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

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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.

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Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

BAs:

Bile acids

IBAT:

Ileal bile acid transporter

HFD:

High-fat diet

LDL:

Low-density lipoprotein

TJ:

Tight junction

MCD:

Methionine and choline deficient

AST:

Aspartate transaminase

HE:

Hematoxylin and eosin

NAS:

NAFLD activity score

TBS:

Tris-buffered saline

MLN:

Mesenteric lymph node

TNF-α:

Tumor necrosis factor-α

IL-6:

Interleukin-6

TGF-β:

Transforming growth factor-β

RT:

Room temperature

RDP:

Ribosomal database project

HCC:

Hepatocellular carcinoma

HSCs:

Hepatic stellate cells

ROS:

Reactive oxygen species

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Acknowledgements

We thank Mark Cleasby, PhD, from Edanz Group (https://en-author-services.edanzgroup.com/ac) for editing a draft of this manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, Fukuoka, 814-0180, Japan

    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 & Fumihito Hirai

  2. The Center of Medical Science, Fukuoka University Faculty of Medicine, Fukuoka, Japan

    Shotaro Sakisaka

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  1. Ryo Yamauchi
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Correspondence to Hidetoshi Takedatsu.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted and ethical approval was obtained from The Animal Care and Use Committee of Fukuoka University (Permit number: 2090). This article does not contain any studies with human participants performed by any of the authors.

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Yamauchi, R., Takedatsu, H., Yokoyama, K. et al. Elobixibat, an ileal bile acid transporter inhibitor, ameliorates non-alcoholic steatohepatitis in mice. Hepatol Int 15, 392–404 (2021). https://doi.org/10.1007/s12072-020-10107-0

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