RNA-sequencing reveals molecular and regional differences in the esophageal mucosa of achalasia patients

Patel, Caroline K; Kahrilas, Peter J.; Hodge, Nathan; Tsikretsis, Lia Elyse; Carlson, Dustin A.; Pandolfino, John E.; Tétreault, Marie–Pier

doi:10.1038/s41598-022-25103-7

Cited by 8 publications

(3 citation statements)

References 43 publications

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“…This discrepancy suggests that esophageal dysmotility in SSc leads to greater acid exposure in the proximal esophagus, since refluxed gastric acid typically affects the distal esophagus significantly more than the proximal esophagus 105 and abnormal peristalsis prolongs acid clearance 106 . This finding coincides with a bulk RNA-seq study of esophageal mucosa of achalasia patients 107 , which likewise identified more differential expression in the proximal esophagus than in the distal esophagus, including significant enrichment of matrisome-associated genes and lower expression of genes associated with reactive oxygen species metabolism 107 . Due to differences in innervation depth 108 , the epithelium of the proximal esophagus has more nociceptive sensitivity than the distal esophagus, which likely contributes to the association between gastrointestinal symptoms and lower quality of life in SSc 109 .…”

Section: Discussionsupporting

confidence: 89%

The esophageal epithelium in systemic sclerosis: cellular and molecular dysregulation revealed by single-cell RNA sequencing

Dapas,

Clevenger,

Makinde

et al. 2024

Preprint

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Systemic sclerosis (SSc) is a rare autoimmune disease characterized by vasculopathy and progressive fibrosis of the skin and internal organs. Individuals with SSc often suffer from chronic acid reflux and dysphagia due to loss of esophageal motility. However, the pathogenesis of esophageal dysmotility in SSc is poorly understood. To determine whether distinct changes in esophageal epithelial cells contribute to impaired motility in SSc, we investigated the stratified squamous esophageal epithelium using single-cell RNA sequencing (n=306,372 cells) in individuals with SSc compared those with gastroesophageal reflux disease (GERD) as well as healthy controls. The proportion of epithelial cells in the outermost, superficial compartment of the esophageal epithelium was significantly reduced in SSc (9.4% vs 21.6% in HCs). Differential gene expression in SSc was primarily limited to the superficial compartment (3,572 genes vs. 232 in all other compartments), with significant upregulation of extracellular matrix and keratinization genes. These cellular and molecular changes in SSc were highly correlated with those seen in GERD, indicating they were secondary to reflux; however, their magnitudes were more pronounced in the proximal esophagus, suggesting that esophageal dysmotility leads to greater proximal acid exposure, which may contribute to aspiration. SSc-specific gene dysregulation implicated immunoregulatory pathways likely pertinent to pathogenic mechanisms. By offering a comprehensive view of transcriptional dysregulation at single-cell resolution in human esophageal epithelial cells in SSc compared to GERD and healthy tissue, this work clarifies the state of epithelial cells in SSc-induced esophageal dysfunction.

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Section: Discussionsupporting

confidence: 89%

The esophageal epithelium in systemic sclerosis: cellular and molecular dysregulation revealed by single-cell RNA sequencing

Dapas,

Clevenger,

Makinde

et al. 2024

Preprint

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“…RNA extraction, DNA libraries generation, sequencing, data filtering and analysis were performed as previously described 26…”

Section: Bulk Rna Sequencingmentioning

confidence: 99%

Esophageal epithelialIkkβdeletion promotes eosinophilic esophagitis in experimental allergy mouse model

Clevenger,

Wei,

Karami

et al. 2024

Preprint

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BackgroundEosinophilic esophagitis (EoE) is a chronic T helper type 2 (Th2)-associated inflammatory disorder triggered by food allergens, resulting in esophageal dysfunction through edema, fibrosis, and tissue remodeling. The role of epithelial remodeling in EoE pathogenesis is critical but not fully understood.ObjectiveTo investigate the role of epithelial IKKβ/NFκB signaling in EoE pathogenesis using a mouse model with conditionalIkkβ knockout in esophageal epithelial cells (IkkβEEC-KO).MethodsEoE was induced inIkkβEEC-KOmice through skin sensitization with MC903/Ovalbumin (OVA) followed by intraesophageal OVA challenge. Histological and transcriptional analyses were performed to assess EoE features. Single-cell RNA sequencing (scRNA-seq) was used to profile esophageal mucosal cell populations and gene expression changes.ResultsIkkβEEC-KO/EoE mice exhibited hallmark EoE features, including eosinophil infiltration, intraepithelial eosinophils, microabscesses, basal cell hyperplasia, and lamina propria remodeling. RNA-seq revealed significant alterations in IKKβ/NFκB signaling pathways, with decreased expression ofRELAand increased expression of IKKβ negative regulators. scRNA- seq analyses identified disrupted epithelial differentiation and barrier integrity, alongside increased type 2 immune responses and peptidase activity.ConclusionOur study demonstrates that loss of epithelial IKKβ signaling exacerbates EoE pathogenesis, highlighting the critical role of this pathway in maintaining epithelial homeostasis and preventing allergic inflammation. TheIkkβEEC-KO/EoE mouse model closely mirrors human EoE, providing a valuable tool for investigating disease mechanisms and therapeutic targets. This model can facilitate the development of strategies to prevent chronic inflammation and tissue remodeling in EoE.Key MessagesCritical Role of Epithelial IKKβ/NFκB Signaling: Loss of this signaling exacerbates EoE, causing eosinophil infiltration, basal cell hyperplasia, and tissue remodeling, highlighting its importance in esophageal health.Molecular Insights and Therapeutic Targets: scRNA-seq identified disrupted epithelial differentiation, barrier integrity, and enhanced type 2 immune responses, suggesting potential therapeutic targets for EoE.Relevance of theIkkβEEC-KO/EoE Mouse Model: This model replicates human EoE features, making it a valuable tool for studying EoE mechanisms and testing treatments, which can drive the development of effective therapies.Capsule SummaryThis study reveals the crucial role of epithelial IKKβ/NFκB signaling in EoE, providing insights into disease mechanisms and potential therapeutic targets, highly relevant for advancing clinical management of EoE.

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“…Incorporating genetic and molecular insights into the CC can personalize patient care. Genetic profiling and biomarker analysis can identify specific patient subsets, enabling tailored therapies and enhanced prognostic predictions [23 ▪ ].…”

Section: Future Directions For Chicago Classification Enhancementmentioning

confidence: 99%

Esophageal motility disorder – has Chicago classification v4.0 simplified our management?

Edeani,

Massey

2023

Current Opinion in Otolaryngology &Amp; Head &Amp; Neck Surgery

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Review purpose Addressing dysphagia is vital due to its prevalence and impact on healthcare expenditure. While high resolution manometry (HRM) effectively evaluates esophageal dysphagia, its role in oropharyngeal dysphagia and upper esophageal sphincter (UES) dysfunction remains debated. The fourth iteration of the Chicago classification (CC) offers an algorithmic approach for diagnosing abnormal motor patterns via HRM. This review assesses the CC's impact on dysphagia management. Recent insights The Chicago classification version 4.0 emphasizes auxiliary and provocative techniques when the algorithm falls short of a conclusive diagnosis. It introduces stricter criteria for previously ambiguous conditions like ineffective motility and esophagogastric junction outflow obstruction. This version also introduces the concept of conclusive and inconclusive classifications based on symptoms, provocation maneuvers, and supportive testing minimizing ambiguity. Summary The Chicago classification v4.0 remains a useful tool for the diagnosis of well characterized esophageal motility disorders. However, major limitations include reliance on HRM and a focus on distal esophagus contractile characteristics without considering proximal esophagus or upper esophageal sphincter, both of which can sometimes be the only evident abnormality in patients with dysphagia. Despite efforts to reduce ambiguity, diagnostic challenges persist. These limitations can be addressed in future updates

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RNA-sequencing reveals molecular and regional differences in the esophageal mucosa of achalasia patients

Cited by 8 publications

References 43 publications

The esophageal epithelium in systemic sclerosis: cellular and molecular dysregulation revealed by single-cell RNA sequencing

The esophageal epithelium in systemic sclerosis: cellular and molecular dysregulation revealed by single-cell RNA sequencing

Esophageal epithelialIkkβdeletion promotes eosinophilic esophagitis in experimental allergy mouse model

Esophageal motility disorder – has Chicago classification v4.0 simplified our management?

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