Relationship of the Esophageal Microbiome and Tissue Gene Expression and Links to the Oral Microbiome: A Randomized Clinical Trial

Abstract

INTRODUCTION: Although the microbiome is altered in various esophageal diseases, there is no direct evidence for a link between the oral or esophageal microbiome and underlying esophageal tissue. Here, we aimed to address these gaps through use of an antimicrobial mouth rinse to modify the esophageal microbiome and tissue gene expression. METHODS: In this randomized controlled trial, patients scheduled to undergo endoscopy for clinical indications used chlorhexidine mouth rinse or no treatment for 2 weeks before endoscopy. Oral swabs and saliva were collected at baseline and at follow-up, and the esophagus was sampled on the day of endoscopy. The microbiome was analyzed by 16S rRNA gene sequencing, and esophageal tissue gene expression was ascertained by RNA-Seq. RESULTS: Twenty subjects were enrolled and included in the analyses. Within individuals, the oral and esophageal microbiome composition was significantly correlated. Chlorhexidine treatment associated with significant alterations to the relative abundance of several esophageal bacterial taxa, and to expression of genes in the esophagus including reductions in periostin, claudin-18, chemokines CXCL1 and CXCL13 , and several members of the tumor necrosis factor receptor superfamily. A taxon in genus Haemophilus in the esophagus also associated with significant changes in tissue gene expression. DISCUSSION: The oral and esophageal microbiomes are closely related within individuals, and esophageal microbiome alterations correlate with tissue gene expression changes. The esophageal microbiome may act as an important cofactor that influences pathogenesis and outcomes of diseases such as eosinophilic esophagitis, gastroesophageal reflux, and Barrett's esophagus.

3D Organoids: An Untapped Platform for Studying Host–Microbiome Interactions in Esophageal Cancers

“…The bacterial microbiome is an emerging co-factor in esophageal health and disease (see recent reviews for more comprehensive discussion [41,46,47]). While the esophagus was long believed to be sterile, a growing body of evidence suggests that there is a stable esophageal bacterial microbiome that is heavily influenced by the oral microbiome [48][49][50]. In health, the esophageal microbiome primarily consists of 95 taxa belonging to six phyla, Firmicutes, Bacteroides, Actinobacteria, Proteobacteria, Fusobacteria, and Saccharibacteria phylum (also known as TM7) [51,52].…”

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

“…For example, this topic has been assessed in the context of the lung microbiome when distinguishing microbiota from bronchoalveolar lavage fluid and contemporaneous oral wash [27]. In a recent randomized controlled trial, the oral microbiome and esophageal microbiome were shown to be tightly linked as assessed by oral swabs and esophageal brushings that were sterilized at the beginning of the upper endoscopy [28]. This study found that intervention with chlorhexidine mouth rinse over 2 weeks caused significant alterations in the oral microbiome when compared to the untreated group (Wilcoxon rank-sum p = 0.013 for pairwise distances measured with weighted UniFrac), and this intervention also changed the expression of several genes associated with inflammation measured by RNAseq of esophageal tissue [28].…”

“…In a recent randomized controlled trial, the oral microbiome and esophageal microbiome were shown to be tightly linked as assessed by oral swabs and esophageal brushings that were sterilized at the beginning of the upper endoscopy [28]. This study found that intervention with chlorhexidine mouth rinse over 2 weeks caused significant alterations in the oral microbiome when compared to the untreated group (Wilcoxon rank-sum p = 0.013 for pairwise distances measured with weighted UniFrac), and this intervention also changed the expression of several genes associated with inflammation measured by RNAseq of esophageal tissue [28]. No study has yet fully revealed whether changes in the microbiome could relieve gastroesophageal reflux symptoms, or if BE metaplasia creates a different microenvironment that attracts different types of microbes compared to the normal esophagus [29]; thus, further investigation is warranted.…”

“…It is important to note that there is a much larger abundance of microbes in the oral cavity compared to the esophagus so saliva would likely represent mainly oral microbiota rather than esophagealspecific microbial communities [90]. In a randomized controlled trial, bacteria from oral swabs have been shown to be highly correlated with the esophageal microbiome within the same patient but this association was weaker when using saliva samples [28]. Wang and colleagues showed that the oral microbial taxa differed when comparing saliva samples from healthy patients versus those with reflux esophagitis, making it a potential biomarker for a diagnosis of reflux esophagitis [91].…”

Minimal Associations between Short-Term Dietary Intake and Salivary Microbiome Composition

“…The esophageal microbiome is broadly similar to the oral microbiome, with an abundance of anaerobes and a high Firmicutes to Bacteroidetes ratio [ 1 , 2 ]. This link between the mouth and esophagus was demonstrated by a recent, randomized controlled trial of an antimicrobial mouth rinse, in which oral microbiome alterations were found to directly impact esophageal microbiome composition and cause marked changes in esophageal tissue gene expression [ 3 ]. In light of the oral–esophageal microbiome connection, esophageal microbiome changes associated with neoplasia may be reflected in the mouth, an easily accessible sampling site.…”