Basic Study
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World J Hepatol. Mar 27, 2025; 17(3): 101340
Published online Mar 27, 2025. doi: 10.4254/wjh.v17.i3.101340
Dysregulation of bile acid signal transduction causes neurological dysfunction in cirrhosis rats
Chao Ren, Li Cha, Shu-Yue Huang, Guo-Hui Bai, Jin-Hui Li, Xin Xiong, Yu-Xing Feng, Dui-Ping Feng, Long Gao, Jin-Yu Li
Chao Ren, Li Cha, Guo-Hui Bai, Jin-Hui Li, College of Medical Imaging, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Shu-Yue Huang, Department of Ultrasound, Qingdao Central Hospital, University of Health and Rehabilitation, Qingdao 266000, Shandong Province, China
Xin Xiong, Academy of Medical Sciences, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Yu-Xing Feng, Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Dui-Ping Feng, Long Gao, Jin-Yu Li, Department of Oncological and Vascular Intervention, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Co-corresponding authors: Dui-Ping Feng and Long Gao.
Author contributions: Feng DP and Gao L co-supervised the manuscript, and they made equal contributions to the study conception and design, data analysis, manuscript writing, critical revision of the manuscript. All authors acknowledge their corresponding authorship. Ren C, Gao L, and Feng DP contributed to study conception and design; Bai GH, Li JH, Xiong X, and Feng DP contributed to data acquisition; Huang SY, Bai GH, Xiong X, Feng YX, Feng DP, and Li JY contributed to analysis and interpretation of data; Ren C, Feng DP, and Gao L contributed to manuscript writing, critical revision of the manuscript, and statistical analysis; and all authors vouch for the veracity and completeness of the data and analyses presented. All authors reviewed and approved the final version of the manuscript.
Supported by the National Natural Science Foundation of China, No. 82200650; the Key Research and Development Projects of Shanxi Province, No. 202102130501014; and the Natural Science Foundation of Shanxi Province, No. 202203021211021, No. 202203021212046, and No. 20210302123258.
Institutional animal care and use committee statement: This study and included experimental procedures were approved by the institutional animal care and use committee of First Hospital of Shanxi Medical University (approval No. DWYJ-2023-016). All animal housing and experiments were conducted in strict accordance with the institutional guidelines for care and use of laboratory animals.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data is not available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Long Gao, PhD, Researcher, Department of Oncological and Vascular Intervention, First Hospital of Shanxi Medical University, No. 56 Xinjian South Road, Yingze District, Taiyuan 030001, Shanxi Province, China. gaolong@sxmu.edu.cn
Received: September 12, 2024
Revised: January 19, 2025
Accepted: February 21, 2025
Published online: March 27, 2025
Processing time: 195 Days and 1 Hours
Abstract
BACKGROUND

The pathogenesis of hepatic encephalopathy (HE) remains unclear, and the classical theory of ammonia toxicity lacks sufficient justification.

AIM

To investigate the potential of bile acids as intervention targets for HE.

METHODS

This study employed 42 wild-type male SD rats weighing 200 ± 20 g. Using a random number table method, two rats were randomly selected to undergo common bile duct ligation (BDL). The remaining 40 rats were randomly assigned to four groups serving as controls: The vehicle + control diet (VC) group, the thioacetamide (TAA) group, the TAA + total bile acids (TAAT) group, and the TAA + cholestyramine (TAAC) group. Except for the VC group, all rats were intraperitoneally injected with 100 mg/kg TAA solution once daily for ten consecutive days to establish a HE model. Simultaneously, the TAAT and TAAC groups were administered a diet containing 0.3% bile acids (derived from BDL rats) and 2% cholestyramine, respectively, by gavage for ten days. For the BDL rat model group, the common BDL procedure was performed following the aforementioned protocol. After four weeks, laparotomy revealed swollen bile ducts at the ligation site, and bile was collected. Following successful modeling, behavioral tests, including the elevated plus maze and open field test, were conducted to assess the HE status of the rats. Peripheral blood, liver, and cerebral cortex tissue samples were collected, and the total bile acid content in the serum and cerebral cortex was measured using an enzyme cycling method. The levels of inflammatory factors in the serum and cerebral cortex were analyzed using enzyme-linked immunosorbent assay. Liver histological examination was performed using the hematoxylin-eosin double-labeling method. Reverse transcription polymerase chain reaction, western blot, immunohistochemistry, and other techniques were employed to observe the expression of microglial activation marker ionized calcium-binding adaptor molecule-1 and Takeda G protein-coupled receptor 5 (TGR5) protein.

RESULTS

Compared to the VC group, the TAA group exhibited an exacerbation of HE in rats. The total bile acid content, pro-inflammatory factors [interleukin-1β (IL-1β), IL-6], and the anti-inflammatory factor IL-10 in both the serum and cerebral cortex were significantly elevated. Similarly, the expression of the TGR5 receptor in the cerebral cortex was upregulated. To investigate the impact of total bile acids on HE in rats, comparisons were made with the TAA group. In the TAAT group, the severity of HE was further aggravated, accompanied by increased total bile acid content in the serum and cerebral cortex, elevated pro-inflammatory factors (IL-1β, IL-6), reduced levels of the anti-inflammatory factor IL-10, and decreased expression of the TGR5 receptor in the cerebral cortex. In the TAAC group, the severity of HE was alleviated. This group showed reductions in total bile acid content in the serum and cerebral cortex, decreased pro-inflammatory factors (IL-1β, IL-6), increased levels of the anti-inflammatory factor IL-10, and enhanced expression of the TGR5 receptor in the cerebral cortex.

CONCLUSION

This study demonstrated that the total bile acid content in the serum and cerebral cortex of TAA-induced liver cirrhosis rats was elevated. Furthermore, total bile acids exacerbate the progression of HE in rats. This effect may be attributed to bile acids’ involvement in the development of neurological dysfunction by mediating TGR5 expression and regulating neuroinflammation.

Keywords: Hepatic encephalopathy; Total bile acid; Thioacetamide; G protein-coupled bile acid receptor 1; Liver cirrhosis

Core Tip: There are many pathogenic factors for hepatic encephalopathy (HE). This experiment confirmed that total bile acids contribute to the development of HE in liver cirrhosis. The main mechanism is that bile acids mediate the expression of bile acid Takeda G protein-coupled receptor 5 in the brain and then affect microglia activation. However, this experiment only verified the role of total bile acids in HE, but there are many types of bile acids, and we still need to continue to explore in depth which bile acids play and what role they play. In short, bile acids and Takeda G protein-coupled receptor 5 in the brain may become effective targets for treating HE in the future.