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

Authors: CHIKKAMENAHALLI, LAKSHMIKANTH - Mayo Clinic; JESSEN, ERIK - Mayo Clinic; BERNARD, CHERYL - Mayo Clinic; IP, W K EDDIE - Mayo Clinic; BREEN-LYLES, MARGARET - Mayo Clinic; CIPRIANI, GIANLUCA - Mayo Clinic; PULLAPANTULA, SURAJ - Mayo Clinic; LI, YING - Mayo Clinic; ALASFOOR, SHEFAA - Mayo Clinic; WILSON, LAURA - Johns Hopkins School Of Public Health; KOCH, KENNETH - Wake Forest University; KUO, BRADEN - Massachusetts General Hospital; SHULMAN, ROBERT - Children'S Nutrition Research Center (CNRC); CHUMPITAZI, BRUNO - Children'S Nutrition Research Center (CNRC); MCKENZIE, TRAVIS - Mayo Clinic; KELLOGG, TODD - Mayo Clinic; TONASCIA, JAMES - Johns Hopkins School Of Public Health; HAMILTON, FRANK - National Institute Of Diabetes And Digestive And Kidney Diseases; SAROSIEK, IRENE - Texas Tech University Health Science Center; MCCALLUM, RICHARD - Texas Tech University Health Science Center; PARKMAN, HENRY - Temple University; PASRICHA, PANKAJ - Mayo Clinic College Of Medicine; ABELL, THOMAS - University Of Louisville; FARRUGIA, GIANRICO - Mayo Clinic; DASARI, SURENDRA - Mayo Clinic; GROVER, MADHUSUDAN - Mayo Clinic

Submitted to: iScience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/17/2024
Publication Date: 1/23/2024
Citation: Chikkamenahalli, L.L., Jessen, E., Bernard, C.E., Ip, W., Breen-Lyles, M., Cipriani, G., Pullapantula, S.R., Li, Y., Alasfoor, S., Wilson, L., Koch, K.L., Kuo, B., Shulman, R.J., Chumpitazi, B.P., McKenzie, T.J., Kellogg, T.A., Tonascia, J., Hamilton, F.A., Sarosiek, I., McCallum, R., Parkman, H.P., Pasricha, P.J., Abell, T.L., Farrugia, G., Dasari, S., Grover, M. 2024. Single cell atlas of human gastric muscle immune cells and macrophage-driven changes in idiopathic gastroparesis. iScience. 27(3). Article 108991. https://doi.org/10.1016/j.isci.2024.108991.
DOI: https://doi.org/10.1016/j.isci.2024.108991

Interpretive Summary: Slow stomach emptying (gastroparesis) often causes multiple severe symptoms including belly pain, vomiting, loss of appetite, and weight loss that affects children and adults and lasts for years. In the vast majority of cases, the cause of slow stomach emptying is unknown. Our earlier studies suggested that changes in certain cells within the stomach may contribute to the presence of slow stomach emptying. In this study we used advanced techniques to investigate specialized cells in the stomach lining that are part of the immune system. We found that individuals with slow stomach emptying had an increased number of a specific type of immune cell. This knowledge will help us direct the development of future treatments.

Technical Abstract: Gastrointestinal immune cells, particularly muscularis macrophages (MM) interact with the 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 the gastric tissue of 20 subjects. 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. In IG, MM had decreased expression of tissue-protective and microglial genes and increased the expression of monocyte trafficking and stromal activating genes. Furthermore, in IG, IL12 mediated JAK-STAT signaling involved in the activation of tissue-resident macrophages and Eph-ephrin signaling involved in monocyte chemotaxis were upregulated. Patients with IG had a greater abundance of monocyte-like cells. These data further link immune dysregulation to the pathophysiology of gastroparesis.