Rifaximin and lubiprostone mitigate liver fibrosis development by repairing gut barrier function in diet-induced rat steatohepatitis

Background: 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. Aims: To explore the effects of combination with rifaximin and lubiprostone on NASH liver fibrosis through the modulation of gut barrier function. Methods: 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. Results: 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. Conclusion: The combination of rifaximin and lubiprostone may provide a novel strategy for treating NASH-related fibrosis. (c) 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Automated summary

The combination of rifaximin and lubiprostone has been shown to effectively suppress the progression of liver fibrosis in non-alcoholic steatohepatitis (NASH) by modulating gut barrier function. This treatment strategy reduces macrophage expansion, inflammatory responses, and liver fibrosis by blocking the translocation of gut-derived lipopolysaccharide (LPS) and inhibiting toll-like receptor 4 signaling. In addition, rifaximin and lubiprostone restore intestinal permeability, improve the abundance of beneficial bacteria, and increase the production of short-chain fatty acids, contributing to the overall improvement of NASH-related fibrosis.