Elobixibat, an ileal bile acid transporter inhibitor, ameliorates non-alcoholic steatohepatitis in mice.

Abstract

BACKGROUND:

Recent studies have suggested that several types of toxic bile acids (BAs) are involved in the pathogenesis of non-alcoholic steatohepatitis (NASH). In the present study, we aimed to determine whether elobixibat, an ileal bile acid transporter (IBAT) inhibitor, would ameliorate NASH in mice.

METHODS:

C57BL/6N mice were fed a methionine and choline-deficient (MCD) to induce NASH or standard diet as control for 8 weeks (n = 5 per group). The MCD diet-fed mice were administered elobixibat 5 days a week for 4 weeks by gavage (n = 5). The effects of the treatments on liver histopathology, proinflammatory cytokine concentrations, intestinal epithelial tight junctions, and the intestinal microbial composition were then assessed.

RESULTS:

In MCD-fed mice, hepatic fibrosis and inflammatory cell infiltration developed, and the serum aspartate transaminase activity and BA concentration were higher than the control. In addition, the proinflammatory cytokine concentrations were high in the liver and mesenteric lymph nodes (MLN), and the expression of intestinal epithelium tight junction proteins, claudin1, was increased. In the intestinal microbial composition, the abundance of the Lachnospiraceae and Ruminococcaeae were decreased, whereas that of the Enterobacteriaceae was increased. Treatment with elobixibat reduced the serum BA and increased the fecal BA concentration, and ameliorated the liver inflammation and fibrosis. It also reduced the expression of proinflammatory cytokines in the liver and MLNs, and transforming growth factor-β expression in the liver. Finally, elobixibat normalized intestinal tight junction protein level and the composition of the intestinal microbiota.

CONCLUSION:

Elobixibat ameliorates NASH-related histopathology, reduces cytokine expression, and normalizes the intestinal microbial composition in MCD-fed mice, which suggests that it may represent a promising candidate for the therapy of NASH.

• Authors: Ryo Yamauchi, Hidetoshi Takedatsu, Keiji Yokoyama, Eri Yamauchi, Motoko Kawashima, Takahiro Nagata, Yotaro Uchida, Takanori Kitaguchi, Tomotaka Higashi, Hiromi Fukuda, Naoaki Tsuchiya, Kazuhide Takata, Takashi Tanaka, Daisuke Morihara, Yasuaki Takeyama, Satoshi Shakado, Shotaro Sakisaka, Fumihito Hirai
• Journal: Hepatology international (Hepatol Int) Vol. 15 Issue 2 Pg. 392-404 (Apr 2021) ISSN: 1936-0541 [Electronic] United States
• PMID: 33398776 (Publication Type: Journal Article)

Chemical References

• Carrier Proteins
• Dipeptides
• Membrane Glycoproteins
• Thiazepines
• bile acid binding proteins
• elobixibat

Topics

• Animals
• Carrier Proteins
• Dipeptides (therapeutic use)
• Disease Models, Animal
• Ileum
• Membrane Glycoproteins
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (drug therapy)
• Thiazepines (therapeutic use)