Teng Guigen, Liu Zilin, Liu Yun, Wu Ting, Dai Yun, Wang Huahong, Wang Weihong
Departments of Gastroenterology, Peking University First Hospital, Beijing, China.
Front Microbiol. 2022 May 6;13:819336. doi: 10.3389/fmicb.2022.819336. eCollection 2022.
Intestinal mucosal inflammation and epithelial barrier dysfunction have been implicated as pathological factors in inflammatory bowel disease (IBD). An emerging area of IBD research focuses on probiotics. The probiotic Nissle 1917 (EcN) is an excellent choice for engineering therapeutic microbes. Elafin is an endogenous specific inhibitor of neutrophil elastase (NE) and proteinase 3, and we previously found Elafin can effectively suppress the development of colitis. Here, we genetically engineered EcN to deliver Elafin (EcN-Elafin) directly to the colonic mucosa and explored the protective effects of EcN-Elafin against colitis in mice. EcN-Elafin significantly alleviated dextran sodium sulfate (DSS) induced colitis. Compared with wild-type EcN, oral administration of EcN-Elafin displayed better effects on loss of weight, colon length shortening, elevated expression of myeloperoxidase (MPO), and proinflammatory cytokines and chemokine in colonic tissues. In addition, EcN-Elafin restored the expression and distribution of tight junction protein ZO-1 in colonic tissues back to normal. In a damaged colonic epithelial model utilizing Caco-2 cells stimulated with TNF-α, EcN-Elafin efficiently downregulated the activation level of NF-κB signaling. EcN-Elafin was also found to have restored the dysbiosis in gut caused by DSS administration. Moreover, EcN-Elafin significantly enhanced the concentrations of butyrate and valerate in the gut lumen. Thus, our findings demonstrated that EcNElafin enhanced the colonic epithelial barrier, promoted the resolution of inflammation, modulated the gut microbiota, and elevated concentrations of short-chain fatty acids (SCFAs) in the gut. EcN-Elafin may be a potential therapeutic method for IBD.
肠道黏膜炎症和上皮屏障功能障碍被认为是炎症性肠病（IBD）的病理因素。IBD研究的一个新兴领域聚焦于益生菌。益生菌Nissle 1917（EcN）是工程化治疗微生物的理想选择。Elafin是中性粒细胞弹性蛋白酶（NE）和蛋白酶3的内源性特异性抑制剂，我们之前发现Elafin可有效抑制结肠炎的发展。在此，我们通过基因工程改造EcN，使其直接向结肠黏膜递送Elafin（EcN-Elafin），并探究EcN-Elafin对小鼠结肠炎的保护作用。EcN-Elafin显著减轻了葡聚糖硫酸钠（DSS）诱导的结肠炎。与野生型EcN相比，口服EcN-Elafin在体重减轻、结肠长度缩短、结肠组织中髓过氧化物酶（MPO）表达升高以及促炎细胞因子和趋化因子方面显示出更好的效果。此外，EcN-Elafin使结肠组织中紧密连接蛋白ZO-1的表达和分布恢复正常。在利用肿瘤坏死因子-α刺激的Caco-2细胞建立的受损结肠上皮模型中，EcN-Elafin有效下调了NF-κB信号的激活水平。还发现EcN-Elafin恢复了由DSS给药引起的肠道菌群失调。此外，EcN-Elafin显著提高了肠腔内丁酸盐和戊酸盐的浓度。因此，我们的研究结果表明，EcN-Elafin增强了结肠上皮屏障，促进了炎症消退，调节了肠道微生物群，并提高了肠道中短链脂肪酸（SCFAs）的浓度。EcN-Elafin可能是一种治疗IBD的潜在方法。
