The gastric enzyme pepsin is a critically under-addressed aggressor during reflux disease and is regarded by many as the most damaging element of laryngopharyngeal reflux. Research over the last 2 decades has elucidated mechanisms by which pepsin causes damage during weakly and nonacid reflux yielding information to exploit its diagnostic and therapeutic potential. These findings have driven advances that, while still in their infancy, harbor important clinical implications.

Gastroesophageal reflux disease (GERD) is increasingly recognized for its associations with extragastric diseases, yet its potential role in pancreatic cancer (PC) etiology remains underexplored. This study investigates the genetic causal relationship between GERD and PC using Mendelian randomization (MR), a method designed to reduce confounding factors.

A two-sample MR analysis was conducted using genome-wide association studies (GWAS) data. The inverse variance weighted (IVW) method was applied, with additional sensitivity analyses performed to evaluate pleiotropy and heterogeneity.

The IVW analysis demonstrated a significant genetic association between the genetic signature predisposing to GERD and an increased risk of PC (OR: 1.36, 95% CI: 1.04-1.80, P = 0.03). There was no evidence of pleiotropy (P = 0.71) or heterogeneity (P = 0.94).

Our study provides robust genetic evidence supporting that the genetic predisposition to GERD is associated with an increased risk of PC. These findings emphasize the necessity of integrating GERD into PC risk assessments and encourage further research to elucidate the underlying biological mechanisms. This insight holds potential to inform strategies for early detection, prevention, and personalized management of PC in GERD patients.

Esophageal adenocarcinoma (EAC) is a rapidly increasing malignancy with significant morbidity and mortality. The progression from gastroesophageal reflux disease (GERD) to Barrett's esophagus (BE) and ultimately to EAC is thought to be influenced by chronic inflammation and immune cell dynamics. Despite the observed correlations in observational studies, the causal relationships between immune cell phenotypes and this disease continuum remain unclear.

This study utilized a two-sample Mendelian Randomization (MR) approach to investigate the causal roles of 731 distinct immune cell phenotypes in the GERD-BE-EAC continuum. The analysis leveraged genome-wide association study (GWAS) data for immune phenotypes from a Sardinian cohort and data for GERD, BE, and EAC from the FinnGen and Open GWAS databases. A comprehensive set of MR methods, including inverse variance weighted (IVW), MR-Egger, and weighted median estimators, was employed to assess causality. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy, ensuring the robustness of the findings.

The study revealed complex and multifaceted roles of immune cells across the GERD-BE-EAC continuum. In GERD, 34 immune phenotypes were found to be causally associated with either increased or decreased risk. Protective effects were observed in phenotypes such as Unswitched Memory B cells, while others like CD45RA- CD4+ T cells were linked to an elevated risk. In the context of BE, 28 immune phenotypes demonstrated significant causal associations, with the majority being protective, including Unswitched Memory B cells and CD62L on Granulocytes. Conversely, certain phenotypes, such as CD24 on Transitional B cells, were identified as risk factors for BE. For EAC, 34 immune phenotypes were implicated, with various B cell subsets, particularly those expressing BAFF-R and CD24, associated with an increased risk, while Switched Memory B cells and specific myeloid cell phenotypes showed protective effects.

This study provides novel insights into the complex role of immune cells in the pathogenesis of EAC, revealing a dynamic interplay where certain immune phenotypes may be protective in early stages but become risk-enhancing in later stages of disease progression. These findings highlight the potential of immune cell phenotypes to serve as biomarkers for early detection and targeted therapeutic interventions across the GERD-BE-EAC continuum. Further research is warranted to validate these findings in diverse populations and to explore the underlying mechanisms driving these immune-mediated effects.

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder that is defined by the reflux of gastric contents into the esophagus, and it results in symptoms such as esophageal inflammation, regurgitation, and indigestion. Although proton pump inhibitors (PPIs) and histamine-2 receptor antagonists are frequently employed to treat GERD, their prolonged administration is associated with adverse effects, necessitating the development of alternative therapeutic strategies. Natural products are now recognized as promising candidates for the management of GERD due to their bioactive compounds, which possess antioxidant, anti-inflammatory, and mucosal-protective properties. The potential of natural products in the treatment of GERD is comprehensively examined in this review, with a focus on their mechanisms of action, which include acid suppression, esophageal mucosal regeneration, anti-inflammatory activity, and gut microbiota modulation. Also, the efficacy and safety of key natural products, including flavonoids, polyphenols, plant-derived oils, herbal extracts, probiotics, and dietary components, in preclinical and clinical studies, are assessed. Additionally, this review addresses the barriers confronting the translation of natural therapies into clinical practice, such as regulatory obstacles, variability in bioavailability, and the need for dosage standardization. The integration of natural products into the management of GERD has the potential to enhance conventional therapies, providing a more comprehensive and secure approach for patients.

Barrett's esophagus (BE) is described by the transformation of the normal squamous epithelium into metaplastic columnar epithelium, driven by chronic gastroesophageal reflux disease (GERD). BE is a recognized premalignant condition and the main precursor to esophageal adenocarcinoma (EAC). Understanding the molecular mechanisms underlying BE carcinogenesis is crucial for improving prevention, surveillance, and treatment strategies.

This narrative review examines the molecular abnormalities associated with the progression of BE to EAC.

This study highlights inflammatory, genetic, epigenetic, and chromosomal alterations, emphasizing key pathways and biomarkers. BE progression follows a multistep process involving dysplasia and genetic alterations such as TP53 and CDKN2A (p16) mutations, chromosomal instability, and dysregulation of pathways like PI3K/AKT/mTOR. Epigenetic alterations, including aberrant microRNA expression or DNA methylation, further contribute to this progression. These molecular changes are stage-specific, with some alterations occurring early in BE during the transition to high-grade dysplasia or EAC. Innovations in chemoprevention, such as combining proton pump inhibitors and aspirin, and the potential of antireflux surgery to halt disease progression are promising. Incorporating molecular biomarkers into surveillance strategies and advancing precision medicine may enable earlier detection and personalized treatments.

BE is the primary preneoplastic condition for EAC. A deeper understanding of its molecular transformation can enhance surveillance protocols, optimize the management of gastroesophageal reflux inflammation, and refine prevention and therapeutic strategies, ultimately contributing to a reduction in the global burden of EAC.

Zuojin Pill (ZJP), a traditional Chinese medicinal formula, is widely recognized for its diverse pharmacological properties in the management of gastrointestinal disorders. However, the precise mechanisms underlying its therapeutic effects in gastroesophageal reflux disease (GERD) remain inadequately understood.

This study aims to investigate the therapeutic effects of ZJP in GERD and to elucidate the molecular mechanisms involved.

The chemical composition of ZJP was characterized using HPLC-Q-Exactive-MS. A rat model of GERD was established through esophagogastric anastomosis, and three different doses of ZJP were administered. Histological changes were assessed via hematoxylin-eosin (H&E) staining, while pro-inflammatory cytokines were quantified to evaluate the anti-inflammatory effects of ZJP. Network pharmacology combined with bioinformatics analysis was employed to predict potential therapeutic targets and signaling pathways of ZJP in GERD. Validation of the mechanisms was conducted through Western blotting, immunofluorescence (IF), transmission electron microscopy (TEM), and immunohistochemistry (IHC).

The results demonstrated that ZJP effectively alleviated pathological alterations and reduced pro-inflammatory cytokine levels in esophageal tissues of GERD rats. Western blotting and IF analysis of E-cadherin and claudin-1 confirmed that ZJP enhanced the integrity of the esophageal mucosal barrier. TEM imaging revealed that ZJP restored intercellular space (DIS), increased desmosome density, thereby protecting esophageal tissues from the detrimental effects of GERD. Furthermore, ZJP modulated macrophage polarization in the GERD rat model. Mechanistic investigations indicated that ZJP exerted its therapeutic effects by inhibiting MAPK/NF-κB signaling pathway activation and downregulating the expression of prostaglandin-endoperoxide synthase 2 (PTGS2) and matrix metalloproteinase 2 (MMP2), consistent with predictions from network pharmacology analysis.

This study provides comprehensive evidence for the therapeutic efficacy of ZJP in GERD, acting through modulation of inflammation, mucosal barrier integrity, and macrophage polarization. Additionally, ZJP downregulated PTGS2 and MMP2 expression and suppressed the activation of MAPK/NF-κB signaling pathways, underscoring its potential as a therapeutic intervention for GERD.

Inflammation is an important physiological response of the organism to restore homeostasis upon pathogenic or damaging stimuli. However, the persistence of the harmful trigger or a deficient resolution of the process can evolve into a state of low-grade, chronic inflammation. This condition is strongly associated with the development of several increasingly prevalent and serious chronic conditions, such as obesity, cancer, and cardiovascular diseases, elevating overall morbidity and mortality worldwide. The current pandemic of chronic diseases underscores the need to address chronic inflammation, its pathogenic mechanisms, and potential preventive measures to limit its current widespread impact. The present review discusses the current knowledge and research gaps regarding the association between low-grade chronic inflammation and chronic diseases, focusing on obesity, cardiovascular diseases, digestive diseases, and cancer. We examine the state of the art in selected aspects of the topic and propose future directions and approaches for the field.

Numerous observational studies have shown a potential association between metabolic dysfunction-associated steatotic liver disease (MASLD) and gastroesophageal reflux disease (GERD). However, causality is unclear. This study utilized genome-wide association study (GWAS) genetic data to explore the causal relationship between MASLD and GERD in European and East Asian populations.

This study utilized a bidirectional, two-sample Mendelian randomization (MR) approach. All disease data were obtained from the GWAS database, and single nucleotide polymorphisms strongly associated with exposure were selected as instrumental variables. The inverse variance weighted (IVW) method is primarily utilized to evaluate the causal relationship between exposure and outcome. Finally, sensitivity analyses were performed to ensure the robustness of the results.

The IVW estimates indicated that non-alcoholic fatty liver disease (NAFLD) (odds ratio (OR) = 1.054, 95% confidence interval (CI), 0.966-1.150, p = 0.236) and percent liver fat (OR = 0.977, 95% CI, 0.937-1.018, p = 0.258) in European population were not linked to a higher risk of GERD. However, GERD in European population was associated with an increased risk of NAFLD (OR = 1.485, 95% CI, 1.274-1.729, p < 0.001) and percent liver fat (OR = 1.244, 95% CI, 1.171-1.321, p < 0.001). In addition, the IVW analysis in East Asian population showed that alanine aminotransferase (ALT) was associated with an increased risk of GERD (OR = 2.305, 95% CI, 1.241-4.281, p = 0.008), whereas aspartate aminotransferase (AST) had no causal effects on GERD risk (OR = 0.973, 95% CI, 0.541-1.749, p = 0.926). Furthermore, the associations between GERD and ALT (OR = 1.007, 95% CI, 0.998-1.015, p = 0.123) or AST (OR = 1.004, 95% CI, 0.997-1.012, p = 0.246) were not significant. After removing outliers, a significant correlation between GERD and ALT was observed (OR = 1.009, 95% CI, 1.001-1.016, p = 0.020).

There was reverse causality between MASLD and GERD in European population, while there was bidirectional causality between a proxie for MASLD (ALT) and GERD in East Asian population. This study can provide novel insights into cross-ethnic genetic research on MASLD and GERD.

Gastroesophageal reflux disease (GERD) is a gastrointestinal tract disorder associated with regurgitation of gastric acid into the oesophagus. It can present itself as non-erosive reflux condition or erosive esophagitis. Our main objective was to evaluate the impact of oesophageal reflux disease on muscle fatigue among patients. The prospective study design was adopted using surveys performed at the South West China Medical University. All patients who were subjected to screening endoscopy at the South West China Medical University were prospectively enrolled in the study. Our study was conducted according to ethical guidelines involving animal and human subjects. Our study used Epworth Sleepiness Scale (ESS), Hospital Anxiety and Depression Scale (HADS), and the Multidimensional Fatigue Inventory (MFI) questionnaires to perform data collection on the levels of fatigue, depression, daytime hypersomnolence and anxiety. In the (HADS, Anxiety (β = 0.657, p < .001) and Depression (β = 2.927, p < .001) exhibited significant positive associations with the predicted fatigue. The Epworth Sleepiness Scale (ESS) showed no significant difference between individuals with and without reflux esophagitis (p = 0.787, power = 0.071). However, a significant difference was observed based on the presence of GERD symptoms (p = 0.003, power = 0.789), with higher mean scores for those with GERD symptoms (6.1±3.5) compared to those without (4.9±2.9). In MFI, significant differences were observed between the two groups for General and Physical Fatigue (p = 0.040, power = 0.823), Mental Fatigue (p = 0.002, power = 0.767), and MFI Total Score (p = 0.002, power = 0.981). In conclusion, GERD symptoms exhibited stronger associations with fatigue and daytime sleepiness than endoscopic findings, emphasizing the impact of symptomatic experiences on well-being.

Esophageal cancer is one of the 10 most common cancers worldwide and its incidence is dramatically increasing. Despite some improvements, the current surveillance protocol with white light endoscopy and random untargeted biopsies collection (Seattle protocol) fails to diagnose dysplastic and cancerous lesions in up to 50% of patients. Therefore, new endoscopic imaging technologies in combination with tumor-specific molecular probes are needed to improve early detection. Herein, we investigated the use of the fluorescent Poly (ADP-ribose) Polymerase 1 (PARP1)-inhibitor PARPi-FL for early detection of dysplastic lesions in patient-derived organoids and transgenic mouse models, which closely mimic the transformation from non-malignant Barrett's Esophagus (BE) to invasive esophageal adenocarcinoma (EAC).

We determined PARP1 expression via immunohistochemistry (IHC) in human biospecimens and mouse tissues. We also assessed PARPi-FL uptake in patient- and mouse-derived organoids. Following intravenous injection of 75 nmol PARPi-FL/mouse in L2-IL1B (n = 4) and L2-IL1B/IL8Tg mice (n = 12), we conducted fluorescence molecular endoscopy (FME) and/or imaged whole excised stomachs to assess PARPi-FL accumulation in dysplastic lesions. L2-IL1B/IL8Tg mice (n = 3) and wild-type (WT) mice (n = 2) without PARPi-FL injection served as controls. The imaging results were validated by confocal microscopy and IHC of excised tissues.

IHC on patient and murine tissue revealed similar patterns of increasing PARP1 expression in presence of dysplasia and cancer. In human and murine organoids, PARPi-FL localized to PARP1-expressing epithelial cell nuclei after 10 min of incubation. Injection of PARPi-FL in transgenic mouse models of BE resulted in the successful detection of lesions via FME, with a mean target-to-background ratio > 2 independently from the disease stage. The localization of PARPi-FL in the lesions was confirmed by imaging of the excised stomachs and confocal microscopy. Without PARPi-FL injection, identification of lesions via FME in transgenic mice was not possible.

PARPi-FL imaging is a promising approach for clinically needed improved detection of dysplastic and malignant EAC lesions in patients with BE. Since PARPi-FL is currently evaluated in a phase 2 clinical trial for oral cancer detection after topical application, clinical translation for early detection of dysplasia and EAC in BE patients via FME screening appears feasible.

Background: The etiological underpinnings of gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) remain elusive, coupled with a scarcity of effective therapeutic interventions for IPF. Angelicae sinensis radix (ASR, also named Danggui) is a Chinese herb with potential anti-fibrotic properties, that holds promise as a therapeutic agent for IPF. Objective: This study seeks to elucidate the causal interplay and potential mechanisms underlying the coexistence of GERD and IPF. Furthermore, it aims to investigate the regulatory effect of ASR on this complex relationship. Methods: A two-sample Mendelian randomization (TSMR) approach was employed to delineate the causal connection between gastroesophageal reflux disease and IPF, with Phennoscanner V2 employed to mitigate confounding factors. Utilizing single nucleotide polymorphism (SNPs) and publicly available microarray data, we analyzed potential targets and mechanisms related to IPF in GERD. Network pharmacology and molecular docking were employed to explore the targets and efficacy of ASR in treating GERD-related IPF. External datasets were subsequently utilized to identify potential diagnostic biomarkers for GERD-related IPF. Results: The IVW analysis demonstrated a positive causal relationship between GERD and IPF (IVW: OR = 1.002, 95%CI: 1.001, 1.003; p < 0.001). Twenty-five shared differentially expressed genes (DEGs) were identified. GO functional analysis revealed enrichment in neural, cellular, and brain development processes, concentrated in chromosomes and plasma membranes, with protein binding and activation involvement. KEGG analysis unveiled enrichment in proteoglycan, ERBB, and neuroactive ligand-receptor interaction pathways in cancer. Protein-protein interaction (PPI) analysis identified seven hub genes. Network pharmacology analysis demonstrated that 104 components of ASR targeted five hub genes (PDE4B, DRD2, ERBB4, ESR1, GRM8), with molecular docking confirming their excellent binding efficiency. GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF (ESR1: AUCGERD = 0.762, AUCIPF = 0.725; GRM8: AUCGERD = 0.717, AUCIPF = 0.908). GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF, validated in external datasets. Conclusion: This study establishes a causal link between GERD and IPF, identifying five key targets and two potential diagnostic biomarkers for GERD-related IPF. ASR exhibits intervention efficacy and favorable binding characteristics, positioning it as a promising candidate for treating GERD-related IPF. The potential regulatory mechanisms may involve cell responses to fibroblast growth factor stimulation and steroidal hormone-mediated signaling pathways.

Non-alcoholic fatty liver disease (NAFLD) and gastroesophageal reflux disease (GERD) are both associated with obesity. However, the relationship of NAFLD with reflux esophagitis (RE) is still unclear in non-obese individuals.

Individuals with a body mass index (BMI) of 28 kg/m2 or higher, as well as waist circumference (WC) no less than 90 cm for men and no less than 85 cm for women were excluded. After controlling for other factors, 1905 eligible adult subjects were included. The components related to metabolic syndrome and the prevalence of NAFLD in the RE group as well as the non-RE group were analyzed. Risk factors for RE were determined using logistic regression.

In non-obese individuals, the prevalence of RE and NAFLD increased with increasing WC and BMI (p < 0.001). Based on the results of logistic regression analysis, NAFLD was found to increase the risk of RE with statistical significance. Even after adjusting for metabolic syndrome and other related factors, NAFLD remained an independent influencing factor for the risk of RE (OR = 2.029; 95% CI 1.459-2.821, p < 0.001).

The prevalence of NAFLD was significantly higher in patients with RE compared to those without RE. These results indicate that NAFLD has a potential as an independent risk factor for RE, even in non-obese individuals.

Gastroesophageal reflux disease (GERD) has the highest prevalence among diseases of the digestive system and is characterized by a significant decrease in patients' quality of life, comparable to arterial hypertension and coronary heart disease. One in every ten cases of reflux esophagitis leads to the formation of Barrett's esophagus, which is associated with a high risk of esophagus adenocarcinoma. The key factors determining the progression of the disease are the frequency and duration of the reflux of the stomach's contents. As a result, refluxate, which includes hydrochloric acid, pepsin, and, in the case of concomitant duodeno-gastric reflux, bile acids and lysolecithin, is thrown into the overlying sections of the digestive tract. At the same time, in addition to aggression factors, it is necessary to take into account the state of resistance in the esophageal mucosa to the effects of aggressive refluxate molecules. This review was prepared using systematized data on the protective properties of the esophageal mucosa and modern methods to assess the mucosal barrier in reflux esophagitis. Lesions of the epithelial barrier structure in the esophagus are recognized as the main pathogenetic factor in the development of reflux esophagitis and are a potentially significant therapeutic target in the treatment of GERD and Barrett's esophagus. This article presents the characteristics of the esophageal mucosal barrier and the protective mechanisms of the esophagus's mucous membrane in conditions of gastroesophageal reflux. Diagnostic approaches for assessing the course of reflux esophagitis are described for both histological criteria and the possibility of a comprehensive assessment of the state of mucins, tight-junction proteins, and the proliferative activity of the mucosa, including under the conditions of ongoing therapy.

Early detection of esophageal cancer through endoscopic imaging is pivotal for effective treatment. However, the intricacies of endoscopic diagnosis, contingent on the physician's expertise, pose challenges. Esophageal cancer features often manifest ambiguously, leading to potential confusions with other inflammatory esophageal conditions, thereby complicating diagnostic accuracy. In recent times, computer-aided diagnosis has emerged as a promising solution in medical imaging, particularly within the domain of endoscopy. Nonetheless, contemporary AI-based diagnostic models heavily rely on voluminous data sources, limiting their applicability, especially in scenarios with scarce datasets. To address this limitation, our study introduces novel data training strategies based on transfer learning, tailored to optimize performance with limited data. Additionally, we propose a hybrid model integrating EfficientNet and Vision Transformer networks to enhance prediction accuracy. Conducting rigorous evaluations on a carefully curated dataset comprising 1002 endoscopic images (comprising 650 white-light images and 352 narrow-band images), our model achieved exceptional outcomes. Our combined model achieved an accuracy of 96.32%, precision of 96.44%, recall of 95.70%, and f1-score of 96.04%, surpassing state-of-the-art models and individual components, substantiating its potential for precise medical image classification. The AI-based medical image prediction platform presents several advantageous characteristics, encompassing superior prediction accuracy, a compact model size, and adaptability to low-data scenarios. This research heralds a significant stride in the advancement of computer-aided endoscopic imaging for improved esophageal cancer diagnosis.

Barrett's esophagus (BE) is an acquired pre-malignant condition that results from chronic gastroesophageal reflux. The malignant transformation occurred in 0.5% of patients/year and was independent of medical and endoscopic conservative treatments. Fatty acid synthase (FAS) is a multifunctional enzyme that catalyzes the synthesis of long-chain fatty acids from acetyl-coenzyme A, malonyl-coenzyme A, a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), and adenosine triphosphate. Activation of FAS is closely linked to malignant transformation. The aim of the present study was to evaluate the variation of FAS, p53, and Ki67 expressions in two groups of 21 BE patients each, after one year of continuous (group A) or discontinuous (group B) treatment with esomeprazole 40 mg/day in comparison to the initial expression. In both the two groups of BE patients, biopsies were taken from pathologic sites of the mucosa for histological and immuno-histochemical detection of FAS, Ki67, and p53 at entry and after one year of Esomeprazole 40 mg treatment. FAS expression was positive when a strong granular cytoplasmic staining was observed in esophageal cells. Ki67 and p53 were defined as positive when nuclear staining was clearly detected at ×10 magnification. FAS expression was reduced in 43% of patients treated with Esomeprazole continuously in comparison to the 10% of patients treated with Esomeprazole on demand (p = 0.002). Ki67 expression was reduced in 28% of continuously treated patients in comparison to 5% of patients treated on demand (p = 0.001). The p53 expression decreased in 19% of continuously treated patients in comparison to an increase in 2 patients (9%) treated on demand (p = 0.05). Continuously Esomeprazole treatment could help in the diminution of metabolic and proliferative activities in the esophageal columnar epithelium and in part it can help prevent the oxidative damage against cellular DNA, resulting in a diminution in p53 expression.

Compelling shreds of evidence derived from both clinical and experimental research have demonstrated the crucial contribution of receptor for advanced glycation end products (RAGE) axis activation in the development of neoplasms, including gastric cancer (GC). This new actor in tumor biology plays an important role in the onset of a crucial and long-lasting inflammatory milieu, not only by supporting phenotypic changes favoring growth and dissemination of tumor cells, but also by functioning as a pattern-recognition receptor in the inflammatory response to Helicobacter pylori infection. In the present review, we aim to highlight how the overexpression and activation of the RAGE axis contributes to the proliferation and survival of GC cells as and their acquisition of more invasive phenotypes that promote dissemination and metastasis. Finally, the contribution of some single nucleotide polymorphisms in the RAGE gene as susceptibility or poor prognosis factors is also discussed.