粪便微生物群移植通过 Toll 样受体 4 信号通路缓解实验性结肠炎。

Fecal microbiota transplantation alleviates experimental colitis through the Toll-like receptor 4 signaling pathway.

机构信息

Department of Gastroenterology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an 223300, Jiangsu Province, China.

出版信息

World J Gastroenterol. 2023 Aug 14;29(30):4657-4670. doi: 10.3748/wjg.v29.i30.4657.

DOI:10.3748/wjg.v29.i30.4657

PMID:37662857

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10472902/

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 decreased, and 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. were the dominant genus in healthy KO mice. The ineffectiveness of FMT in KO mice was related to the decreased abundance of . 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 included Aqp4, Clca4a, Dpm, Fau, Mcrip1, Meis3, Nupr1 L, Pank3, and Rps13 ( > 0.9, < 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. bear great therapeutic potential for colitis.

摘要

背景

粪便微生物群移植（FMT）已显示出对实验性结肠炎和溃疡性结肠炎（UC）患者的治疗作用。FMT 调节 Toll 样受体 4（TLR4）信号通路来治疗其他一些疾病。然而，尚不清楚这种调节是否也参与了 UC 的治疗。

目的

通过关联分析小鼠肠道微生物群与结肠转录组，阐明 TLR4 信号通路在 FMT 对葡聚糖硫酸钠（DSS）诱导的小鼠中的必要性，并解释 FMT 对 UC 的作用机制。

方法

采用野生型（WT）和 TLR4 敲除（KO）小鼠构建小鼠结肠炎模型。通过灌胃进行粪便微生物群移植。通过疾病活动指数（DAI）评分和苏木精和伊红染色测量结肠炎症严重程度。通过 16S 核糖体 RNA 测序分析肠道微生物群结构。通过转录组测序获得小鼠结肠的基因表达。

结果

KO（DSS+水）和 KO（DSS+FMT）组的体重减轻、结肠长度、DAI 评分和组织学评分无明显差异，表明 FMT 不能抑制 KO 小鼠的疾病。在接受 FMT 治疗的小鼠中，减少，成为优势菌。与 WT 小鼠相比，KO-DSS 组的 DAI 和结肠组织学评分明显降低。肠道微生物群结构在 KO 和 WT 小鼠之间存在显著差异。健康 KO 小鼠中以为主导属。FMT 在 KO 小鼠中的无效性与的丰度降低有关。基因本体论富集分析表明，各组之间差异表达的基因主要参与细胞质翻译和细胞对 DNA 损伤刺激的反应。与相关性最强的前 9 个基因包括 Aqp4、Clca4a、Dpm、Fau、Mcrip1、Meis3、Nupr1L、Pank3 和 Rps13（>0.9，<0.01）。