Wang Mingkai, Li Ruiyang, Sheng Shihao, Dong Zhenglin, Bai Long, Wang Xiuhui, Wang Jianhua, Lai Yuxiao, Chen Xiao, Gao Jie, He Chongru, Liu Han, Su Jiacan
Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China.
MedEng-X Institutes, Shanghai University, Shanghai, 200444, China.
J Orthop Translat. 2025 Jun 3;53:26-36. doi: 10.1016/j.jot.2025.05.008. eCollection 2025 Jul.
Inflammatory bowel disease (IBD) with osteoporosis (OP) exhibits a clinically significant comorbidity, for which no effective treatment is currently available. Intestinal organoids (IOs), engineered through three-dimensional (3D) coculture systems, demonstrated intrinsic regenerative potentials. Additionally, extracellular vesicles derived from IOs (IOEVs) have been identified as potent nanoscale mediators capable of modulating intestinal inflammation.
In this study, we successfully established IOs and isolated IOEVs. miRNA sequencing in IOEVs revealed IBD-associated miRNAs, which may alleviate inflammatory response and have osteogenic effects. An in vitro model of IBD was established using lipopolysaccharide (LPS) to induce inflammation. Additionally, the dextran sulfate sodium (DSS)-induced IBD mouse model was employed to evaluate in vivo effects.
In the LPS-induced in vitro model, treatment with IOs and IOEVs resulted in reduced cell necrosis and apoptosis. In DSS-induced IBD mouse models, treatment led to restoration of body weight and colon morphology. Histological assessment revealed an increase in intestinal crypts and normalization of tissue architecture. Immunological analyses showed upregulation of ZO-1 and Ki67 and downregulation of Caspase-3, suggesting enhanced mucosal barrier integrity and cellular proliferation with decreased apoptosis. Cytokine profiling showed downregulation of pro-inflammatory cytokines TNF-α, IL-1β, IL-6 and upregulation of anti-inflammatory cytokine IL-10. Importantly, the combination of IOs and IOEVs reversed osteoporosis progression in IBD, improving bone mass and quality.
Collectively, these multimodal findings establish a novel paradigm for gut-bone axis modulation through organoid-derived biologics, offering a promising therapeutic strategy for managing IBD-associated osteoporosis.
This study highlights the translational potential of intestinal organoids and their extracellular vesicles as a dual-action biologic therapy that alleviates intestinal inflammation and reverses bone loss in IBD-associated osteoporosis. The identification of functional miRNAs within IOEVs supports their development as minimally invasive, cell-free therapeutics for systemic complications in inflammatory disease.
炎症性肠病（IBD）合并骨质疏松症（OP）是一种具有临床显著意义的共病，目前尚无有效的治疗方法。通过三维（3D）共培养系统构建的肠道类器官（IO）显示出内在的再生潜力。此外，源自IO的细胞外囊泡（IOEV）已被确定为能够调节肠道炎症的有效纳米级介质。
在本研究中，我们成功构建了IO并分离出IOEV。对IOEV进行的miRNA测序揭示了与IBD相关的miRNA，这些miRNA可能减轻炎症反应并具有成骨作用。使用脂多糖（LPS）诱导炎症建立了IBD的体外模型。此外，采用葡聚糖硫酸钠（DSS）诱导的IBD小鼠模型评估体内效应。
在LPS诱导的体外模型中，用IO和IOEV处理可减少细胞坏死和凋亡。在DSS诱导的IBD小鼠模型中，治疗导致体重恢复和结肠形态恢复。组织学评估显示肠道隐窝增加且组织结构正常化。免疫学分析显示紧密连接蛋白1（ZO-1）和增殖细胞核抗原（Ki67）上调，半胱天冬酶-3（Caspase-3）下调，表明黏膜屏障完整性增强、细胞增殖增加且细胞凋亡减少。细胞因子分析显示促炎细胞因子肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）下调，抗炎细胞因子白细胞介素-10（IL-10）上调。重要的是，IO和IOEV的联合使用逆转了IBD中骨质疏松症的进展，改善了骨量和骨质量。
总体而言，这些多模式研究结果通过类器官衍生的生物制剂建立了一种调节肠-骨轴的新范例，为管理IBD相关骨质疏松症提供了一种有前景的治疗策略。
本研究突出了肠道类器官及其细胞外囊泡作为一种双作用生物疗法的转化潜力，该疗法可减轻肠道炎症并逆转IBD相关骨质疏松症中的骨质流失。在IOEV中鉴定出功能性miRNA支持将其开发为用于治疗炎症性疾病全身并发症的微创、无细胞疗法。
