肠道作为人体最大的免疫细胞区室，因其持续接触外源性抗原而形成。肠道黏膜是宿主细胞与环境因素（如膳食代谢物、共生微生物及肠道腔内病原体）动态互动的重要场所。肠屏障由单层上皮细胞构成，将免疫细胞与肠道腔体分隔开来。上皮细胞与免疫区室之间的双向互动对维持肠道稳态至关重要——既能限制感染风险，又能防止过度免疫激活，还能促进组织修复过程。然而，由于体内模型的复杂性可能阻碍机制研究，且细胞培养模型缺乏肠道细胞异质性（即使从原代细胞建立的模型也难以长期维持），我们对上皮-免疫相互作用的理解仍存在局限。近十年来，类器官模型作为肠道可靠模型崭露头角，成功复现了天然组织的关键细胞特征和结构特征。此外，类器官模型还可用于生成具有组织特异性表型的免疫细胞，并探究疾病相关风险基因对肠道免疫环境的影响。

尽管肠道类器官培养最初是利用小鼠建立的，但相关技术已发展成熟，现可基于人类活检样本制备小型肠道“肠类器官”或大型肠道“结肠类器官”。过去十年间，肠道类器官技术从原理验证阶段逐步发展成为功能完备、可定制化的科研工具，在基础研究和转化医学领域展现出巨大潜力。

肠道类器官目前仍是研究肠道的最精准体外系统，为探究肠道免疫-上皮相互作用提供了基础研究范式，展现出在基础研究和转化医学领域的重要应用价值。

图1. Generation of tissue- or PSC-derived intestinal organoids and reported immune-organoid co-culture approaches. Intestinal organoids are primarily generated following two approaches. (A)Tissue-derived intestinal organoids can be grown from isolated crypts or single Lgr5+ISC to produce epithelial-only cell structures. (B) Embryonic stem cells or induced pluripotent stem cells can be pushed sequentially towards endoderm and gut differentiation to produce PSC-derived intestinal organoids with both epithelial and mesenchymal cell compartments. (C) Organoids can be used for immunological studies in several different ways.This includes addition of cytokines or immune cell conditioned media (1), co-culture with immune cells (2–4), inclusion of microbial components, (5–7) or as air-liquid interface organoids which co-develop native immune cells (8).Figure created with BioRender.com.

图2：Overview of the data obtained from mouse and human co-cultures of intestinal organoids with immune cells, bacterial cells or cytokines in models of infection, infammation and colorectal cancer (CRC). (A) For infection studies, organoid monolayers grown in transwell cell culture inserts are usually used. Co-culture of organoids with commensal strains such as Lactobacillus murinus and Lactobacillus reuteri showed the production of the anti-infammatory IL-10 by DCs and macrophages in the intestine.The role of Helminths and other bacteria such as Shigella and E. coli has also been studied in an organoid-coculture model. (B)To study the contribution of a specifc gene to intestinal infammation development, many studies have used genetically engineered mice to generate intestinal organoids (epithelial cells defcient in LRH1 and PGE2-EP4) or to obtain genetically modifed immune cells including dendritic cells (NF-kB2 KO) and macrophages (PTPN2 or PTGER4+KO macrophages). Organoids have also been challenged with cytokines such as IL-22 and IFN-γ and co-cultured with immune cells including ILC1s, dendritic cells, macrophages, and intraepithelial lymphocytes (IELs) to analyse how specifc cells or cytokines impact the epithelial barrier function thereby promoting intestinal infammation. (C) For CRC studies, organoids established from ApcMin/+ murine model and patient-derived tumour organoids are normally applied.To increase the understanding in which molecules or cells drive or prevent tumorogenesis co-culture systems of organoids with immune cells such as IELs and macrophages, cytokines (IL-22) and conditioned medium derived from NK cells have been described. Furthermore, a modifedT-cell co-culture system with patient-derived tumour organoids has been developed to expand and select patient-specifc tumour reactive cellsT-cells ex vivo. Figure created with BioRender.com.

参考文献：

Organoids as a tool to study homeostatic and pathological immune–epithelial interactions in the gut. Emma HøjmoseKromann, Ainize PeñaCearra, and Joana F.Neves. Clinical and Experimental Immunology, 2024, 218, 28–39 

https://doi.org/10.1093/cei/uxad118

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