Abstract
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.
Key words
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Article info
Publication history
Published online: May 02, 2022
Accepted:
April 20,
2022
Received:
January 8,
2022
Footnotes
☆This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Identification
Copyright
© 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
