Single cell atlas of human gastric muscle immune cells and macrophage-driven changes in idiopathic gastroparesis

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. Overall design: Our aim in this study was to characterize the immune cell populations in human gastric muscle and determine changes in patients with idiopathic gastroparesis. [contributor] NIDDK Gastroparesis Clinical Research Consortium