並列タイトル等ラット非アルコール性脂肪肝炎モデルに対するプロバイオティクスとアンギオテンシンⅡ受容体拮抗薬併用療法の肝線維化に対する有効性
一般注記type:Thesis
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.
博士（医学）・乙第1465号・令和2年9月30日
© 2018 The Japan Society of Hepatology
This is the pre-peer reviewed version of the following article: [https://onlinelibrary.wiley.com/doi/full/10.1111/hepr.13281], which has been published in final form at [https://doi.org/10.1111/hepr.13281]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
identifier:Hepatology research Vol.49 No.3 p.284-295 (2020 Mar)
identifier:13866346
identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/3781
identifier:Hepatology research, 49(3): 284-295
DOIinfo:doi/10.1111/hepr.13281
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