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Combining probiotics and an angiotensin‐II type 1 receptor blocker has beneficial effects on hepatic fibrogenesis in a rat model of non‐alcoholic steatohepatitis
Author(s) -
Sawada Yasuhiko,
Kawaratani Hideto,
Kubo Takuya,
Fujinaga Yukihisa,
Furukawa Masanori,
Saikawa Soichiro,
Sato Shinya,
Seki Kenichiro,
Takaya Hiroaki,
Okura Yasushi,
Kaji Kosuke,
Shimozato Naotaka,
Mashitani Tsuyoshi,
Kitade Mitsuteru,
Moriya Kei,
Namisaki Tadashi,
Akahane Takemi,
Mitoro Akira,
Yamao Junichi,
Yoshiji Hitoshi
Publication year - 2019
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/hepr.13281
Subject(s) - steatohepatitis , small intestinal bacterial overgrowth , medicine , hepatic fibrosis , fibrosis , fatty liver , ursodeoxycholic acid , hepatic stellate cell , intestinal permeability , tlr4 , pharmacology , endocrinology , biology , receptor , disease , irritable bowel syndrome
Aim Intestinal endotoxin is important for the progression of non‐alcoholic steatohepatitis (NASH). Circulating endotoxin levels are elevated in most animal models of diet‐induced non‐alcoholic fatty liver disease (NAFLD) and NASH. Furthermore, plasma endotoxin levels are significantly higher in NAFLD patients, which is associated with small intestinal bacterial overgrowth and increased intestinal permeability. By improving the gut microbiota environment and restoring gut‐barrier functions, probiotics are effective for NASH treatment in animal models. It is also widely known that hepatic fibrosis and suppression of activated hepatic stellate cells (Ac‐HSCs) can be attenuated using an angiotensin‐II type 1 receptor blocker (ARB). We thus evaluated the effect of combination probiotics and ARB treatment on liver fibrosis using a rat model of NASH. Methods Fisher 344 rats were fed a choline‐deficient/ L ‐amino acid‐defined (CDAA) diet for 8 weeks to generate the NASH model. Animals were divided into ARB, probiotics, and ARB plus probiotics groups. Therapeutic efficacy was assessed by evaluating liver fibrosis, the lipopolysaccharide Toll‐like receptor (TLR)4 regulatory cascade, and intestinal barrier function. Results Both probiotics and ARB inhibited liver fibrosis, with concomitant HSC activation and suppression of liver‐specific transforming growth factor‐β and TLR4 expression. Probiotics reduced intestinal permeability by rescuing zonula occludens‐1 disruption induced by the CDAA diet. Angiotensin‐II type 1 receptor blocker was found to directly suppress Ac‐HSCs. Conclusions Probiotics and ARB are effective in suppressing liver fibrosis through different mechanisms. Currently both drugs are in clinical use; therefore, the combination of probiotics and ARB is a promising new therapy for NASH.