Alterations to the Esophageal Microbiome Associated with Progression from Barrett's Esophagus to Esophageal Adenocarcinoma

Abstract

Background: The incidence of esophageal adenocarcinoma has risen dramatically over the past half century, and the underlying reasons are incompletely understood. Broad shifts to the upper gastrointestinal microbiome may be partly responsible. The goal of this study was to describe alterations in the esophageal microbiome that occur with progression from Barrett's esophagus to esophageal adenocarcinoma.Methods: A case-control study was performed of patients with and without Barrett's esophagus who were scheduled to undergo upper endoscopy. Demographic, clinical, and dietary intake data were collected, and esophageal brushings were collected during the endoscopy. 16S rRNA gene sequencing was performed to characterize the microbiome.Results: A total of 45 patients were enrolled and included in the analyses [16 controls; 14 Barrett's esophagus without dysplasia (NDBE); 6 low-grade dysplasia (LGD); 5 highgrade dysplasia (HGD); and 4 esophageal adenocarcinoma]. There was no difference in alpha diversity between non-Barrett's esophagus and Barrett's esophagus, but there was evidence of decreased diversity in patients with esophageal adenocarcinoma as assessed by Simpson index. There was an apparent shift in composition at the transition from LGD to HGD, and patients with HGD and esophageal adenocarcinoma had decreased Firmicutes and increased Proteobacteria. In addition, patients with HGD or esophageal adenocarcinoma had increased Enterobacteriaceae and Akkermansia muciniphila and reduced Veillonella. In the study population, patients taking proton pump inhibitors had increased Streptococcus and decreased Gram-negative bacteria overall.Conclusions: Shifts in the Barrett's esophagus-associated microbiome were observed in patients with HGD and esophageal adenocarcinoma, with increases in certain potentially pathogenic bacteria.Impact: The microbiome may play a role in esophageal carcinogenesis.

The esophageal mucosal barrier in health and disease: mucosal pathophysiology and protective mechanisms

“…86,89 Dysplastic BE and EAC are associated with an overall decline in the esophageal microbial diversity 87 and specific changes in taxa, including a rise in Enterobacteriaceae, Akkermansia, and Lactobacillus and a reduction in Veillonella. 83,87,97 A similar decline in microbial diversity has also been observed in patients with dysplastic squamous epithelium. 95 Fusobacterium is both enriched in esophageal squamous cell carcinoma and associated with poor survival, [91][92][93] suggesting a potential role in carcinogenesis.…”

“…80 Alterations in the esophageal microbiome have also been observed with the use of PPIs. [81][82][83] Assessing the microbial composition of the esophagus before and after 8 weeks of PPI therapy, Amir et al found significant changes, including increases in members of Clostridia due to the medication. 81 Whether such changes are specific to PPIs or can be seen with other medications, including other classes of heartburn medications, antibiotics, or immunosuppressants, is unknown but may have important implications for conditions like esophageal candidiasis.…”

“…84 Esophageal diseases, including GERD, BE, esophageal cancer, and EoE, influence the esophageal microbiome. [81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96] Yang et al found that esophagitis and BE were associated with a rise in Gram negative anaerobes, including Prevotella, Veillonella, Haemophilus, Neisseria, Fusobacterium, and Campylobacter, at the expense of Streptococcus. 94 In two other studies, increase of Campylobacter was also found in patients with GERD and BE.…”

Exploring Esophageal Microbiomes in Esophageal Diseases: A Systematic Review

“…Additionally, noxious products from these bacteria, including hydrogen peroxide, may directly inhibit the growth of other bacteria and enable Lactobacillus to dominate in the lower esophagus. 23 A study by Snider et al 32 also showed that microbial diversity decreased in patients with EAC. The proportion of Firmicutes phylum (including Streptococcus) increased in the low-grade dysplasia, as compared to high- grade dysplasia or adenocarcinoma.…”

Effects of proton pump inhibitor use on the esophageal microbial community

“…The lack of alteration of the microbial community with PPI use is an important finding. Previous studies have shown that patients who develop Barrett’s esophagus have a different microbial community in their esophagus than patients without Barrett’s esophagus [ 28 ]. It is likely that there are factors other than pH and PPI use which cause this conversion of the esophageal mucosa and increased risk for esophageal cancer.…”