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BACKGROUND: Gut microbiota(GM) have been proven associated with lots of gastrointestinal diseases, but its causal relationship with Gastroesophageal reflux disease(GERD) and Barrett\'s esophagus(BE) hasn\'t been explored. We aimed to uncover the causal relation between GM and GERD/BE and potential mediators by utilizing Mendelian Randomization(MR) analysis.
METHODS: Summary statistics of GM(comprising 301 bacteria taxa and 205 metabolism pathways) were extracted from MiBioGen Consortium(N = 18,340) and Dutch Microbiome Project(N = 7,738), GERD and BE from a multitrait meta-analysis(NGERD=602,604, NBE=56,429). Bidirectional two-sample MR analysis and linkage disequilibrium score regression(LDSC) were used to explore the genetic correlation between GM and GERD/BE. Mediation MR analysis was performed for the risk factors of GERD/BE, including Body mass index(BMI), weight, type 2 diabetes, major depressive disorder(MDD), smoking initiation, alcohol consumption, and dietary intake(including carbohydrate, sugar, fat, protein intake), to detect the potential mediators between GM and GERD/BE.
RESULTS: 11 bacterial taxa and 13 metabolism pathways were found associated with GERD, and 18 taxa and 5 pathways exhibited causal relationship with BE. Mediation MR analysis suggested weight and BMI played a crucial role in these relationships. LDSC identified 1 taxon and 4 metabolism pathways related to GERD, and 1 taxon related to BE. Specie Faecalibacterium prausnitzii had a suggestive impact on both GERD(OR = 1.087, 95%CI = 1.01-1.17) and BE(OR = 1.388, 95%CI = 1.03-1.86) and LDSC had determined their correlation. Reverse MR indicated that BE impacted 10 taxa and 4 pathways.
CONCLUSIONS: This study established a causal link between gut microbiota and GERD/BE, and identified the probable mediators. It offers new insights into the role of gut microbiota in the development and progression of GERD and BE in the host.

OBJECTIVE: Barrett\'s esophagus (BE) is a precancerous condition that has the potential to develop into esophageal cancer (EC). Currently, there is a wide range of management options available for individuals at different pathological stages in Barrett\'s esophagus (BE). However, there is currently a lack of knowledge regarding their comparative efficacy. To address this gap, we conducted a network meta-analysis of published randomized controlled trials to examine the comparative effectiveness of all regimens.
METHODS: Data extracted from eligible randomized controlled trials were utilized in a Bayesian network meta-analysis to examine the relative effectiveness of BE\'s treatment regimens and determine their ranking in terms of efficacy. The ranking probability for each regimen was assessed using the surfaces under cumulative ranking values. The outcomes under investigation were complete ablation of BE, neoplastic progression of BE, and complete eradication of dysplasia.
RESULTS: We identified twenty-three RCT studies with a total of 1675 participants, and ten different interventions. Regarding complete ablation of non-dysplastic BE, the comparative effectiveness ranking indicated that argon plasma coagulation (APC) was the most effective regimen, with the highest SUCRA value, while surveillance and PPI/H2RA were found to be the least efficacious regimens. For complete ablation of BE with low-grade dysplasia, high-grade dysplasia, or esophageal cancer, photodynamic therapy (PDT) had the highest SUCRA value of 94.1%, indicating it as the best regimen. Additionally, for complete eradication of dysplasia, SUCRA plots showed a trend in ranking PDT as the highest with a SUCRA value of 91.2%. Finally, for neoplastic progression, radiofrequency ablation (RFA) and surgery were found to perform significantly better than surveillance. The risk of bias assessment revealed that 6 studies had an overall high risk of bias. However, meta-regression with risk of bias as a covariate did not indicate any influence on the model. In terms of the Confidence in Network Meta-Analysis evaluation, a high level of confidence was found for all treatment comparisons.
CONCLUSIONS: Endoscopic surveillance alone or PPI/H2RA alone may not be sufficient for managing BE, even in cases of non-dysplastic BE. However, APC has shown excellent efficacy in treating non-dysplastic BE. For cases of BE with low-grade dysplasia, high-grade dysplasia, or esophageal cancer, PDT may be the optimal intervention as it can induce regression of BE metaplasia and prevent future progression of BE to dysplasia and EC.

BACKGROUND: Epithelial-mesenchymal plasticity (EMP), the process through which epithelial cells acquire mesenchymal features, is needed for wound repair but also might contribute to cancer initiation. Earlier, in vitro studies showed that Barrett\'s cells exposed to acidic bile salt solutions (ABS) develop EMP. Now, we have (1) induced reflux oesophagitis in Barrett\'s oesophagus (BO) patients by stopping proton pump inhibitors (PPIs), (2) assessed their biopsies for EMP and (3) explored molecular pathways underlying reflux-induced EMP in BO cells and spheroids.
METHODS: 15 BO patients had endoscopy with biopsies of Barrett\'s metaplasia while on PPIs, and 1 and 2 weeks after stopping PPIs; RNA-seq data were assessed for enrichments in hypoxia-inducible factors (HIFs), angiogenesis and EMP pathways. In BO biopsies, cell lines and spheroids, EMP features (motility) and markers (vascular endothelial growth factor (VEGF), ZEB1, miR-200a&b) were evaluated by morphology, migration assays, immunostaining and qPCR; HIF-1α was knocked down with siRNA or shRNA.
RESULTS: At 1 and/or 2 weeks off PPIs, BO biopsies exhibited EMP features and markers, with significant enrichment for HIF-1α, angiogenesis and EMP pathways. In BO cells, ABS induced HIF-1α activation, which decreased miR-200a&b while increasing VEGF, ZEB1 and motility; HIF-1α knockdown blocked these effects. After ABS treatment, BO spheroids exhibited migratory protrusions showing nuclear HIF-1α, increased VEGF and decreased miR-200a&b.
CONCLUSIONS: In BO patients, reflux oesophagitis induces EMP changes associated with increased HIF-1α signalling in Barrett\'s metaplasia. In Barrett\'s cells, ABS trigger EMP via HIF-1α signalling. Thus, HIF-1α appears to play a key role in mediating reflux-induced EMP that might contribute to cancer in BO.
BACKGROUND: NCT02579460.

OBJECTIVE: The causal associations of circulating lipids with Barrett\'s Esophagus (BE) and Esophageal Cancer (EC) has been a topic of debate. This study sought to elucidate the causality between circulating lipids and the risk of BE and EC.
METHODS: We conducted two-sample Mendelian randomization (MR) analyses using single nucleotide polymorphisms (SNPs) of circulating lipids (n = 94,595 - 431,167 individuals), BE (218,792 individuals), and EC (190,190 individuals) obtained from the publicly available IEU OpenGWAS database. The robustness and reliability of the results were ensured by employing inverse-variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO methods. The presence of horizontal pleiotropy, heterogeneities, and stability of instrumental variables were assessed through MR-Egger intercept test, Cochran\'s Q test, and leave-one-out sensitivity analysis. Additionally, bidirectional MR and multivariable MR (MVMR) were performed to explore reverse causality and adjust for known confounders, respectively.
RESULTS: None of the testing methods revealed statistically significant horizontal pleiotropy, directional pleiotropy, or heterogeneity. Univariate MR analyses using IVW indicated a robust causal relationship between increased triglycerides and BE (odds ratio [OR] = 1.79, p-value = 0.009), while no significant association with EC was observed. Inverse MR analysis indicated no evidence of reverse causality in the aforementioned outcomes. In MVMR analyses, elevated triglycerides (TRG) were significantly and positively associated with BE risk (OR = 1.79, p-value = 0.041).
CONCLUSIONS: This MR study suggested that genetically increased triglycerides were closely related to an elevated risk of BE, potentially serving as a biomarker for the diagnosis of BE in the future.

OBJECTIVE: To investigate the esophageal motility characteristics of gastroesophageal reflux disease (GERD) and their relationship with symptoms.
METHODS: We examined 101 patients diagnosed with GERD by endoscopy and divided them into 3 groups as follows: nonerosive reflux disease (NERD), reflux esophagitis, and Barrett esophagus. Esophageal high-resolution manometry and the GERD Questionnaire were used to investigate the characteristics of esophageal dynamics and symptoms. In addition, the reflux symptom index was completed and the patients were divided into 7 groups according to symptoms. We then determined the correlation between dynamic esophageal characteristics and clinical symptoms.
RESULTS: Upper (UES) and lower (LES) esophageal sphincter pressures and the 4-second integrated relaxation pressure in the RE group were lower than those in the NERD group. The 4-second integrated relaxation pressure in the Barrett esophagus group was also lower than that in the NERD group. In the analysis of extraesophageal symptoms, high-resolution manometry showed significant differences in UES pressures among all groups. Further subgroup analysis showed that compared with the group without extraesophageal symptoms, the UES pressure of the groups with pharyngeal foreign body sensation, throat clearing, and multiple extraesophageal symptoms was lower.
CONCLUSIONS: As GERD severity increases, motor dysfunction of the LES and esophageal body gradually worsens, and the LES plays an important role in GERD development. Decreased UES pressure plays an important role in the occurrence of extraesophageal symptoms, which is more noticeable in patients with pharyngeal foreign body sensation and throat clearing.

Recent genomic studies suggest that esophageal adenocarcinoma (EAC) is not homogeneous and can be divided into true (tEAC) and probable (pEAC) groups. We compared clinicopathologic and prognostic features between the two groups of EAC. Based on endoscopic, radiologic, surgical, and pathologic reports, tumors with epicenters beyond 2 cm of the gastroesophageal junction (GEJ) were assigned to the tEAC group (N = 63), while epicenters within 2 cm of, but not crossing the GEJ, were allocated to the pEAC group (N = 83). All 146 consecutive patients were male (age: median 70 years, range: 51-88) and White-predominant (98.6 %). There was no significant difference in gastroesophageal reflux disease, obesity, comorbidity, and the prevalence of Barrett\'s esophagus, and cases diagnosed during endoscopic surveillance. However, compared to the pEAC group, the tEAC group had significantly more cases with hiatal hernia (P = 0.003); their tumors were significantly smaller in size (P = 0.007), more frequently with tubular/papillary adenocarcinoma (P = 0.001), had fewer cases with poorly cohesive carcinoma (P = 0.018), and demonstrated better prognosis in stage I disease (P = 0.012); 5-year overall survival (34.9 months) was significantly longer (versus 16.8 months in pEACs) (P = 0.043). Compared to the patients without resection, the patients treated with endoscopic or surgical resection showed significantly better outcomes, irrespective of stages. We concluded that EACs were heterogeneous with two distinct tEAC and pEAC groups in clinicopathology and prognosis; resection remained the better option for improved outcomes. CONDENSED ABSTRACT: Esophageal adenocarcinoma can be divided into true or probable groups with distinct clinicopathology and better prognosis in the former than in the latter. we showed that resection remained the better option for improved outcomes.

Barrett\'s esophagus (BE) belongs to a pathological phenomenon occurring in the esophagus, this paper intended to unveil the underlying function of miR-378a-5p and its target TSPAN8 in BE progression. GEO analysis was conducted to determine differentially expressed genes in BE samples. Non-dysplastic metaplasia BE samples, high-grade dysplastic BE samples and controls were collected from subjects. CP-A and CP-B cells were exposed to bile acids (BA) to mimic gastroesophageal reflux in BE cells. RT-qPCR as well as western blot were applied for verifying expressions of miR-378a-5p, TSPAN8, CDX2 and SOX9. CCK-8, wound scratch together with Transwell assays were exploited for ascertaining cell proliferation, migration as well as invasion. The targeted relationship of miR-378a-5p and TSPAN8 could be verified by correlation analysis, dual-luciferase reporter experiment, and rescue experiments. Through analyzing GSE26886 dataset, we screened the most abundantly expressed gene TSPAN8 in BE samples. miR-378a-5p was reduced whereas TSPAN8 was elevated in CP-A as well as CP-B cells after triggering with BA. Knocking down TSPAN8 could counteract BA-triggered enhancement in BE cell proliferation, migration along with invasion. miR-378a-5p could suppress BE cell proliferation, and migration along with invasion via targeting TSPAN8. In BE, miR-378a-5p targeted TSPAN8 to inhibit BE cell proliferation, and migration along invasion. miR-378a-5p deletion or elevation of TSPAN8 may be key point in regulating CDX2 and SOX9 levels, thereby promoting BE formation.

Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett\'s esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10-5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.

Aims: Dietary habits are reported to be associated with Barrett\'s esophagus (BE) risk; however, whether there is a causal relationship remains controversial. Here, we systematically examined the causal effects of genetically predicted dietary habits on BE risk through a Mendelian randomization (MR) analysis approach. Methods: Data for exposures were obtained from the UK Biobank (UKB), while the summary-level data for outcomes were obtained from a large sample-size GWAS meta-analysis. Genetic variants associated with 17 ordinary dietary habits at the genome-wide significance level were regarded as instrumental variables (IVs). Univariable and multivariable MR analyses were conducted to explore the causal relationships between dietary habits and BE risk. Sensitivity analyses were implemented to evaluate robustness of the results and determine the potential pleiotropy bias. Results: Univariable MR (UVMR) analysis showed that genetic predisposition to alcohol intake frequency, cooked vegetable intake, beef intake, bread intake, fresh fruit intake, salad/raw vegetable intake, and dried fruit intake were associated with BE risk, with all P values <0.05. After adjusting confounders, the effects of four dietary habits on BE risk persisted; multivariable MR (MVMR) analysis revealed that alcohol intake frequency (adjusted odds ratio (OR) = 1.74 (1.34, 2.27); P = 3.42 × 10-5) was causally associated with higher BE risk, the cooked vegetable intake (adjusted OR = 2.64 (1.16, 5.97); P = 0.02) had suggestively increased BE risk, while higher consumption of bread (adjusted OR = 0.54 (0.32-0.91); P = 0.02) and fresh fruit (adjusted OR = 0.34 (0.15, 0.77); P = 0.01) were suggestively associated with lower BE risk. Conclusions: These MR analyses demonstrate evidence of causal relationships between dietary habits and BE risk. These findings provide new insights into targeted dietary intervention strategies for BE prevention.