While intestinal microbiomes have been relatively well studied, upper gastrointestinal tract microbiomes have not been thoroughly evaluated. Especially, studies on esophageal microbiomes are relatively limited. Traditionally, the esophagus is regarded as devoid of a significant bacterial population. 1,2 In addition, microbial flora in a normal esophagus has been considered transient and translocated from the oropharynx. 3 In 1998, Gagliardi et al 3 revealed that
However, next-generation sequencing techniques such as 16S ribosomal RNA (rRNA) gene sequencing have been increasingly used to open a new horizon for microbial research nowadays. 4 The technique allowed recognition of uncultured bacteria, facilitating easy identification of differences in microbial composition between a normal and diseased esophagus. 5 Currently, the esophagus has been found to contain a diverse microbiome. 6,7 Additionally, several studies evaluated the microbial composition of a normal esophagus as well as various esophageal diseases such as gastroesophageal reflux disease (GERD), Barrett’s esophagus, esophageal cancer, and eosinophilic esophagitis (EoE). 2 Here, we performed a systematic review on the variation in microbial composition according to the esophageal diseases.
We searched for all relevant studies published between January 1980 and February 2020 that examined the human esophageal microbiome using the MEDLINE, EMBASE, and Cochrane Library databases. The following search string was used: ([esophagus] OR [oesophagus] OR [esophageal] OR [oesophageal]) AND ([microbiome] OR [microbiota] OR [microbial] OR [microflora] OR [biota] OR [bacterial flora] OR [bacterial biofilm]). Appendix 1 shows the detailed search strategies in each database.
The inclusion criteria were as follows: (1) healthy individuals or patients with esophageal diseases including GERD, esophageal cancer, EoE, and achalasia, and (2) composition or any other findings about the esophageal microbiome. Non-original studies, non-human studies, abstract-only publications, and studies published in languages other than English were excluded.
First, we reviewed the titles and abstracts of the research papers found during our keyword search. Duplicates from multiple search engines were removed. Next, irrelevant studies were excluded by title and abstract review according to our inclusion and exclusion criteria. We screened the full text of all remaining studies. Two investigators (C.H.P. and S.K.L.) independently evaluated the studies for eligibility. Any disagreements were resolved through discussion and consensus.
Data were extracted using a data extraction form that had been developed in advance. Two investigators (C.H.P. and S.K.L.) independently extracted the following information: first author, year of publication, country, study period, population, publication language, and study outcomes.
Figure 1 shows the study flow diagram for our systematic review. Our literature search identified 682 studies. After examining the titles and abstracts, we discarded 200 duplicate articles, which were retrieved through multiple search engines. Another 444 irrelevant articles were excluded on the basis of their titles and abstracts. After reviewing the full text of the 38 remaining articles, we further excluded 5 articles that did not report the relevant outcomes. Additionally, 1 non-original article and 2 articles in which full-texts were unavailable were excluded. Finally, 30 studies were included in the systematic review. 3,5,6,8-34 The main findings about esophageal microbiome of these studies are summarized in Table.
The first study on microbiomes in a normal esophagus, based on bacterial cultures, was conducted by Mannell et al 9 in 1983. In their study,
Since the early 2000s, esophageal microbiomes have been evaluated using culture-independent methods. Pei et al 6 examined esophageal biopsy samples obtained from 4 individuals. They performed a broad-range 16S rRNA gene polymerase chain reaction (PCR) analysis and obtained 900 PCR cloned products representing 833 unique sequences belonging to 41 genera. A majority of clones belonged to 13 of 41 genera, which were shared by all 4 individuals. 6 Specifically,
In summary, the most common bacterial taxa in a normal esophagus include
Additionally, proton pump inhibitors (PPIs) may also affect esophageal microbiomes. Amir et al 17 showed a significant change of esophageal microbiomes after 8 weeks of PPI treatment (unweighted UniFrac analysis of similarities R = 0.17,
The impact of low fiber intake is similar to that of reflux esophagitis or Barrett's esophagus on the esophageal microbiome composition, which will be described in the next section.
In addition to demographic factors and medications, various diseases affect the esophageal microbial composition. In a study on gastric microbiomes, bacterial taxa other than
In 2009, Yang et al 13 suggested that the esophageal microbiome could be classified into 2 groups: type I microbiome dominated by Gram-positive taxa of
The difference in esophageal microbiome among the reflux disease status was also shown in the Liu et al study, 16 conducted using 16S rRNA gene sequencing.
In another study by Blackett et al 15 conducted using a cultural analysis with PCR for specific bacterial taxa, the abundance of
Based on results of these previous studies, the schematic diagram on differences in esophageal microbiome composition was observed according to the disease status in Figure 2.
In contrast to changes toward increasing various bacterial taxa in GERD and Barrett's esophagus, microbial diversity decreased in esophageal adenocarcinoma (EAC) when compared with the control, which enriched acid-tolerant bacteria such as
Until recently, characteristics of the esophageal microbiome in patients with esophageal squamous cell carcinoma (ESCC) have not been well known. However, in a recent case-control study including 25 patients with ESCC and 50 matched controls,
EoE is a chronic immune/antigen-mediated disorder caused by T helper 2-mediated immune response triggered by food or environmental allergens. 43,44 As an increase in incidence and prevalence of EoE, interest in the esophageal microbiome in patients with EoE has been increasing. 43 In patients with EoE,
Achalasia is a motility disorder presented as dysphagia, regurgitation of undigested food, weight loss, and chest pain. 45 It is caused by the inability to lower the esophageal sphincter to facilitate relaxation in the setting of absent peristalsis. 46 The relationship between achalasia and esophageal microbiome has not been evaluated. Although several case reports showed the association between
Owing to the advancement of next-generation sequencing techniques, associations between the esophageal microbiomes and various diseases have been widely investigated. Nowadays, the esophagus is found to be unsterile, and many bacterial taxa exist depending on the disease status. However, whether the esophageal microbiome induces esophageal diseases remains unknown. Most changes in esophageal microbiome composition may likely be a secondary change due to acid reflux, aggravation of inflammation, and other predisposing factors such as alcohol and smoking. To determine the causal relationship between esophageal microbiome and diseases, well-designed experiments using germ-free animal models are warranted. Nevertheless, understanding the esophageal microbiome in various diseases may have a clinical implication because oral microbiomes are usually correlated with esophageal microbiomes. We will be able to predict various esophageal diseases via oral samples that can be easily obtained compared to esophageal samples. Further researches will be conducted on oral and esophageal microbiomes in various esophageal diseases.