Basic Study
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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:
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.
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
Research background

It is well known that microbiota dysbiosis contributes to the occurrence of inflammatory bowel disease (IBD). Fecal microbiota transplantation (FMT) has shown promising therapeutic effects on both clinical and basic studies of ulcerative colitis (UC). Substantial evidence supports a negative pro-inflammatory role of Toll-like receptor 4 (TLR4) signaling pathway in IBD. However, it remains unknown whether this modulation is also involved in the treatment of FMT on UC.

Research motivation

FMT treats other diseases by regulating the TLR4 signaling pathway. Previous studies have shown that the expression of TLR4 is higher in the intestinal mucosa of patients with effective FMT and lower in patients with poor FMT. We speculate that the TLR4 signaling pathway may be involved in the therapeutic mechanism of FMT on IBD.

Research objectives

To clarify the necessity of TLR4 signaling pathway in FMT on regulating gut microbiota in dextran sodium sulphate (DSS)-induced colitis.

Research methods

Experimental colitis was constructed in wild-type (WT) and TLR4-knockout (KO) mice and fecal microbiota was transplanted by gavage. Colon inflammation severity in mouse model was measured by disease activity index (DAI) score and hematoxylin and eosin (H&E) staining. Gut microbiota alteration was analyzed through 16S ribosomal RNA sequencing. The difference of gene expression in mouse colon was obtained by transcriptome sequencing of colon tissue.

Research results

In KO mice treated with FMT or water, these two groups displayed indistinguishable body weight loss, colon length, DAI score, and histology score, which showed that FMT could hardly alter the disease progress in KO mice. Next, compared with WT mice, the scores of DAI and colon histology clearly decreased in the KO-DSS group. KO mice experienced enhanced resistibility to DSS-induced colitis. There was a significant difference in the microbiota structure between KO and WT mice. Akkermansia was the dominant genus in healthy KO mice. But unexpectedly, after treatment with FMT, the relative abundance of Akkermansia decreased, while the level of Lactobacillus in the intestine of mice was maintained. The ineffectiveness in KO mice after FMT was related to the decrease of Akkermansia. GO enrichment analysis showed that DEGs between each group were mainly involved in cytoplasmic translation and cellular response to DNA damage stimulus. Finally, we listed the top nine genes related to Akkermansia.

Research conclusions

FMT may ameliorate DSS-induced colitis by regulating the TLR4 signaling pathway.

Research perspectives

This study provides new insights into the underlying mechanisms of FMT as a treatment for UC, which greatly helps to optimize FMT treatment in the future.