Chen Songfeng, Jiang Dianxuan, Zhuang Qianjun, Hou Xun, Jia Xingyu, Chen Jing, Lin Huiting, Zhang Mengyu, Tan Niandi, Xiao Yinglian
Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, Guangdong, 510080, China.
Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
J Transl Med. 2024 Dec 24;22(1):1145. doi: 10.1186/s12967-024-05878-1.
Previous research on the lower gastrointestinal tract has proved that microbial dysbiosis can lead to intestinal barrier dysfunction and enhanced visceral sensitivity, thus triggering bowel symptoms. Whether esophageal microbial dysbiosis also contributes to the development of gastroesophageal reflux (GER) symptoms, which are known to be associated with impaired esophageal barrier integrity, remains to be explored.
Patients with GER symptoms (gastroesophageal reflux disease [GERD] and functional esophageal disorders [FED]), duodenal ulcer patients and healthy controls were prospectively included for esophageal microbial analysis. The expression of toll-like receptors (TLRs) and tight junction proteins and intercellular spaces were assessed through transcriptome analysis and immunohistochemistry. The human esophageal epithelial cell (HEEC) line was used to explore how esophageal microbial dysbiosis induced GER symptoms.
Patients with GER symptoms, whether GERD or FED, had a very similar pattern of microbial composition, which showed a significantly increased proportion of Gram-negative bacteria than controls. Patients with GER symptoms (GERD and FED) also exhibited significantly higher TLR2 expression, reduced claudin-1 expression and dilated intercellular spaces (DIS). In vitro, exposure of HEECs to lipopolysaccharide resulted in marked up-regulation of TLR2 and interleukin (IL)-6, down-regulation of claudin-1 and DIS. These effects were mitigated by blocking TLR2 or IL-6.
This study demonstrated that regardless of objective evidence of reflux, patients with GER symptoms presented esophageal microbial dysbiosis characterized by an elevated proportion of Gram-negative bacteria. Enriched Gram-negative bacteria could induce esophageal barrier dysfunction via LPS-TLR2-IL-6-claudin-1-DIS pathway.
先前关于下消化道的研究已证明，微生物群落失调可导致肠道屏障功能障碍和内脏敏感性增强，从而引发肠道症状。食管微生物群落失调是否也会导致胃食管反流（GER）症状的发生，而胃食管反流症状已知与食管屏障完整性受损有关，仍有待探索。
前瞻性纳入有GER症状的患者（胃食管反流病[GERD]和功能性食管疾病[FED]）、十二指肠溃疡患者和健康对照者进行食管微生物分析。通过转录组分析和免疫组织化学评估Toll样受体（TLR）、紧密连接蛋白的表达以及细胞间隙。使用人食管上皮细胞（HEEC）系来探究食管微生物群落失调如何诱发GER症状。
有GER症状的患者，无论GERD还是FED，其微生物组成模式非常相似，革兰氏阴性菌比例相较于对照组显著增加。有GER症状的患者（GERD和FED）还表现出TLR2表达显著升高、claudin-1表达降低以及细胞间隙增宽（DIS）。在体外，将HEECs暴露于脂多糖导致TLR2和白细胞介素（IL）-6显著上调、claudin-1下调以及DIS。通过阻断TLR2或IL-6可减轻这些效应。
本研究表明，无论有无反流的客观证据，有GER症状的患者均存在以革兰氏阴性菌比例升高为特征的食管微生物群落失调。富集的革兰氏阴性菌可通过LPS-TLR2-IL-6-claudin-1-DIS途径诱导食管屏障功能障碍。
