IJMS, Vol. 26, Pages 6710: Rifaximin Attenuates Liver Fibrosis and Hepatocarcinogenesis in a Rat MASH Model by Suppressing the Gut–Liver Axis and Epiregulin–IL-8-Associated Angiogenesis
International Journal of Molecular Sciences doi: 10.3390/ijms26146710
Authors:
Naoki Nishimura
Kosuke Kaji
Norihisa Nishimura
Junichi Hanatani
Tatsuya Nakatani
Masafumi Oyama
Akihiko Shibamoto
Yuki Tsuji
Koh Kitagawa
Shinya Sato
Tadashi Namisaki
Satoru Tamaoki
Hitoshi Yoshiji
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease linked to fibrosis and hepatocellular carcinoma (HCC). Gut-derived lipopolysaccharide (LPS) promotes hepatic inflammation, fibrosis, and angiogenesis through toll-like receptor 4 (TLR4) signaling. This study examined the effects of rifaximin, a non-absorbable, gut-targeted antibiotic, on MASH-related liver fibrosis and early hepatocarcinogenesis, with a focus on the LPS–epiregulin–IL-8–angiogenesis axis.MASH was induced in Fischer 344 rats using a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD). Rifaximin (30 mg/kg/day) was orally administered for 12 weeks. Liver histology, gene expression, intestinal permeability, LPS levels, and angiogenic markers were evaluated. Rifaximin reduced hepatic inflammation, fibrosis, hydroxyproline content, and fibrogenic gene expression. The number and size of GST-P-positive preneoplastic lesions and proliferation-related genes were decreased. Portal LPS levels and Kupffer cell activation declined, with downregulation of Lbp, Cd14, Tlr4, and inflammatory cytokines. Rifaximin decreased hepatic epiregulin and IL-8 expression, attenuated CD34-positive neovascularization, and suppressed proangiogenic gene expression, accompanied by improved intestinal barrier function and reduced gut permeability. Rifaximin mitigates MASH progression by restoring gut barrier integrity, limiting LPS translocation, and inhibiting fibrogenic and angiogenic pathways. These results suggest its potential as a chemopreventive agent in MASH-related hepatocarcinogenesis.
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Naoki Nishimura www.mdpi.com
