Chemoprevention of esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a major cause of cancer-related death, particularly in Western populations, and is rapidly rising in Asian populations at this time. Virtually all EACs develop from the precursor lesion Barrett's esophagus (BE), which is the most significant risk factor for EAC. However, the rates of progression from BE to EAC are low and patients with BE are asymptomatic. Thus, any strategy for EAC prevention must carry a low risk of harm in order to be clinically useful. Since current EAC-screening and BE-surveillance methods carry some procedural risk and are burdensome, there is an opportunity for chemoprevention, i.e. medications or dietary factors that may prevent BE from progressing to EAC. A variety of candidate chemoprevention therapies have been assessed to date. Proton-pump inhibitors (PPIs) are the best studied and have modest EAC-chemoprevention efficacy in BE patients, with a recent randomized trial showing that high-dose PPI may be more effective than low-dose PPI. Aspirin and other non-steroidal anti-inflammatory drugs have moderate quality observational and randomized-trial evidence for preventing progression of BE to EAC, but their risks for harm have precluded their routine clinical use. Other therapies (statins, metformin, female sex hormones) generally do not have strong evidence to support their use in EAC chemoprevention. Although progress has been made in this field, there is still a need for more effective and safe chemoprevention therapies for EAC.

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

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 high-grade 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.

Increasing Dietary Fiber Intake Is Associated with a Distinct Esophageal Microbiome.

INTRODUCTION: There is increasing evidence that the microbiome contributes to esophageal disease. Diet, especially fiber and fat intake, is a known potent modifier of the colonic microbiome, but its impact on the esophageal microbiome is not well described. We hypothesized that dietary fiber and fat intake would be associated with a distinct esophageal microbiome. METHODS: We collected esophageal samples from 47 ambulatory patients scheduled to undergo endoscopy who completed a validated food frequency questionnaire quantifying dietary fiber and fat intake. Using 16S high-throughput sequencing, we determined composition of the esophageal microbiome and predicted functional capacity of microbiota based on fiber and fat intake. RESULTS: Among all samples, the most abundant phyla were Firmicutes (54.0%), Proteobacteria (19.0%), Bacteroidetes (17.0%), Actinobacteria (5.2%), and Fusobacteria (4.3%). Increasing fiber intake was significantly associated with increasing relative abundance of Firmicutes (p = 0.04) and decreasing relative abundance of Gram-negative bacteria overall (p = 0.03). Low fiber intake was associated with increased relative abundance of several Gram-negative bacteria, including Prevotella, Neisseria, and Eikenella. Several predicted metabolic pathways differed between highest and lowest quartile of fiber intake. Fat intake was associated with altered relative abundance of few taxa, with no alterations at the phylum level and no changes in microbiome functional composition. CONCLUSIONS: Dietary fiber, but not fat, intake was associated with a distinct esophageal microbiome. Diet should be considered an important modifier of the esophageal microbiome in future studies. Studies are also needed to elucidate how the effects of dietary fiber on the esophageal microbiome may contribute to esophageal disease.

Rapid gastrointestinal loss of Clostridial Clusters IV and XIVa in the ICU associates with an expansion of gut pathogens.

Commensal gastrointestinal bacteria resist the expansion of pathogens and are lost during critical illness, facilitating pathogen colonization and infection. We performed a prospective, ICU-based study to determine risk factors for loss of gut colonization resistance during the initial period of critical illness. Rectal swabs were taken from adult ICU patients within 4 hours of admission and 72 hours later, and analyzed using 16S rRNA gene sequencing and selective culture for vancomycin-resistant Enterococcus (VRE). Microbiome data was visualized using principal coordinate analyses (PCoA) and assessed using a linear discriminant analysis algorithm and logistic regression modeling. 93 ICU patients were analyzed. At 72 hours following ICU admission, there was a significant decrease in the proportion of Clostridial Clusters IV/XIVa, taxa that produce short chain fatty acids (SCFAs). At the same time, there was a significant expansion in Enterococcus. Decreases in Cluster IV/XIVa Clostridia were associated with loss of gut microbiome colonization resistance (reduced diversity and community stability over time). In multivariable analysis, both decreased Cluster IV/XIVa Clostridia and increased Enterococcus after 72 hours were associated with receipt of antibiotics. Cluster IV/XIVa Clostridia, although a small fraction of the overall gastrointestinal microbiome, drove distinct clustering on PCoA. During initial treatment for critical illness, there was a loss of Cluster IV/XIVa Clostridia within the distal gut microbiome which associated with an expansion of VRE and with a loss of gut microbiome colonization resistance. Receipt of broad-spectrum antibiotics was associated with these changes.

Barrett's esophagus is associated with a distinct oral microbiome.

OBJECTIVES: The esophageal microbiome is composed of predominantly oral flora and is altered in reflux-related conditions including Barrett's esophagus (BE). Changes to the esophageal microbiome may be reflected in the oral cavity. Assessing the oral microbiome thus represents a potential non-invasive method to identify patients with BE. METHODS: Patients with and without BE undergoing upper endoscopy were prospectively enrolled. Demographics, clinical data, medications, and dietary intake were assessed. 16S rRNA gene sequencing was performed on saliva samples collected prior to endoscopy. Taxonomic differences between groups were assessed via linear discriminant analysis effect size (LEfSe). Logit models were used to develop microbiome signatures to distinguish BE from non-BE, assessed by area under the receiver operating curve (AUROC). RESULTS: A total of 49 patients were enrolled (control = 17, BE = 32). There was no significant difference in alpha diversity comparing all BE patients vs. CONTROLS: At the phylum level, the oral microbiome in BE patients had significantly increased relative abundance of Firmicutes (p = 0.005) and decreased Proteobacteria (p = 0.02). There were numerous taxonomic differences in the oral microbiome between BE and controls. A model including relative abundance of Lautropia, Streptococcus, and a genus in the order Bacteroidales distinguished BE from controls with an AUROC 0.94 (95% CI: 0.85-1.00). The optimal cutoff identified BE patients with 96.9% sensitivity and 88.2% specificity. CONCLUSIONS: The oral microbiome in BE patients was markedly altered and distinguished BE with relatively high accuracy. The oral microbiome represents a potential screening marker for BE, and validation studies in larger and distinct populations are warranted.

Potential Role of the Microbiome in Barrett's Esophagus and Esophageal Adenocarcinoma.

Esophageal adenocarcinoma and its precursor Barrett's esophagus have been rapidly increasing in incidence for half a century, for reasons not adequately explained by currently identified risk factors such as gastroesophageal reflux disease and obesity. The upper gastrointestinal microbiome may represent another potential cofactor. The distal esophagus has a distinct microbiome of predominantly oral-derived flora, which is altered in Barrett's esophagus and reflux esophagitis. Chronic low-grade inflammation or direct carcinogenesis from this altered microbiome may combine with known risk factors to promote Barrett's metaplasia and progression to adenocarcinoma.

Multifaceted effects of ATP on cardiolipin-bound cytochrome c.

Using a collection of dye-labeled cytochrome c (cyt c) variants, we identify transformations of the heterogeneous cardiolipin (CL)-bound cyt c ensemble with added ATP. Distributions of dye-to-heme distances P(r) from time-resolved fluorescence resonance energy transfer show that ATP decreases the population of largely unfolded cyt c conformers, but its effects are distinct from those of a simple salt. The high peroxidase activity of CL-bound cyt c with added ATP suggests binding interactions that favor protein structures with the open heme pocket. Although ATP weakens cyt c-CL binding interactions, it also boosts the apoptosis-relevant peroxidase activity of CL-bound cyt c.