Gene expression and clinical outcomes after dietary treatment for eosinophilic esophagitis: a prospective study

Abstract

Background: Eosinophilic esophagitis (EoE) is an allergen-mediated disease and elimination diets have proven to be effective to obtain clinical and histological remission.However, the effect of elimination diets on specific EoE transcripts and their clinical correlates is relatively unknown. The main aim of the study was to evaluate the effect of dietary treatment (four-food elimination diet [FFED]) with or without addition of amino acid-based formula (AAF) on a variety of pro-/anti-inflammatory, epithelial/ barrier function and remodeling/fibrosis-related markers of disease activity and clinical correlates (eosinophils, symptoms, and endoscopic signs) in adult EoE patients. Methods:We conducted an analysis of biopsy samples and data collected during a randomized controlled trial with an elimination diet in adult patients with active EoE (≥15 eosinophils [eos] per high-power field [hpf]). Demographics, symptoms (SDIscore), endoscopic signs (EREFS) and peak eosinophil counts/hpf were recorded at baseline and after 6 weeks of treatment. Transcripts of 10 indicated genes were measured (qPCR) and compared to clinical correlates at baseline and after treatment. Key Results: Forty patients (pooled FFED + FFED + AAF) (60% male, age 34.5 (interquartile range [IQR] 29-42.8 years) completed the diet. Peak eosinophil counts/ hpf, symptoms and endoscopic signs were significantly decreased after 6 weeks dietary treatment. DSG-1 levels were significantly upregulated from baseline to week 6, whereas IL-13, CAPN-14, IL-5, IL-10, CCL-26, POSTN, TSLP, CPA-3, and TGFβ were significantly downregulated after 6 weeks of diet (all; <0.01). Prior to treatment, upregulation of CAPN-14 and lower levels of DSG-1 were associated with clinical fibrotic phenotypes, whereas upregulation of IL-10 was linked to food impaction phenotypes. Conclusion:These findings strongly suggest that elimination diets, besides a clinical and histological response, are associated with a broad transcriptional response at the level of the esophageal epithelium.How to cite this article: de Rooij WE, Diks MAP, Warners MJ, Ampting MTJV, van Esch BCAM, Bredenoord AJ. Gene expression and clinical outcomes after dietary treatment for eosinophilic esophagitis: a prospective study.

Changes in IgG4 and IL-10 expression in adults with eosinophilic esophagitis on a two-food elimination diet

“…2C) is in line with a study measuring IL10 transcripts in EoE biopsies after a four-food elimination diet. 52 Earlier work showed that IL10 and IGHG4 expression correlated in pediatric EoE and were in turn related to histologic variables. 26 In contrast, we did not observe a relationship between the frequencies of IL-10 + and IgG4 + cells in baseline or follow-up biopsies, and only IL-10 + cells correlated with PEC or EoEHSS determinations (Fig.…”

“…53 Thus, a higher prevalence of IL-10-expressing cells could be associated with an EoE phenotype that responds more promptly to elimination diets, as hinted at in a study showing that esophageal IL10 expression associated with a "food impaction" phenotype, whereas genes responsible for barrier integrity were dysregulated in a fibrotic, more refractory phenotype. 52 The contribution of IL-10 to disease activity is suggested in studies linking EoE histopathology to the accumulation of IgG4, an antibody class whose switch is promoted by this cytokine. 33 IGHE and IGHG4 germline transcripts, indicia of IgE and IgG4 switching, have been documented in the esophageal mucosa of EoE patients.…”

“…[62][63][64] The reasons for this apparent discrepancy are unclear and may reflect the relative prevalence of distinct EoE phenotypes. 52,53 Regardless, in no study to date has the effect of elimination diets been stratified by BMI or related variables. Based on our findings, we would envision that a lower BMI, being associated with higher numbers of IL-10 + cells in the esophageal mucosa, would in turn be predictive of a more substantial histologic response to the diet.…”

Fibrous Remodeling in Eosinophilic Esophagitis: Clinical Facts and Pathophysiological Uncertainties

“…Several studies, using different experimental approaches, tried to describe the potential involvement of TGF-β1 in the fibrous remodeling that happens in EoE [1] (Table 1). Used strategies ranged from esophageal epithelial cell cultures [104] to murine experimental models of EoE [105,106], while most evaluated biopsies were obtained from EoE patients [103,[107][108][109][110][111][112][113][114][115][116]. Tissue results from human EoE were also applied to a murine model [25], and blood samples were exceptionally used [117].…”

“…The approach to determine TGF-β1 also varied from one study to another. Some of them attempted to demonstrate the protein mainly by staining TGF-β1-positive cells with immunohistochemistry (IHC) [103,105,108,111,112,114] or immunofluorescence (IF) staining [107,109], while others used ELISA [104,117] or measured the changes in TGF-β1 gene expression in EoE biopsies compared to controls [108][109][110][112][113][114][115][116][117] and the changes after therapy [103,110,111]. As demonstrated, the results of these different approaches have not always been comparable (Table 1).…”