Case Control Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 28, 2021; 27(24): 3609-3629
Published online Jun 28, 2021. doi: 10.3748/wjg.v27.i24.3609
Altered profiles of fecal bile acids correlate with gut microbiota and inflammatory responses in patients with ulcerative colitis
Zhen-Huan Yang, Fang Liu, Xiao-Ran Zhu, Fei-Ya Suo, Zi-jun Jia, Shu-Kun Yao
Zhen-Huan Yang, Xiao-Ran Zhu, Fei-Ya Suo, Zi-jun Jia, Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
Zhen-Huan Yang, Fang Liu, Xiao-Ran Zhu, Fei-Ya Suo, Shu-Kun Yao, Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
Author contributions: Yang ZH designed and performed the study, analyzed the data, and drafted the manuscript; Liu F and Jia ZJ collected the samples and clinical data of the patients; Zhu XR and Suo FY took part in designing the study and analyzing the data; Yao SK designed the study, supervised the study performance, revised the manuscript, and obtained the funding.
Supported by National Key Technology Support Program during “12th Five-Year Plan” Period of China, No. 2014BAI08B00; National Key Research and Development Plan for Precision Medicine Research, No. 2017YFC0910002; and Leap-forward Development Program for Beijing Biopharmaceutical Industry (G20), No. Z171100001717008.
Institutional review board statement: This study was approved by the Ethics Committee of China-Japan Friendship Hospital (No. 2019-K16).
Informed consent statement: All study participants provided written informed consent prior to study enrollment.
Conflict-of-interest statement: All authors report no conflicts of interest.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
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: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Shu-Kun Yao, MD, Professor, Department of Gastroenterology, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing 100029, China. shukunyao@126.com
Received: February 6, 2021
Peer-review started: February 6, 2021
First decision: March 14, 2021
Revised: March 22, 2021
Accepted: May 25, 2021
Article in press: May 25, 2021
Published online: June 28, 2021
Abstract
BACKGROUND

Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease. Several clinical studies have recently shown that patients with ulcerative colitis (UC) have altered profiles of fecal bile acids (BAs). It was observed that BA receptors Takeda G-protein-coupled receptor 5 (TGR5) and vitamin D receptor (VDR) participate in intestinal inflammatory responses by regulating NF-ĸB signaling. We hypothesized that altered profiles of fecal BAs might be correlated with gut microbiota and inflammatory responses in patients with UC.

AIM

To investigate the changes in fecal BAs and analyze the relationship of BAs with gut microbiota and inflammation in patients with UC.

METHODS

The present study used 16S rDNA sequencing technology to detect the differences in the intestinal flora between UC patients and healthy controls (HCs). Fecal BAs were measured by targeted metabolomics approaches. Mucosal TGR5 and VDR expression was analyzed using immunohistochemistry, and serum inflammatory cytokine levels were detected by ELISA.

RESULTS

Thirty-two UC patients and twenty-three HCs were enrolled in this study. It was found that the diversity of gut microbiota in UC patients was reduced compared with that in HCs. Firmicutes, Clostridium IV, Butyricicoccus, Clostridium XlVa, Faecalibacterium, and Roseburia were significantly decreased in patients with UC (P = 3.75E-05, P = 8.28E-07, P = 0.0002, P = 0.003, P = 0.0003, and P = 0.0004, respectively). Proteobacteria, Escherichia, Enterococcus, Klebsiella, and Streptococcus were significantly enriched in the UC group (P = 2.99E-09, P = 3.63E-05, P = 8.59E-05, P = 0.003, and P = 0.016, respectively). The concentrations of fecal secondary BAs, such as lithocholic acid, deoxycholic acid, glycodeoxycholic acid, glycolithocholic acid, and taurolithocholate, in UC patients were significantly lower than those in HCs (P = 8.1E-08, P = 1.2E-07, P = 3.5E-04, P = 1.9E-03, and P = 1.8E-02, respectively) and were positively correlated with Butyricicoccus, Roseburia, Clostridium IV, Faecalibacterium, and Clostridium XlVb (P < 0.01). The concentrations of primary BAs, such as taurocholic acid, cholic acid, taurochenodeoxycholate, and glycochenodeoxycholate, in UC patients were significantly higher than those in HCs (P = 5.3E-03, P = 4E-02, P = 0.042, and P = 0.045, respectively) and were positively related to Enterococcus, Klebsiella, Streptococcus, Lactobacillus, and pro-inflammatory cytokines (P < 0.01). The expression of TGR5 was significantly elevated in UC patients (0.019 ± 0.013 vs 0.006 ± 0.003, P = 0.0003). VDR expression in colonic mucosal specimens was significantly decreased in UC patients (0.011 ± 0.007 vs 0.016 ± 0.004, P = 0.033).

CONCLUSION

Fecal BA profiles are closely related to the gut microbiota and serum inflammatory cytokines. Dysregulation of the gut microbiota and altered constitution of fecal BAs may participate in regulating inflammatory responses via the BA receptors TGR5 and VDR.

Keywords: Ulcerative colitis, Gut microbiota, Bile acids, Takeda G-protein-coupled receptor 5, Vitamin D receptor

Core Tip: This study comprehensively investigated the changes in gut microbiota and fecal bile acid profiles and analyzed the relationship of bile acids with gut microbiota and inflammation in patients with ulcerative colitis. It was demonstrated that fecal bile acid profiles are closely related to gut microbiota and serum inflammatory cytokines. Dysregulation of gut microbiota and altered constitution of fecal bile acids may participate in regulating inflammatory responses via the bile acid receptors Takeda G-protein-coupled receptor 5 and vitamin D receptor.