Rhonda Souza M.D.

Dellon, E. S., Gonsalves, N., Abonia, J. P., Alexander, J. A., Arva, N. C., Atkins, D., Attwood, S. E., Auth, M. K., Bailey, D. D., Biederman, L., Blanchard, C., Bonis, P. A., Bose, P., Bredenoord, A. J., Chang, J. W., Chehade, M., Collins, M. H., Di Lorenzo, C., Dias, J. A., Dohil, R., Dupont, C., Falk, G. W., Ferreira, C. T., Fox, A. T., Genta, R. M., Greuter, T., Gupta, S. K., Hirano, I., Hiremath, G. S., Horsley-Silva, J. L., Ishihara, S., Ishimura, N., Jensen, E. T., Gutiérrez-Junquera, C., Katzka, D. A., Khoury, P., Kinoshita, Y., Kliewer, K. L., Koletzko, S., Leung, J., Liacouras, C. A., Lucendo, A. J., Martin, L. J., McGowan, E. C., Menard-Katcher, C., Metz, D. C., Miller, T. L., Moawad, F. J., Muir, A. B., Mukkada, V. A., Murch, S., Nhu, Q. M., Nomura, I., Nurko, S., Ohtsuka, Y., Oliva, S., Orel, R., Papadopoulou, A., Patel, D. A., Pesek, R. D., Peterson, K. A., Philpott, H., Putnam, P. E., Richter, J. E., Rosen, R., Ruffner, M. A., Safroneeva, E., Schreiner, P., Schoepfer, A., Schroeder, S. R., Shah, N., Souza, R. F., Spechler, S. J., Spergel, J. M., Straumann, A., Talley, N. J., Thapar, N., Vandenplas, Y., Venkatesh, R. D., Vieira, M. C., von Arnim, U., Walker, M. M., Wechsler, J. B., Wershil, B. K., Wright, B. L., Yamada, Y., Yang, G. Y., Zevit, N., Rothenberg, M. E., Furuta, G. T. and Aceves, S. S. (2022). “International consensus recommendations for eosinophilic gastrointestinal disease nomenclature.” Clin Gastroenterol Hepatol.

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BACKGROUND & AIMS: Substantial heterogeneity in terminology used for eosinophilic gastrointestinal diseases (EGID), particularly the catchall term “eosinophilic gastroenteritis”, limits clinical and research advances. We aimed to achieve an international consensus for standardized EGID nomenclature. METHODS: This consensus process utilized Delphi methodology. An initial naming framework was proposed and refined in iterative fashion, then assessed in a first round of Delphi voting. Results were discussed in two consensus meetings, the framework was updated, and re-assessed in a second Delphi vote, with a 70% threshold set for agreement. RESULTS: Of 91 experts participating, 85 (93%) completed the first and 82 (90%) completed the second Delphi surveys. Consensus was reached on all but two statements. “EGID” was the preferred umbrella term for disorders of GI tract eosinophilic inflammation in the absence of secondary causes (100% agreement). Involved GI tract segments will be named specifically and use an “Eo” abbreviation convention: eosinophilic gastritis (now abbreviated EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). The term “eosinophilic gastroenteritis” is no longer preferred as the overall name (96% agreement). When >2 GI tract areas are involved, the name should reflect all of the involved areas. CONCLUSIONS: This international process resulted in consensus for updated EGID nomenclature for both clinical and research use. EGID will be the umbrella term rather than “eosinophilic gastroenteritis”, and specific naming conventions by location of GI tract involvement are recommended. As more data are developed, this framework can be updated to reflect best practices and the underlying science.

Paris, S., R. Ekeanyanwu, Y. Jiang, D. Davis, S. J. Spechler and R. F. Souza (2021). “Obesity and its effects on the esophageal mucosal barrier.” Am J Physiol Gastrointest Liver Physiol 321(3): G335-g343.

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Obesity is associated with gastroesophageal reflux disease (GERD) and its complications including reflux esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma. Traditionally, these associations have been attributed to the mechanical effect of abdominal fat in increasing intra-abdominal pressure, thereby promoting gastroesophageal reflux and causing disruption of antireflux mechanisms at the esophagogastric junction. However, recent studies suggest that visceral adipose tissue (VAT) produces numerous cytokines that can cause esophageal inflammation and impair esophageal mucosal barrier integrity through reflux-independent mechanisms that render the esophageal mucosa especially susceptible to GERD-induced injury. In this report, we review mechanisms of esophageal mucosal defense, the genesis and remodeling of visceral adipose tissue during obesity, and the potential role of substances produced by VAT, especially the VAT that encircles the esophagogastric junction, in the impairment of esophageal mucosal barrier integrity that leads to the development of GERD complications.

Odiase, E., Zhang, X., Chang, Y., Nelson, M., Balaji, U., Gu, J., Zhang, Q., Pan, Z., Spechler, S.J. and Souza, R.F. (2021). “In Esophageal Squamous Cells From Eosinophilic Esophagitis Patients, Th2 Cytokines Increase Eotaxin-3 Secretion Through Effects on Intracellular Calcium and a Non-Gastric Proton Pump.” Gastroenterology 160(6): 2072-2088.e2076.

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BACKGROUND & AIMS: In upper airway cells, T helper 2 cytokines that signal through interleukin-4 (IL-4) receptor-α have been shown to stimulate eotaxin-3 secretion via a nongastric proton pump (ngH(+),K(+)ATPase). To seek novel targets for eosinophilic esophagitis (EoE) treatments, we evaluated ngH(+),K(+)ATPase expression in EoE squamous cells, and explored molecular pathways involved in eotaxin-3 secretion by IL-4 receptor-α signaling. METHODS: ngH(+),K(+)ATPase expression in EoE cells was evaluated by quantitative real-time polymerase chain reaction and Western blotting. IL-4-stimulated eotaxin-3 secretion was measured by enzyme-linked immunosorbent assay after treatment with omeprazole, SCH 28080 (potassium-competitive acid blocker), ethylene glycol-bis(β-aminoethyl)-N,N,N’,N’-tetraacetoxymethyl ester (calcium chelator), 2-aminoethoxydiphenyl borate (inhibitor of endoplasmic reticulum calcium release), verapamil, and diltiazem (L-type calcium channel inhibitors). Intracellular calcium transients were measured by Fluo-4 fluorescence. Key experiments were confirmed in EoE primary cells and in RNA sequencing datasets from mucosal biopsies of patients with EoE and controls. RESULTS: EoE cells expressed ngH(+),K(+)ATPase messenger RNA and protein. Omeprazole and SCH 28080 decreased IL-4-stimulated eotaxin-3 secretion. IL-4 increased intracellular calcium transients, and IL-4-stimulated eotaxin-3 secretion was blocked by ethylene glycol-bis(β-aminoethyl)-N,N,N’,N’-tetraacetoxymethyl ester, 2-aminoethoxydiphenyl borate, verapamil, and diltiazem. The combination of omeprazole and verapamil suppressed IL-4-stimulated eotaxin-3 secretion more than either agent alone. EoE biopsies expressed higher ngH+,K+ATPase and exhibited more calcium signaling than controls. CONCLUSIONS: EoE cells express a nongastric proton pump that mediates T helper 2 cytokine-stimulated eotaxin-3 secretion. IL-4 induces calcium release from the endoplasmic reticulum and calcium entry via L-type calcium channels, increasing intracellular calcium that contributes to eotaxin-3 secretion by EoE cells. L-type calcium channel inhibitors block T helper 2 cytokine-stimulated eotaxin-3 secretion, suggesting a potential role for these agents in EoE treatment.

Odiase, E., Zhang, X., Chang, Y., Nelson, M., Balaji, U., Gu, J., Zhang, Q., Pan, Z., Spechler, S.J. and Souza, R.F. (2021). “In Esophageal Squamous Cells from Eosinophilic Esophagitis Patients, Th2 Cytokines Increase Eotaxin-3 Secretion through Effects on Intracellular Calcium and a Non-Gastric Proton Pump.” Gastroenterology Feb 10;S0016-5085(21)00403-0. [Epub ahead of print].

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BACKGROUND & AIMS: In upper airway cells, Th2 cytokines that signal through IL-4 receptor alpha (IL4Rα) have been shown to stimulate eotaxin-3 secretion via a non-gastric proton pump (ngH(+),K(+)ATPase). To seek novel targets for eosinophilic esophagitis (EoE) treatments, we evaluated ngH(+),K(+)ATPase expression in EoE squamous cells, and explored molecular pathways involved in eotaxin-3 secretion by IL4Rα signaling. METHODS: ngH(+),K(+)ATPase expression in EoE cells was evaluated by qPCR and western blotting. IL-4-stimulated eotaxin-3 secretion was measured by ELISA after treatment with omeprazole, SCH 28080 (potassium-competitive acid blocker), EGTA-AM (calcium chelator), 2-APB (inhibitor of endoplasmic reticulum calcium release), verapamil and diltiazem (L-type calcium channel inhibitors). Intracellular calcium transients were measured by Fluo-4 fluorescence. Key experiments were confirmed in EoE primary cells and in RNA sequencing datasets from mucosal biopsies of EoE patients and controls. RESULTS: EoE cells expressed ngH(+),K(+)ATPase mRNA and protein. Omeprazole and SCH 28080 decreased IL-4-stimulated eotaxin-3 secretion. IL-4 increased intracellular calcium transients, and IL-4-stimulated eotaxin-3 secretion was blocked by EGTA-AM, 2-APB, verapamil, and diltiazem. The combination of omeprazole and verapamil suppressed IL-4-stimulated eotaxin-3 secretion more than either agent alone. EoE biopsies expressed higher ngH+,K+ATPase and exhibited more calcium signaling than controls. CONCLUSIONS: EoE cells express a non-gastric proton pump that mediates Th2 cytokine-stimulated eotaxin-3 secretion. IL-4 induces calcium release from the endoplasmic reticulum and calcium entry via L-type calcium channels, increasing intracellular calcium that contributes to eotaxin-3 secretion by EoE cells. L-type calcium channel inhibitors block Th2 cytokine-stimulated eotaxin-3 secretion, suggesting a potential role for these agents in EoE treatment.

Stavniichuk, R., DeLaForest, A., Thompson, C.A., Miller, J., Souza, R.F. and Battle, M.A. (2021). “GATA4 blocks squamous epithelial cell gene expression in human esophageal squamous cells.” Sci Rep 11(1): 3206.

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GATA4 promotes columnar epithelial cell fate during gastric development. When ectopically expressed in the developing mouse forestomach, the tissue emerges as columnar-like rather than stratified squamous with gene expression changes that parallel those observed in the pre-malignant squamous to columnar metaplasia known as Barrett’s esophagus (BE). GATA4 mRNA up-regulation and gene amplification occur in BE and its associated cancer, esophageal adenocarcinoma (EAC), and GATA4 gene amplification correlates with poor patient outcomes. Here, we explored the effect of ectopic expression of GATA4 in mature human esophageal squamous epithelial cells. We found that GATA4 expression in esophageal squamous epithelial cells compromised squamous cell marker gene expression and up-regulated expression of the canonical columnar cell cytokeratin KRT8. We observed GATA4 occupancy in the p63, KRT5, and KRT15 promoters, suggesting that GATA4 directly represses expression of squamous epithelial cell marker genes. Finally, we verified GATA4 protein expression in BE and EAC and found that exposure of esophageal squamous epithelial cells to acid and bile, known BE risk factors, induced GATA4 mRNA expression. We conclude that GATA4 suppresses expression of genes marking the stratified squamous epithelial cell lineage and that this repressive action by GATA4 may have implications in BE and EAC.