Parabacteroides distasonis promotes liver regeneration by increasing β-hydroxybutyric acid (BHB) production and BHB-driven STAT3 signals

https://doi.org/10.1016/j.apsb.2025.01.024

This new article publication from Acta Pharmaceutica Sinica B, discusses how Parabacteroides distasonis promotes liver regeneration by increasing β-hydroxybutyric acid (BHB) production and BHB-driven STAT3 signals.

The liver regenerative capacity is crucial for patients with end-stage liver disease following partial hepatectomy (PHx). The specific bacteria and mechanisms regulating liver regeneration post-PHx remain unclear. This study demonstrated dynamic changes in the abundance of Parabacteroides distasonis (P. distasonis) post-PHx, correlating with hepatocyte proliferation. Treatment with live P. distasonis significantly promoted hepatocyte proliferation and liver regeneration after PHx. Targeted metabolomics revealed a significant positive correlation between P. distasonis and β-hydroxybutyric acid (BHB), as well as hyodeoxycholic acid and 3-hydroxyphenylacetic acid in the gut after PHx. Notably, treatment with BHB, but not hyodeoxycholic acid or 3-hydroxyphenylacetic acid, significantly promoted hepatocyte proliferation and liver regeneration in mice after PHx. Moreover, STAT3 inhibitor Stattic attenuated the promotive effects of BHB on cell proliferation and liver regeneration both in vitro and in vivo. Mechanistically, P. distasonis upregulated the expression of fatty acid oxidation-related proteins, and increased BHB levels in the liver, and then BHB activated the STAT3 signaling pathway to promote liver regeneration. This study, for the first time, identifies the involvement of P. distasonis and its associated metabolite BHB in promoting liver regeneration after PHx, providing new insights for considering P. distasonis and BHB as potential strategies for promoting hepatic regeneration.

Keywords: Liver regeneration; Gut microbiota; Parabacteroides distasonis; β-hydroxybutyric acid

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383525000309-ga1_lrg.jpg

Parabacteroides distasonis promotes liver regeneration by increasing BHB production and BHB-driven STAT3 signals, which provides a relevant argument for using P. distasonis or BHB as a potential strategy for promoting hepatic regeneration after PHx or transplantation.

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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.

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CiteScore: 22.4

Impact Factor: 14.8 (Top 5 journal in the category of Pharmacology and pharmacy)

JIF without self-citation: 13.9

ISSN 2211-3835

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Manlan Guo, Xiaowen Jiang, Hui Ouyang, Xianglong Zhang, Shuaishuai Zhang, Peng Wang, Guofang Bi, Ting Wu, Wenhong Zhou, Fengting Liang, Xiao Yang, Shicheng Fan, Jian-hong Fang, Peng Chen, Huichang Bi, Parabacteroides distasonis promotes liver regeneration by increasing β-hydroxybutyric acid (BHB) production and BHB-driven STAT3 signals, Acta Pharmaceutica Sinica B, Volume 15, Issue 3, 2025, Pages 1430-1446, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2025.01.024.