Mechanism of Asbt (Slc10a2)-related bile acid malabsorption in diarrhea after pelvic radiation

Abstract

Background: Radiation is a mode of treatment for many pelvic malignancies, most of which originate in the gynecologic, gastrointestinal, and genitourinary systems. However, the healthy gut is unavoidably included in the irradiation volume, resulting in undesirable results that manifest as radiation-induced diarrhea (RID), which is the most common side effect of radiation therapy and significantly affects the patients’ quality of life. This study aimed to investigate the potential mechanism of diarrhea after pelvic radiotherapy in rats based on the effect of radiation on bile acid homeostasis and sodium-dependent bile acid transporter (Asbt).

Methods: In this experimental study, male Sprague-Dawley rats were divided into the following groups – pelvic irradiation, cholestyramine-concurrent radiation, and control groups. The rats in the pelvic irradiation group were irradiated in the pelvic region with 2 Gy per day for five consecutive days. The total bile acid (TBA) levels in the ileum, colon, and feces were measured using automatic biochemical analyzer, and the levels of individual bile acids were evaluated by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). The mRNA and protein expression of Asbt in ileum were assessed by qRT-PCR and Western blot assay. The rats in the cholestyramine-concurrent radiation group were administered with cholestyramine, a bile acid-chelating resin, and concurrent radiation for 5 days. The body weight of rats was monitored daily, and the degree of diarrhea was scored.

Results: Diarrhea was observed at 2 and 3 days post-pelvic radiation. The TBA levels were significantly decreased at 4 and 5 days post-radiation in the ileum (p < .01, p < .01) and increased at 4 and 5 days post-radiation in the colon (p < .05, p < .05). The fecal excretions of TBA were significantly increased at 3, 4, and 5 days post-radiation (p < .05). The levels of individual bile acids were significantly decreased in the ileum and increased in the colon and feces, post-radiation. The mRNA and protein expression of Asbt in the ileum gradually decreased with increasing days of pelvic radiation and significantly decreased at 3 and 5 days post-radiation, respectively. Furthermore, a significant decrease in body weight was observed post-pelvic radiation, and cholestyramine administration did not reverse the weight loss. However, the incidence of RID was decreased after administration of cholestyramine.

Conclusions: Bile acid malabsorption is partially responsible for RID post-pelvic radiation in rats, and the potential mechanism is related to the downregulation of the ileal Asbt.

Keywords:

• Sodium-dependent bile acid transporter
• bile acid malabsorption
• pelvic radiation
• diarrhea

Acknowledgments

The authors thank Elsevier Language Editing Services and Taylor & Francis Services for the language editing of the manuscript. The authors thank the reviewers for their hard work, which has contributed to the improvement in the quality of the manuscript.

Author contributions

Lina Wang carried out acquisition of data, analysis, and interpretation of data, and wrote the manuscript. Xiaohu Wang, in this paper, contributed to choose the conception and design of the study. All coauthors approved the final version of the paper.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This work was supported by the Lanzhou innovation and entrepreneurship talent project under Grant [number 2017-RC-23]; the Hospital Fund Project of the First Hospital of Lanzhou University under Grant [number ldyyyn2018-09]; and Natural Science for Youth Foundation under Grant [number 81603211].

Notes on contributors

Lina Wang

Lina Wang is a PhD student in Radiation Oncology at Lanzhou University.

Yan Zhou

Yan Zhou is associate researcher and doctoral student, and engaged in cholate transporter research for 5 years.

Xiaohu Wang

Xiaohu Wang is a professor and PhD supervisor of radiation oncology at Lanzhou University.

Guangwen Zhang

Guangwen Zhang, Technician, is engaged in animal experiment technology at Affiliated Hospital of Gansu University of Chinese Medicine.

Bin Guo

Bin Guo, Technician, is engaged in animal experiment technology at The First Hospital of Lanzhou University.

Xiaoming Hou

Xiaoming Hou, PhD, is a Chief Physician in The First Hospital of Lanzhou University.

Juntao Ran

Juntao Ran, PhD, is an Associate Chief Physician in Department of Radiotherapy, the First Hospital of Lanzhou University.

Qiuning Zhang

Qiuning Zhang, PhD, is a Chief Physician in Gansu Provincial Cancer Hospital.

Chengcheng Li

Chengcheng Li is a PhD student in Radiation Oncology at Lanzhou University.

Xueshan Zhao

Xueshan Zhao is a PhD student in Radiation Oncology at Lanzhou University.

Yichao Geng

Yichao Geng is a PhD student in Radiation Oncology at Lanzhou University.

Shuangwu Feng

Shuangwu Feng is a PhD student in Radiation Oncology at Lanzhou University.