肠道菌群通过诱导上皮细胞-间充质转化参与肛瘘发病的机制探讨

叶倩倩; 柳奕诚; 罗春生; 徐进; 汪庆明

doi:10.16766/j.cnki.issn.1674-4152.003346

肠道菌群通过诱导上皮细胞-间充质转化参与肛瘘发病的机制探讨

doi: 10.16766/j.cnki.issn.1674-4152.003346

叶倩倩¹,
柳奕诚²,
罗春生¹,
徐进²,
汪庆明^{1, 2, ,}

1.
上海中医药大学附属曙光医院肛肠科, 上海 201203
2.
上海市宝山区中西医结合医院肛肠科，上海 201901

基金项目:

上海申康医院发展中心临床三年行动计划资助项目 SHDC2020CR3094B

上海市青年科技英才扬帆计划资助项目 21YF1433300

上海市2023年度“科技创新行动计划”医学创新研究专项 23Y11921800

“十四五”中医特色专科和中医急诊能力提升项目 ZYTSZK1-8

详细信息

通讯作者:
汪庆明，E-mail：davidwqm@163.com

中图分类号: R657.16
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- 被引次数: 0
出版历程
- 收稿日期: 2023-07-28
- 网络出版日期: 2024-03-09

Discussion on the mechanism of intestinal flora participating in the pathogenesis of anal fistula by inducing EMT

1.
Anorectal Department, Shuguang Hospital affiliated to Shanghai University of Chinese Medicine, Shanghai 201203, China

摘要

摘要: 肛瘘是肛肠疾病中的常见病、多发病，以肛周流脓、疼痛、瘙痒为主要症状，男性青壮年为主要发病人群。目前肛瘘发病机制尚不明确，治疗仍以手术为主，手术预后与术者对于内口的把握以及括约肌的保护有密切的关系。近年来，肠道菌群的研究被推上热门，其在多种疾病中的作用也逐渐被证实，已有研究表示菌群变化与肠道微环境的紊乱参与肛瘘的发生，具体表现在菌群丰度多样性的增加和肠源性细菌的感染。上皮细胞-间充质转化(EMT)是癌症等疾病重要的表型变化，随着研究的深入，已被证明参与肛瘘的发生发展，尤以克罗恩病多见。本文基于肛瘘解剖学特征和主流发病机制，通过梳理国内外相关研究，总结肠道菌群-EMT-肛瘘之间存在的相关联系，从肠道菌群与肛瘘、肠道菌群与EMT、EMT与肛瘘三个方面阐述肛瘘发病机制，并得出肛门瘘管的形成可能是由于肠道菌群变化影响肠黏膜屏障稳态，进而诱导EMT发生并参与炎症诱导纤维化和瘘管的发展，由于EMT与隐腺肛瘘的研究较少，此机制仍需在隐腺肛瘘中进一步验证。该机制提示未来可以通过调节患者肠道菌群，减轻炎症反应和干预EMT进程参与肛瘘的预防和治疗，以期为肛瘘提供非手术的治疗新途径，达到减轻患者诊疗痛苦的目的。
- 肠道菌群 /
- 上皮细胞-间充质转化 /
- 肛瘘 /
- 发病机制
Abstract: Anal fistula is a common and frequently-occurring disease in anorectal diseases, with perianal pus, pain, and itching as the main symptoms, and young men as the main patients. At present, the pathogenesis of anal fistula is still unclear, and the main treatment is surgery. The prognosis of surgery is closely related to the surgeon's grasp of the internal opening and the protection of the sphincter. In recent years, the study of intestinal flora has become a hot topic, and its role in various diseases has been gradually confirmed. Studies have shown that changes in the bacterial flora and disturbance of the intestinal microenvironment are involved in the occurrence of anal fistulas, which are specifically manifested in the increase in the abundance and diversity of bacterial flora and the infection of enterogenic bacteria. Epithelial-mesenchymal transition (EMT) is an important phenotypic change in diseases such as cancer. With the deepening of research, it has been proven to be involved in the occurrence and development of anal fistulas, which is especially common in Crohn's disease. Based on the anatomical characteristics and mainstream pathogenesis of anal fistula, this article summarizes the correlation between intestinal flora-EMT-anal fistula by sorting out relevant domestic and foreign researches, from the perspective of intestinal flora and anal fistula, intestinal flora and EMT, and expounds the pathogenesis of anal fistula from three aspects: intestinal flora and anal fistula, intestinal flora and EMT, and EMT and anal fistula. It is concluded that the formation of anal fistula may be due to changes in intestinal flora that affect the homeostasis of the intestinal mucosal barrier, thereby inducing the occurrence of EMT and participating in the development of inflammation-induced fibrosis and fistulas. Since there are few studies on EMT and cryptoglandular anal fistula, this mechanism still needs to be further verified in cryptoglandular anal fistula.This mechanism suggests that in the future, we can participate in the prevention and treatment of anal fistula by regulating the intestinal flora of patients, reducing inflammation and intervening in the process of EMT, in order to provide a new way of non-surgical treatment for anal fistula and reduce the pain of diagnosis and treatment of patients.
- Intestinal flora /
- Epithelial-mesenchymal transition /
- Anal fistula /
- Pathogenesis

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图 1 肛瘘发病机制

Figure 1. Pathogenesis of anal fistula

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表 1 肠道菌群与EMT的相关研究

Table 1. The correlation between intestinal flora and EMT

第一作者	发表年份	涉及指标	具体机制
CHANDRAKESAN P^[40]	2014	Wnt/β-catenin、Notch、TGF-β通路	肠道病原体通过诱导Wnt/β-catenin、Notch和TGF-β通路激活促进了EMT发生。
WAN G S^[38]	2018	IL-6、TNF-α	外周IL-6和TNF-α升高随后促进结直肠癌的EMT过程，并参与癌症的进展和转移。
XU S Y^[39]	2019	IL-6、TNF-α	肠道生态失调通过分泌IL-6和TNF-α刺激卵巢癌中肿瘤相关巨噬细胞活化，最终诱导EMT的发展。
SONG X L^[41]	2022	VEGFR2	菌群代谢物脱氧胆酸通过VEGFR2活化促进肿瘤血管生成拟态形成和EMT，进一步加剧了肠道癌变。

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表 2 EMT与肛瘘的修改意见相关研究

Table 2. Study on modification of EMT and anal fistula

第一作者	发表年份	涉及指标	具体机制
RATTO C^[11]	2016	IL-1β、IL-8	隐腺瘘中存在慢性炎症，瘘管两端的炎症模式不同，但都存在EMT。细胞因子IL-1β和IL-8可能在瘘管形成中发挥作用。
BRUCKNER R S^[48]	2021	CD3⁺CD8^- T细胞、CD3⁺CD8⁺ T细胞、TNF-α	CD3⁺CD8^-和CD3⁺CD8⁺ T两个细胞亚群都以时间依赖性方式促进EMT相关基因表达和TNF-α的产生，从而在克罗恩病肛周瘘中起重要作用。
OSMAN N H^[47]	2023	Vimentin、Snail、α-SMA、E-cadherin、Vimentin、TGF-β1、miR-200b、Zeb-1、PERK、NF-κB	E-cadherin和miR-200b仅在正常肛门黏膜中表达，PERK和NF-κB在瘘管中表达较强，Snail和α-SMA在克罗恩病患者中高表达，所有IBD患者Vimentin和TGF-β1均高表达。
MCGREGOR C G C^[46]	2023	MMP、TNF-α、IL-13、TGF-β	严重的肠道炎症导致细胞因子TNF-α的分泌，IL-13和TGF-β，TGF-β是最有效的EMT诱导剂。MMP的过表达利于瘘管的形成。

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