Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 14, 2023; 29(30): 4657-4670
Published online Aug 14, 2023. doi: 10.3748/wjg.v29.i30.4657
Fecal microbiota transplantation alleviates experimental colitis through the Toll-like receptor 4 signaling pathway
Xin Wen, Rui Xie, Hong-Gang Wang, Min-Na Zhang, Le He, Meng-Hui Zhang, Xiao-Zhong Yang
Xin Wen, Rui Xie, Hong-Gang Wang, Min-Na Zhang, Le He, Meng-Hui Zhang, Xiao-Zhong Yang, Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
Author contributions: Wen X, Xie R, and Wang HG contributed equally to this work; Wen X, Xie R, and Wang HG conceived and designed this work, and drafted and revised the manuscript; Wen X, Zhang MN, He L, and Zhang MH performed the experiments, collected samples, and analyzed the data; Yang XZ and Wang HG worked on the concept and guidance of this study; Yang XZ and Wang HG provided the funding support and project administration; All authors have read and approved the final manuscript.
Supported by the Scientific Research Project of Jiangsu Provincial Health Commission, No. H2018082; Huai’an Natural Science Research Project Project, No. HAB201926; and Scientific Research Project of Translational Medicine Innovation Team of Huai’an First People’s Hospital, No. YZHT201905.
Institutional animal care and use committee statement: The animal experimental protocol was approved by experimental animal ethics committee of the Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University (Approval No. DW-P-2018-008-01).
Conflict-of-interest statement: The authors have no conflicts interest to declare.
Data sharing statement: The data presented in the study are available in article. The datasets analysed during the current study are available in the NCBI Sequence Read Archive (SRA) database, submission number: SUB11829874.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Xiao-Zhong Yang, MD, PhD, Chief Doctor, Doctor, Professor, Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, No. 1 Huanghe Road, Huai’an 223300, Jiangsu Province, China. hayyyxzh@njmu.edu.cn
Received: May 22, 2023
Peer-review started: May 22, 2023
First decision: June 20, 2023
Revised: July 3, 2023
Accepted: July 11, 2023
Article in press: July 11, 2023
Published online: August 14, 2023
Processing time: 79 Days and 23.3 Hours
Abstract
BACKGROUND

Fecal microbiota transplantation (FMT) has shown promising therapeutic effects on mice with experimental colitis and patients with ulcerative colitis (UC). FMT modulates the Toll-like receptor 4 (TLR4) signaling pathway to treat some other diseases. However, it remains unknown whether this modulation is also involved in the treatment of UC.

AIM

To clarify the necessity of TLR4 signaling pathway in FMT on dextran sodium sulphate (DSS)-induced mice and explain the mechanism of FMT on UC, through association analysis of gut microbiota with colon transcriptome in mice.

METHODS

A mouse colitis model was constructed with wild-type (WT) and TLR4-knockout (KO) mice. Fecal microbiota was transplanted by gavage. Colon inflammation severity was measured by disease activity index (DAI) scoring and hematoxylin and eosin staining. Gut microbiota structure was analyzed through 16S ribosomal RNA sequencing. Gene expression in the mouse colon was obtained by transcriptome sequencing.

RESULTS

The KO (DSS + Water) and KO (DSS + FMT) groups displayed indistinguishable body weight loss, colon length, DAI score, and histology score, which showed that FMT could not inhibit the disease in KO mice. In mice treated with FMT, the relative abundance of Akkermansia decreased, and Lactobacillus became dominant. In particular, compared with those in WT mice, the scores of DAI and colon histology were clearly decreased in the KO-DSS group. Microbiota structure showed a significant difference between KO and WT mice. Akkermansia were the dominant genus in healthy KO mice. The ineffectiveness of FMT in KO mice was related to the decreased abundance of Akkermansia. Gene Ontology enrichment analysis showed that differentially expressed genes between each group were mainly involved in cytoplasmic translation and cellular response to DNA damage stimulus. The top nine genes correlating with Akkermansia included Aqp4, Clca4a, Dpm3, Fau, Mcrip1, Meis3, Nupr1 L, Pank3, and Rps13 (|R| > 0.9, P < 0.01).

CONCLUSION

FMT may ameliorate DSS-induced colitis by regulating the TLR4 signaling pathway. TLR4 modulates the composition of gut microbiota and the expression of related genes to ameliorate colitis and maintain the stability of the intestinal environment. Akkermansia bear great therapeutic potential for colitis.

Keywords: Toll-like receptor 4, Fecal microbiota transplantation, Colitis, Akkermansia, Lactobacillus, Aquaporin 4, Transcriptome sequencing

Core Tip: Recent studies have shown that fecal microbiota transplantation (FMT) has a therapeutic role in patients with inflammatory bowel disease. The Toll-like receptor 4 (TLR4) signaling pathway may play a critical role in intestinal injury and repair. Here, we conducted animal experiments to explore the role of TLR4 in dextran sodium sulphate-induced colitis in mice and the treatment of FMT.