Inflammatory bowel disease (IBD) is a chronic and unspecific inflammatory disorder of the gastrointestinal tract, and current treatment options often fail to maintain long‐term remission. Studies have shown that propionate level is reduced in fecal samples from patients with IBD. Propionate can ameliorate IBD through intestinal epithelial cells and immune regulation, but its effects on the inflammatory microenvironment and macrophage differentiation have not been widely studied. To address this, we constructed an engineered propionate‐producing probiotic (EcNP3) to achieve sustained restoration of propionate levels in the gut and increase its bioavailability. DSS‐induced experimental intestinal inflammation model was used to evaluate the effect of EcNP3 on improving the intestinal mucosal barrier and increasing the proportion of anti‐inflammatory macrophages. It was found that EcNP3 exhibited a restorative effect on the depletion of peritoneal anti‐inflammatory macrophages (F4/80hiCD11bhi) and significantly improved the expression level of IL‐10. Simultaneously, the expression of IL‐1β, IL‐6, and CXCL1 was downregulated while inhibiting apoptosis of tissue‐resident macrophages ex vivo. Further investigation revealed that EcNP3 regulates IL‐10 expression through G protein‐coupled receptor 43 and histone deacetylase. Furthermore, EcNP3 significantly inhibited the protein expression of HDAC1 and promoted the histone acetylation level of cells. Finally, EcNP3 significantly improved DSS‐induced colitis in mice by increasing mucus production and reducing inflammatory infiltration. Our results suggest that the engineered live biotherapeutic product EcNP3 is a safe and potently efficacious treatment for IBD, which defines a novel strategy in IBD therapy through macrophage IL‐10 signaling.

中文翻译：

---

产丙酸盐的工程益生菌通过 GPR43/HDAC1/IL-10 轴恢复抗炎巨噬细胞，从而改善小鼠溃疡性结肠炎


炎症性肠病 （IBD） 是一种慢性和非特异性的胃肠道炎症性疾病，目前的治疗方案往往无法维持长期缓解。研究表明，IBD 患者粪便样本中的丙酸盐水平降低。丙酸盐可以通过肠上皮细胞和免疫调节改善 IBD，但其对炎症微环境和巨噬细胞分化的影响尚未得到广泛研究。为了解决这个问题，我们构建了一种工程化的丙酸盐生产益生菌 （EcNP3），以实现肠道中丙酸盐水平的持续恢复并提高其生物利用度。采用 DSS 诱导的实验性肠道炎症模型评价 EcNP3 对改善肠粘膜屏障和增加抗炎巨噬细胞比例的影响。研究发现，EcNP3 对腹膜抗炎巨噬细胞 （F4/80hiCD11bhi） 的耗竭表现出修复作用，并显着提高 IL-10 的表达水平。同时，IL-1β 、 IL-6 和 CXCL1 的表达下调，同时在体外抑制组织驻留巨噬细胞的凋亡。进一步研究显示，EcNP3 通过 G 蛋白偶联受体 43 和组蛋白脱乙酰酶调节 IL-10 表达。此外，EcNP3 显著抑制 HDAC1 的蛋白表达，促进细胞组蛋白乙酰化水平。最后，EcNP3 通过增加粘液产生和减少炎症浸润，显著改善了 DSS 诱导的小鼠结肠炎。 我们的结果表明，工程活体生物治疗产品 EcNP3 是一种安全有效的 IBD 治疗方法，它定义了一种通过巨噬细胞 IL-10 信号传导治疗 IBD 的新策略。