Challenges in Determining the Role of Microbiome Evolution in Barrett's Esophagus and Progression to Esophageal Adenocarcinoma

Abstract

Esophageal adenocarcinoma (EAC) claims the lives of half of patients within the first year of diagnosis, and its incidence has rapidly increased since the 1970s despite extensive research into etiological factors. The changes in the microbiome within the distal esophagus in modern populations may help explain the growth in cases that other common EAC risk factors together cannot fully explain. The precursor to EAC is Barrett's esophagus (BE), a metaplasia adapted to a reflux-mediated microenvironment that can be challenging to diagnose in patients who do not undergo endoscopic screening. Non-invasive procedures to detect microbial communities in saliva, oral swabs and brushings from the distal esophagus allow us to characterize taxonomic differences in bacterial population abundances within patients with BE versus controls, and may provide an alternative means of BE detection. Unique microbial communities have been identified across healthy esophagus, BE, and various stages of progression to EAC, but studies determining dynamic changes in these communities, including migration from proximal stomach and oral cavity niches, and their potential causal role in cancer formation are lacking. Helicobacter pylori is negatively associated with EAC, and the absence of this species has been implicated in the evolution of chromosomal instability, a main driver of EAC, but joint analyses of microbiome and host genomes are needed. Acknowledging technical challenges, future studies on the prediction of microbial dynamics and evolution within BE and the progression to EAC will require larger esophageal microbiome datasets, improved bioinformatics pipelines, and specialized mathematical models for analysis.

Keywords: Barrett’s esophagus; Helicobacter pylori; esophageal adenocarcinoma; esophagus microbiome; microbiome evolution.

Figure 1

Microbial and genomic changes in the progression from BE to EAC. The stages of progression from normal tissue to EAC with corresponding non-genetic risk factors for BE and BE-EAC progression [7,40,41,42,43], common genomic changes frequently detected [44,45,46,47,48,49,50,51] as well as general trends expected in increasing Gram-negative bacterial species in BE [38,52]. Relative abundances reported across the phylum level at each stage are provided in aggregate (pie charts) and in each study individually (bar plots) to highlight study-specific heterogeneity [34,35,36,37,38,39,53]. Note, technical differences including analysis pipelines can lead to differences among studies beyond the biological differences likely to be present in the samples. Additional methods would need to be applied to distinguish methodological differences from cohort or stage differences across studies. Recent analysis methods such as differential ranking can help resolve stage differences and identify clinically significant microbial changes [54]. Hematoxylin and eosin stain images courtesy of Matthew Stachler, UCSF. GERD, gastroesophageal reflux disease; BE, Barrett’s esophagus; EAC, esophageal adenocarcinoma.

Figure 2

Microbiome of a healthy patient. Microbial abundances at the phylum level from patients without Barrett’s esophagus or cancer shown for the oral [14,18,89], esophageal [34,35,36,38,39,53] and H. pylori negative gastric [14] microbiomes. Esophageal microbes can migrate from and between the stomach and oral cavity, therefore influencing the expected diversity of the esophageal microbiome in clinical studies.