Abstract
The progression of nonalcoholic steatohepatitis (NASH) is complicated. The multiple parallel-hits theory is advocated, which includes adipocytokines, insulin resistance, endotoxins, and oxidative stress. Pathways involving the gut–liver axis also mediate the progression of NASH. Angiotensin-II receptor blockers (ARB) suppress hepatic fibrosis via the activation of hepatic stellate cells (HSCs). Rifaximin, a nonabsorbable antibacterial agent, is used for the treatment of hepatic encephalopathy and has been recently reported to improve intestinal permeability. We examined the inhibitory effects on and mechanism of hepatic fibrogenesis by combining ARB and rifaximin administration. Fischer 344 rats were fed a choline-deficient/l-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. The therapeutic effect of combining an ARB and rifaximin was evaluated along with hepatic fibrogenesis, the lipopolysaccharide–Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. ARBs had a potent inhibitory effect on hepatic fibrogenesis by suppressing HSC activation and hepatic expression of transforming growth factor-β and TLR4. Rifaximin reduced intestinal permeability by rescuing zonula occludens-1 (ZO-1) disruption induced by the CDAA diet and reduced portal endotoxin. Rifaximin directly affect to ZO-1 expression on intestinal epithelial cells. The combination of an ARB and rifaximin showed a stronger inhibitory effect compared to that conferred by a single agent. ARBs improve hepatic fibrosis by inhibiting HSCs, whereas rifaximin improves hepatic fibrosis by improving intestinal permeability through improving intestinal tight junction proteins (ZO-1). Therefore, the combination of ARBs and rifaximin may be a promising therapy for NASH fibrosis.
Highlights
In recent years, the number of patients with metabolic syndrome has been increasing worldwide due to lack of satiety or exercise
We previously demonstrated that blockade of angiotensin-II (AT-II) signaling through AT-II type 1 receptor (AT1R) prevents hepatic fibrogenesis in rats [19,20]
We demonstrated that AT-II augments LPS-Toll-like receptor 4 (TLR4)-NF-κB signaling, which plays a pivotal role in hepatic fibrogenesis, through Angiotensin-II receptor blockers (ARB), and AT1R improves liver fibrogenesis and decreases TLR4-mediated innate immune signaling in Ac-hepatic stellate cells (HSCs) [22,23]
Summary
The number of patients with metabolic syndrome has been increasing worldwide due to lack of satiety or exercise. The gut–liver axis has garnered much attention as it is one of the most important links between gut microbiota and extra-intestinal organs It acts as a communication portal between the intestine and the liver. When the intestinal barrier is damaged and becomes increasingly permeable, the liver is automatically exposed to many enterotoxic factors in addition to intestinal bacteria [8] They can act on cells of the hepatic innate immune system, like Kupffer cells or astrocytes [9]. Previous studies have reported that decrease in LPS and restoration of intestinal TJP suppress liver fibrosis development in NASH [5,12]. Rifaximin may inhibit liver fibrosis by reducing LPS through improving intestinal tight junctions. We hypothesized that the combination of ARB and rifaximin may be useful in suppressing NASH fibrosis
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call