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Impact of elobixibat on liver tumors, microbiome, and bile acid levels in a mouse model of nonalcoholic steatohepatitis

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Abstract

Background

Elevated bile acid levels have been associated with liver tumors in fatty liver. Ileal bile acid transporter inhibitors may inhibit bile acid absorption in the distal ileum and increase bile acid levels in the colon, potentially decreasing the serum and hepatic bile acid levels. This study aimed to investigate the impact of these factors on liver tumor.

Methods

C57BL/6J mice received a one-time intraperitoneal injection of 25-mg/kg diethylnitrosamine. They were fed a choline-deficient high-fat diet for 20 weeks starting from 8 weeks of age, with or without elobixibat (EA Pharma, Tokyo, Japan).

Results

Both groups showed liver fat accumulation and fibrosis, with no significant differences between the two groups. However, mice with elobixibat showed fewer liver tumors. The total serum bile acid levels, including free, tauro-conjugated, glyco-conjugated, and tauro-α/β-muricholic acids in the liver, were noticeably reduced following elobixibat treatment. The proportion of gram-positive bacteria in feces was significantly lower in the group treated with elobixibat (5.4%) than in the group without elobixibat (33.7%).

Conclusion

Elobixibat suppressed tumor growth by inhibiting bile acid reabsorption, and decreasing total bile acid and primary bile acid levels in the serum and liver. Additionally, the presence of bile acids in the colon may have led to a significant reduction in the proportion of gram-positive bacteria, potentially resulting in decreased secondary bile acid synthesis.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the Division of Experimental Animals and Medical Research Engineering, Nagoya University Graduate School of Medicine, for housing the animals and for maintenance of experimental equipment. The authors wish to acknowledge the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, for the use of MiSeq.

Funding

This work was supported in part by a Grant-in-Aid for Young Scientists (Grant number 21K15970 for KY) and Grant-in-Aid for Scientific Research (C) (Grant number 20K08382 for TH) from the Japan Society for the Promotion of Science (JSPS).

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-Cho, Showa-Ku, Nagoya, 466-8550, Japan

    Yoshiaki Sugiyama, Kenta Yamamoto, Takashi Honda, Asuka Kato, Hisanori Muto, Shinya Yokoyama, Takanori Ito, Norihiro Imai, Yoji Ishizu, Masanao Nakamura, Masatoshi Ishigami & Hiroki Kawashima

  2. College of Human Life and Environment, Kinjo Gakuin University, 2-1723 Omori, Moriyama-Ku, Nagoya, 463-8521, Japan

    Tomomi Asano

  3. Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan

    Atsushi Enomoto

  4. Multimodal Informatics and Wide-Data Analytics Laboratory (MiWA-Lab.), Department of Computational Systems Biology, Faculty of Biology-Oriented Science and Technology, Kindai University, 930 Nishi Mitani, Kinokawa, Wakayama, 649-6493, Japan

    Kei Zaitsu

  5. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Mitsuhiro Fujishiro

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  1. Yoshiaki Sugiyama
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Contributions

YS, KY, and TH conceived the project and designed the experiments. YS, KY, AK, HM, SY, and TH collected and processed the samples with the help of TI, NI, YI, and MI. TA and KZ measured the bile acid levels and revised the manuscript. YS, KY, and TH performed the data analyses and wrote the manuscript. MN, AE, MF, and HK edited the manuscript.

Corresponding author

Correspondence to Takashi Honda.

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Conflict of interest

Yoshiaki Sugiyama, Kenta Yamamoto, Takashi Honda, Asuka Kato, Hisanori Muto, Shinya Yokoyama, Takanori Ito, Norihiro Imai, Yoji Ishizu, Masanao Nakamura, Tomomi Asano, Atsushi Enomoto, Kei Zaitsu, Masatoshi Ishigami, Mitsuhiro Fujishiro, Hiroki Kawashima have no relevant financial or non-financial interest to disclose.

Ethical approval

The Animal Care and Research and Development Committees of the Division of Experimental Animals at Nagoya University approved all experiments. All institutional and national guidelines for the care and use of laboratory animals were followed.

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Sugiyama, Y., Yamamoto, K., Honda, T. et al. Impact of elobixibat on liver tumors, microbiome, and bile acid levels in a mouse model of nonalcoholic steatohepatitis. Hepatol Int 17, 1378–1392 (2023). https://doi.org/10.1007/s12072-023-10581-2

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