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Title: Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis

item GROVER, MADHUSUDAN - Mayo Clinic
item GIBBONS, SIMON - Mayo Clinic
item NAIR, ASHA - Mayo Clinic
item BERNARD, CHERYL - Mayo Clinic
item ZUBAIR, ADEEL - Mayo Clinic
item EISENMAN, SETH - Mayo Clinic
item WILSON, LAURA - Johns Hopkins School Of Public Health
item MIRIEL, LAURA - Johns Hopkins School Of Public Health
item PASRICHA, PANKAJ - Johns Hopkins University School Of Medicine
item PARKMAN, HENRY - Temple University
item SAROSIEK, IRENE - Texas Tech University
item MCCALLUM, RICHARD - Texas Tech University
item KOCH, KENNETH - Wake Forest University
item ABELL, THOMAS - University Of Louisville
item SNAPE, WILLIAM - California Pacific Medical Center
item KUO, BRADEN - Massachusetts General Hospital
item SHULMAN, ROBERT - Children'S Nutrition Research Center (CNRC)
item MCKENZIE, TRAVIS - Mayo Clinic
item KELLOGG, TODD - Mayo Clinic
item KENDRICK, MICHAEL - Mayo Clinic
item TONASCIA, JAMES - Johns Hopkins School Of Public Health
item HAMILTON, FRANK - National Institute Of Diabetes And Digestive And Kidney Diseases
item FARRUGIA, GIANRICO - Mayo Clinic

Submitted to: BMC Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/23/2018
Publication Date: 8/7/2018
Citation: Grover, M., Gibbons, S.J., Nair, A.A., Bernard, C.E., Zubair, A.S., Eisenman, S.T., Wilson, L.A., Miriel, L., Pasricha, P.J., Parkman, H.P., Sarosiek, I., McCallum, R.W., Koch, K.L., Abell, T.L., Snape, W.J., Kuo, B., Shulman, R.J., McKenzie, T.J., Kellogg, T.A., Kendrick, M.L., Tonascia, J., Hamilton, F.A., Farrugia, G. 2018. Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis. BMC Genomics. 11:62.

Interpretive Summary: Gastroparesis is a condition whereby the stomach does not empty well. Poor emptying often results in symptoms that can be debilitating. The cause of gastroparesis in unknown. In this study, biopsies of adults with gastroparesis were examined using cutting edge methods to investigate genes in the stomach. The results showed that individuals who had poor stomach emptying related to diabetes had changes in genes, some of which overlapped with, and some that were different from adults without diabetes. Both types of individuals appeared to have altered signaling in the immune system that likely contributes to poor stomach emptying and its symptoms. Futher investigation is needed to identify strategies, including nutritional approaches, to address this concern.

Technical Abstract: Cellular changes described in human gastroparesis have revealed a role for immune dysregulation, however, a mechanistic understanding of human gastroparesis and the signaling pathways involved are still unclear. Diabetic gastroparetics, diabetic non-gastroparetic controls, idiopathic gastroparetics and non-diabetic non-gastroparetic controls underwent full-thickness gastric body biopsies. Deep RNA sequencing was performed and pathway analysis of differentially expressed transcripts was done using Ingenuity®. A subset of differentially expressed genes in diabetic gastroparesis was validated in a separate cohort using QT-PCR. 111 genes were differentially expressed in diabetic gastroparesis and 181 in idiopathic gastroparesis with a log2fold difference of >=2 and false detection rate (FDR) <5%. Top canonical pathways in diabetic gastroparesis included genes involved with macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, osteoarthritis pathway and differential regulation of cytokine production in macrophages and T helper cells by IL-17A and IL-17F. Top canonical pathways in idiopathic gastroparesis included genes involved in granulocyte adhesion and diapedesis, agranulocyte adhesion and diapedesis, and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Sixty-five differentially expressed genes (log2fold difference >=2, FDR <5%) were common in both diabetic and idiopathic gastroparesis with genes in the top 5 canonical pathways associated with immune signaling. 4/5 highly differentially expressed genes (SGK1, APOLD1, CXCR4, CXCL2, and FOS) in diabetic gastroparesis were validated in a separate cohort of patients using RT-PCR. Immune profile analysis revealed that genes associated with M1 (pro inflammatory) macrophages were enriched in tissues from idiopathic gastroparesis tissues compared to controls (p<0.05). Diabetic and idiopathic gastroparesis have both unique and overlapping transcriptomic signatures. Innate immune signaling likely plays a central role in pathogenesis of human gastroparesis.