Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis

• Main Authors: Madhusudan Grover (Author), Simon J. Gibbons (Author), Asha A. Nair (Author), Cheryl E. Bernard (Author), Adeel S. Zubair (Author), Seth T. Eisenman (Author), Laura A. Wilson (Author), Laura Miriel (Author), Pankaj J. Pasricha (Author), Henry P. Parkman (Author), Irene Sarosiek (Author), Richard W. McCallum (Author), Kenneth L. Koch (Author), Thomas L. Abell (Author), William J. Snape (Author), Braden Kuo (Author), Robert J. Shulman (Author), Travis J. McKenzie (Author), Todd A. Kellogg (Author), Michael L. Kendrick (Author), James Tonascia (Author), Frank A. Hamilton (Author), Gianrico Farrugia (Author), the NIDDK Gastroparesis Clinical Research Consortium (GpCRC) (Author)
• Format: Book
• Published: BMC, 2018-08-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Abstract Background 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. Methods 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. Results 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). Conclusions Diabetic and idiopathic gastroparesis have both unique and overlapping transcriptomic signatures. Innate immune signaling likely plays a central role in pathogenesis of human gastroparesis.

Item Description

10.1186/s12920-018-0379-1
1755-8794