ScRNA-seq identified the metabolic reprogramming of human colonic immune cells in different locations and disease states

Abstract

Different regions and states of the human colon are likely to have a distinct influence on immune cell functions. Here we studied the immunometabolic mechanisms for spatial immune specialization and dysregulated immune response during ulcerative colitis at single-cell resolution. We revealed that the macrophages and CD8⁺ T cells in the lamina propria of the human colon possessed an effector phenotype and were more activated, while their lipid metabolism was suppressed compared with those in the epithelial. Also, IgA⁺ plasma cells accumulated in lamina propria of the sigmoid colon were identified to be more metabolically activated versus those in the cecum and transverse colon, and the improved metabolic activity was correlated with the expression of CD27. In addition to the immunometabolic reprogramming caused by spatial localization colon, we found dysregulated cellular metabolism was related to the impaired immune functions of macrophages and dendritic cells in patients with ulcerative colitis. The cluster of OSM⁺ inflammatory monocytes was also identified to play its role in resistance to anti-TNF treatment, and we explored targeted metabolic reactions that could reprogram them to a normal state. Altogether, this study revealed a landscape of metabolic reprogramming of human colonic immune cells in different locations and disease states, and offered new insights into treating ulcerative colitis by immunometabolic modulation.

Keywords: Anti-TNF therapy Resistance; Human colon; Immunometabolic modulation; Inflammation; Single-cell immunometabolism; Spatial immune specialization; Ulcerative colitis.