Esophageal microbial dysbiosis impairs mucosal barrier integrity via toll-like receptor 2 pathway in patients with gastroesophageal reflux symptoms

J Transl Med. 2024 Dec 24;22(1):1145. doi: 10.1186/s12967-024-05878-1.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Esophageal barrier integrity; Esophageal microbiota; Interleukin-6; Lipopolysaccharide.

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • Cell Line
  • Dysbiosis* / complications
  • Dysbiosis* / microbiology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Esophageal Mucosa / metabolism
  • Esophageal Mucosa / microbiology
  • Esophageal Mucosa / pathology
  • Esophagus / microbiology
  • Esophagus / pathology
  • Extracellular Space / metabolism
  • Female
  • Gastroesophageal Reflux* / complications
  • Gastroesophageal Reflux* / microbiology
  • Gastroesophageal Reflux* / pathology
  • Humans
  • Interleukin-6 / metabolism
  • Male
  • Middle Aged
  • Signal Transduction*
  • Toll-Like Receptor 2* / metabolism

Substances

  • Toll-Like Receptor 2
  • TLR2 protein, human
  • Interleukin-6