人结肠的不同区域和状态可能对免疫细胞功能具有不同的影响。在这里，我们研究了溃疡性结肠炎在单细胞分辨率下空间免疫特化和免疫反应失调的免疫代谢机制。我们发现，人结肠固有层中的巨噬细胞和CD8+T细胞具有效应子表型，并且被更多地激活，与上皮相比，它们的脂质代谢受到抑制。此外，与盲肠和横结肠相比，乙状结肠固有层中积累的IgA浆细胞被鉴定为代谢活性更高，代谢活性的提高与CD27的表达相关。除了由结肠空间定位引起的免疫代谢重编程，我们发现溃疡性结肠炎患者的细胞代谢失调与巨噬细胞和树突状细胞的免疫功能受损有关.OSM+炎性单核细胞簇也被鉴定为在对抗TNF治疗的抗性中发挥作用。我们探索了有针对性的代谢反应，可以将它们重新编程为正常状态。总之,这项研究揭示了人类结肠免疫细胞在不同位置和疾病状态下的代谢重编程，并为通过免疫代谢调节治疗溃疡性结肠炎提供了新的见解。
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.
