Proteomics in gastroparesis: Unique and overlapping protein signatures in diabetic and idiopathic gastroparesis

Authors: GROVER, MADHUSUDAN - Mayo Clinic; DASARI, SURENDRA - Mayo Clinic; BERNARD, CHERYL - Mayo Clinic; CHIKKAMENAHALLI, LAKSHMIKANTH - Mayo Clinic; YATES, KATHERINE - Johns Hopkins School Of Public Health; PASRICHA, PANKAJ - Johns Hopkins University School Of Medicine; SAROSIEK, IRENE - Texas Tech University Health Science Center; MCCALLUM, RICHARD - Texas Tech University Health Science Center; KOCH, KENNETH - Wake Forest University; ABELL, THOMAS - University Of Louisville; KUO, BRADEN - Massachusetts General Hospital; SHULMAN, ROBERT - Children'S Nutrition Research Center (CNRC); GIBBONS, SIMON - Mayo Clinic; MCKENZIE, TRAVIS - Mayo Clinic; KELLOGG, TODD - Mayo Clinic; KENDRICK, MICHAEL - Mayo Clinic; TONASCIA, JAMES - Johns Hopkins School Of Public Health; HAMILTON, FRANK - National Institute Of Diabetes And Digestive And Kidney Diseases; PARKMAN, HENRY - Temple University; FARRUGIA, GIANRICO - Mayo Clinic

Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/27/2019
Publication Date: 11/1/2019
Citation: Grover, M., Dasari, S., Bernard, C.E., Chikkamenahalli, L.L., Yates, K.P., Pasricha, P.J., Sarosiek, I., McCallum, R., Koch, K.L., Abell, T.L., Kuo, B., Shulman, R.J., Gibbons, S.J., McKenzie, T.J., Kellogg, T.A., Kendrick, M.L., Tonascia, J., Hamilton, F.A., Parkman, H.P., Farrugia, G. 2019. Proteomics in gastroparesis: Unique and overlapping protein signatures in diabetic and idiopathic gastroparesis. American Journal of Physiology - Gastrointestinal and Liver Physiology. 317(5):G716-G726. https://doi.org/10.1152/ajpgi.00115.2019.
DOI: https://doi.org/10.1152/ajpgi.00115.2019

Interpretive Summary: Slow stomach emptying can be a crippling disorder affecting children and adults. Because it causes nausea and vomiting, it can be associated with malnutrition. The cause is poorly understood. A recent study by researchers in Houston, in collaboration with the NIH Gastroparesis Consortium, used a cutting edge technique called proteomics to detect changes in the types of proteins found in the stomach of individuals with slow stomach emptying as compared to healthy people. The results showed abnormal immune function in those with slow stomach emptying. These results will help lead to new treatment strategies for addressing this debilitating disorder which may involve nutritional intervention.

Technical Abstract: Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full-thickness gastric biopsies from gastroparesis patients. We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying, and symptoms. Full-thickness gastric antrum biopsies were obtained from nine DG patients, seven IG patients, and five nondiabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1,305 human proteins was used. Protein fold changes were computed, and differential expressions were calculated using Limma. Ingenuity pathway analysis and correlations were carried out. Multiple-testing corrected P < 0.05 was considered statistically significant. Seventy-three proteins were differentially expressed in DG, 132 proteins were differentially expressed in IG, and 40 proteins were common to DG and IG. In both DG and IG, "Role of Macrophages, Fibroblasts and Endothelial Cells" was the most statistically significant altered pathway [DG false discovery rate (FDR) = 7.9 x 10-9; IG FDR = 6.3 x 10-12]. In DG, properdin expression correlated with GCSI bloating (r = -0.99, FDR = 0.02) and expressions of prostaglandin G/H synthase 2, protein kinase C- type, and complement C2 correlated with 4 h gastric retention (r = -0.97, FDR = 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Protein expression changes suggest a central role of macrophage-driven immune dysregulation in gastroparesis, specifically, complement activation in diabetic gastroparesis.