Human Microbiota in Esophageal Adenocarcinoma: Pathogenesis, Diagnosis, Prognosis and Therapeutic Implications

Abstract

Esophageal adenocarcinoma (EAC) is one of the main subtypes of esophageal cancer. The incidence rate of EAC increased progressively while the 5-year relative survival rates were poor in the past two decades. The mechanism of EAC has been studied extensively in relation to genetic factors, but less so with respect to human microbiota. Currently, researches about the relationship between EAC and the human microbiota is a newly emerging field of study. Herein, we present the current state of knowledge linking human microbiota to esophageal adenocarcinoma and its precursor lesion-gastroesophageal reflux disease and Barrett's esophagus. There are specific human bacterial alternations in the process of esophageal carcinogenesis. And bacterial dysbiosis plays an important role in the process of esophageal carcinogenesis via inflammation, microbial metabolism and genotoxicity. Based on the human microbiota alternation in the EAC cascade, it provides potential microbiome-based clinical application. This review is focused on novel targets in prevention, diagnosis, prognosis, and therapy for esophageal adenocarcinoma.

Keywords: Barrett’s esophagus; esophageal adenocarcinoma; gastroesophageal reflux disease; microbial therapy; microbiota.

FIGURE 1

The predominant phyla of esophageal microbiota and oral microbiota. The top six most abundant phyla of esophageal microbiota consisted of Firmicutes (69.60%), Bacteroides (20.20%), Actinobacteria (4.30%), Proteobacteria (2.20%), Fusobacteria (2.20%), TM7 (1.40%); And the top six most abundant phyla of oral microbiota consisted of Proteobacteria (35.34%), Bacteroides (32.20%), Firmicutes (14.48%), Actinobacteria (9.26%), Fusobacteria (3.76%), TM7 (3.25%).

FIGURE 2

The process of esophageal carcinogenesis and associated human microbiota. This figure describes specific human bacterial alternations in the normal esophagus, esophageal adenocarcinoma and its precursor lesion—gastroesophageal reflux disease and Barrett’s esophagus.

FIGURE 3

The molecular mechanisms of microbe-mediated in EAC carcinogenesis. On the basis of the known contribution of human microbiota in esophageal carcinogenesis, the main mechanisms included inflammation, metabolism, and genotoxicity. Alteration of human microbiota in EAC showed a shift toward Gram-negative bacteria. Some specific pathogens, such as Campylobacter concisus, Helicobacter pylori, and Escherichia coli, involved in the process of inflammation and EAC cascade by regulating the expressions of toll-like receptors (TLRs) and pro-inflammatory mediators such as TNF-α, IL-18, COX-2, prostaglandins. And the components of Gram-negative bacteria activated the NLRP3 inflammasome and NF-κB pathway. Besides, detrimental metabolites, such as hydrogen sulfide, products of protein fermentation and bile acid metabolism, could play an important role in the initiation and progression of EAC. Some Gram-negative bacteria produced the cytolethal distending toxin (CDT), which could induce DNA damage and trigger EAC carcinogenesis. LPS, lipopolysaccharides; NF-κB, nuclear factor kappa B; TLRs, toll-like receptors; CDT, cytolethal distending toxin; TNF-α, tumor necrosis factor-α; IL, interleukin; COX, cyclooxygenase; PG, prostaglandin; p53, tumor protein 53; NLRP3, nucleotide-binding domain and leucine-rich repeat-containing protein 3.

FIGURE 4

The novel microbiota-related targets in screening, diagnosis, prognosis, and therapy for esophageal adenocarcinoma.