摘要
Inflammatory bowel disease (IBD) is a spectrum of autoimmune diseases affecting the gastrointestinal tract characterized by a relapsing and remitting course of gut mucosal inflammation. Disease flares can be difficult to predict, and the current practice of IBD disease activity surveillance through endoscopy is invasive and requires medical expertise. Recent advancements in synthetic biology raise the possibility that symbiotic microbes can be engineered to selectively detect disease biomarkers used in current clinical practice. Here, we introduce an engineered probiotic capable of detecting the clinical gold standard IBD biomarker, calprotectin, with sensitivity and specificity in IBD patients. Specifically, we identified a bacterial promoter in the probiotic strain Escherichia coli Nissle 1917 (EcN) which exhibits a specific expression increase in the presence of calprotectin. Using murine models of colitis, we show that the reporter signal is activated in vivo during transit of the GI tract following oral delivery. Furthermore, our engineered probiotic can successfully discriminate human patients with active IBD from those in remission and without IBD using patient stool samples, where the intensity of reporter signal quantitatively tracks with clinical laboratory–measured levels of calprotectin. Our pilot study sets the stage for probiotics that can be engineered to detect fecal calprotectin for precise noninvasive disease activity monitoring in IBD patients.
摘要译文
炎症性肠病（IBD）是影响胃肠道的一系列自身免疫性疾病，其特征为肠粘膜炎症的复发和缓解过程。 疾病发作可能难以预测，目前通过内窥镜进行IBD疾病活动性监测的做法具有侵入性，需要医学专业知识。 合成生物学的最新进展提高了共生微生物可以被工程化以选择性地检测当前临床实践中使用的疾病生物标志物的可能性。 在此，我们引入了一种能够在IBD患者中检测具有灵敏度和特异性的临床金标准IBD生物标志物钙卫蛋白（calprotectin）的工程益生菌。 具体而言，我们在益生菌菌株Escherichia coli Nissle 1917（EcN）中鉴定了细菌启动子，其在钙卫蛋白存在下表现出特异性表达增加。 使用鼠结肠炎模型，我们显示报告信号在口服递送后胃肠道通过期间在体内被激活。 此外，我们的工程益生菌能够使用患者粪便样本成功区分患有活动性IBD的人类患者和处于缓解期和无IBD的患者，其中报告信号强度通过临床实验室测量的钙卫蛋白水平定量跟踪。 我们的初步研究为益生菌奠定了基础，该益生菌可用于检测粪便钙卫蛋白，从而对IBD患者进行精确的无创疾病活动监测。
Jonathan Y. Xia [1];Chelsea Hepler [2];Peter Tran [3];Nathan J. Waldeck[2];Joseph Bass [2];Arthur Prindle [4]. Engineered calprotectin-sensing probiotics for IBD surveillance in humans[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2023,120(32)