脂肪酸增加，肠道唾液酸酶活性降低。两种药物还直接抑制 LPS 诱导的 Caco-2 细胞屏障功能障碍和 TJPs 耗竭。
利福昔明和鲁比前列酮的联合应用可能为治疗 NASH 相关纤维化提供一种新策略。
