Proteomics in gastroparesis: Unique and overlapping protein signatures in diabetic and idiopathic gastroparesis
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PROVIDER: PRJNA540941 | ENA |
REPOSITORIES: ENA
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Project description:Background: Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in animal models of diabetes. Human studies have also revealed loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages in full thickness gastric biopsies from gastroparesis patients. Aim: We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in full thickness gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying and symptoms. Methods: Full-thickness gastric antrum biopsies were obtained from nine DG, seven IG patients and five non-diabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1300 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-values <0.05 were considered statistically significant. Results: 73 proteins were differentially expressed in DG, 132 proteins 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 FDR: 7.9x10-9; IG FDR: 6.3x10-12). 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 zeta type and complement C2 correlated with 4 hr gastric retention (r: -0.97, FDR: 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Conclusions: Protein expression changes suggest a central role of macrophage-driven immune dysregulation and complement activation in gastroparesis.
2019-09-15 | GSE130672 | GEO
Project description: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 × 10-9; IG FDR = 6.3 × 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.NEW & NOTEWORTHY This study uses SOMAscan, a novel proteomics assay for determination of altered proteins and associated molecular pathways in human gastroparesis. Seventy-three proteins were changed in diabetic gastroparesis, 132 in idiopathic gastroparesis compared with controls. Forty proteins were common in both. Macrophage-based immune dysregulation pathway was most significantly affected in both diabetic and idiopathic gastroparesis. Proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis.
| S-EPMC6879892 | biostudies-literature
Project description:Both diabetic and idiopathic gastroparesis have unique and overlapping changes in the transcriptome. Immune signaling predominately plays a role in the pathogenesis of gastroparesis.
2018-09-03 | GSE115601 | GEO
Project description:We report the high-throughput miRNA sequencing of plasma isolated from human patients with type 2 diabetes & gastroparesis, idiopathic gastroparesis alone, and healthy control patients.
2020-12-31 | GSE139577 | GEO
Project description:Gastrointestinal immune cells, particularly muscularis macrophages (MM) interact with enteric nervous system and influence gastrointestinal motility. Here we determine the human gastric muscle immunome and its changes in patients with idiopathic gastroparesis (IG). Single cell sequencing was performed on 26,000 CD45+ cells obtained from gastric tissue of 20 subjects (13 controls, 7 IG). Canonical markers, differential expression, and signalling were determined. We demonstrate 11 immune cell clusters with T cells being most abundant followed by myeloid cells. The proportions of cells belonging to the 11 clusters were similar between IG and controls. However, 9/11 clusters showed 578-11,429 differentially expressed genes (FDR<0.05). In IG, MM had decreased expression of tissue-protective and microglial genes and increased expression of monocyte trafficking and stromal activating genes. Furthermore, in IG, IL12 mediated JAK-STAT signaling involved in activation of tissue-resident macrophages and Eph-ephrin signaling involved in monocyte chemotaxis to inflammatory sites were upregulated. In summary, human gastric muscle has a rich representation of immune cells; and IG patients demonstrate a higher expression of pro-inflammatory genes and signaling in MM. These data further link immune dysregulation to pathophysiology of gastroparesis.
2024-01-31 | GSE252126 | GEO
Project description:Cellular changes associated with diabetic and idiopathic gastroparesis are not well described. The aim of this study was to describe histologic abnormalities in gastroparesis and compare findings in idiopathic versus diabetic gastroparesis.Full-thickness gastric body biopsy specimens were obtained from 40 patients with gastroparesis (20 diabetic) and matched controls. Sections were stained for H&E and trichrome and immunolabeled with antibodies against protein gene product (PGP) 9.5, neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide, substance P, and tyrosine hydroxylase to quantify nerves, S100? for glia, Kit for interstitial cells of Cajal (ICC), CD45 and CD68 for immune cells, and smoothelin for smooth muscle cells. Tissue was also examined by transmission electron microscopy.Histologic abnormalities were found in 83% of patients. The most common defects were loss of ICC with remaining ICC showing injury, an abnormal immune infiltrate containing macrophages, and decreased nerve fibers. On light microscopy, no significant differences were found between diabetic and idiopathic gastroparesis with the exception of nNOS expression, which was decreased in more patients with idiopathic gastroparesis (40%) compared with diabetic patients (20%) by visual grading. On electron microscopy, a markedly increased connective tissue stroma was present in both disorders.This study suggests that on full-thickness biopsy specimens, cellular abnormalities are found in the majority of patients with gastroparesis. The most common findings were loss of Kit expression, suggesting loss of ICC, and an increase in CD45 and CD68 immunoreactivity. These findings suggest that examination of tissue can lead to valuable insights into the pathophysiology of these disorders and offer hope that new therapeutic targets can be found.
| S-EPMC3081914 | biostudies-literature
Project description:Background & aimsGastroparesis can be diabetic or idiopathic, yet little is known about differences in their presentation. We compared clinical characteristics, symptoms, and gastric emptying in patients with type 1 or type 2 diabetic (DG) or idiopathic (IG) gastroparesis.MethodsWe analyzed data from 416 patients with gastroparesis who were enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Registry; 254 had IG (most were female and white), and 137 had DG (78 had type 1 and 59 had type 2). Registry data included detailed histories, physical examinations, results from gastric emptying scintigraphy, and responses to validated symptom questionnaires.ResultsPatients with type 2 diabetes mellitus (DM) were an average of 13 years older at the onset of symptoms of gastroparesis and heavier than patients with IG. Patients with type 1 DM had more hospitalizations in the past year than patients with IG. Symptoms that prompted evaluation more often included vomiting for DG and abdominal pain for IG. Patients with DG had more severe retching and vomiting than those with IG, whereas patients with IG had more severe early satiety and postprandial fullness subscores. Compared with IG, gastric retention was greater in patients with type 1 DM. More than 50% of patients with type 1 DM had severe retention (>35% at 4 hours); they took prokinetic agents more frequently and were more likely to receive gastric electric stimulation.ConclusionsThere are similarities and differences in clinical characteristics of DG and IG. Gastroparesis is a heterogeneous disorder; its etiology affects symptoms and severity. Long-term studies are needed to determine whether the differences in symptoms and gastric emptying affect progression and treatment responses.
| S-EPMC3499102 | biostudies-literature
Project description:Nausea and vomiting are classic symptoms of gastroparesis. It remains unclear if characteristics of nausea and vomiting are similar in different etiologies of gastroparesis. The aims of this article were as follows: to describe characteristics of nausea and vomiting in patients with gastroparesis and to determine if there are differences in nausea and vomiting in diabetic (DG) and idiopathic gastroparesis (IG).Gastroparetic patients enrolling in the NIDDK Gastroparesis Registry underwent assessment with history and questionnaires assessing symptoms, quality of life, and a questionnaire characterizing nausea and vomiting.Of 159 gastroparesis patients (107 IG, 52 DG), 96% experienced nausea, whereas 65% experienced vomiting. Nausea was predominant symptom in 28% and vomiting was predominant in 4%. Nausea was severe or very severe in 41%. PAGI-SYM nausea/vomiting subscore was greater with increased vomiting severity, but not nausea severity in DG than IG. Nausea was related to meals in 71%; lasting most of the day in 41%. Increasing nausea severity was related to decreased quality of life. Nausea often preceded vomiting in 82% of patients and vomiting often relieved nausea in 30%. Vomiting was more common in DG (81%) compared to IG (57%; p = 0.004). Diabetic patients more often had vomiting in the morning before eating, during the night, and when not eating.Nausea is present in essentially all patients with gastroparesis irrespective of cause and associated with decreased quality of life. In contrast, vomiting was more prevalent, more severe, and occurred more often in DG than IG. Thus, characteristics of vomiting differ in IG vs DG.
| S-EPMC5125878 | biostudies-literature
Project description:Single cell atlas of human gastric muscle immune cells and macrophage-driven changes in idiopathic gastroparesis
| PRJNA1057833 | ENA
Project description:RNA seq in human gastroparesis
| PRJNA475559 | ENA