Discovery of a bacterial peptide as a modulator of GLP-1 and metabolic disease.
Discovery of a bacterial peptide as a modulator of GLP-1 and metabolic disease.
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发现一种细菌肽作为 GLP-1 和代谢疾病的调节剂。
DOI：
10.1038/s41598-020-61112-0
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发表时间：
2020
影响因子：
4.6
通讯作者：
Britton,RobertA
中科院分区：
文献类型：
--
作者：
Tomaro-Duchesneau,Catherine;LeValley,StephanieL;Roeth,Daniel;Sun,Liang;Horrigan,FrankT;Kalkum,Markus;Hyser,JosephM;Britton,RobertA
啮齿动物的早期研究强调了肠道微生物群在代谢性疾病（包括2型糖尿病（T2DM）和肥胖）中的重要性。胰高血糖素样肽-1 （Glucagon-like peptide-1, GLP-1）是胃肠道上皮内l细胞分泌的一种肠促素，具有促进胰岛素分泌、胰岛素敏感性和β细胞团数的重要功能，同时抑制胃排空和食欲。我们开始鉴定具有GLP-1刺激活性的微生物菌株作为潜在的代谢性疾病治疗药物。从健康人群中分离出1500多株人源性菌株，通过与NCI H716 l-细胞孵育细菌无细胞上清，筛选GLP-1调节。发现了大约45株能增加GLP-1的菌株。所有GLP-1阳性菌株经16S rRNA测序鉴定为表皮葡萄球菌。质谱分析发现，GLP-1阳性上清液中存在一种3 kDa的肽，Hld （δ毒素），但在GLP-1中性上清液中不存在。对NCI-H716细胞和人类空肠样细胞的研究表明，Hld本身足以促进GLP-1的分泌。当给高脂肪喂养的小鼠注射时，产生。表皮显著降低与肥胖和2型糖尿病相关的标志物。Hld的进一步表征表明GLP-1刺激Hld的作用是通过钙信号传导发生的。提出的结果确定了一种新的宿主-微生物相互作用，这可能最终导致基于微生物肽的代谢性疾病治疗的发展。
Early work in rodents highlighted the gut microbiota’s importance in metabolic disease, including Type II Diabetes Mellitus (T2DM) and obesity. Glucagon-like peptide-1 (GLP-1), an incretin secreted by L-cells lining the gastrointestinal epithelium, has important functions: promoting insulin secretion, insulin sensitivity, and β-cell mass, while inhibiting gastric emptying and appetite. We set out to identify microbial strains with GLP-1 stimulatory activity as potential metabolic disease therapeutics. Over 1500 human-derived strains were isolated from healthy individuals and screened for GLP-1 modulation by incubating bacterial cell-free supernatants with NCI H716 L-cells. Approximately 45 strains capable of increasing GLP-1 were discovered. All GLP-1 positive strains were identified asStaphylococcus epidermidisby 16S rRNA sequencing. Mass spectrometry analysis identified a 3 kDa peptide, Hld (delta-toxin), present in GLP-1 positive supernatants but absent in GLP-1 neutral supernatants. Studies in NCI-H716 cells and human jejunal enteroids engineered to make more enteroendocrine cells demonstrated that Hld alone is sufficient to enhance GLP-1 secretion. When administered in high-fat-fed mice, Hld-producingS. epidermidissignificantly reduced markers associated with obesity and T2DM. Further characterization of Hld suggests GLP-1 stimulatory action of Hld occurs via calcium signaling. The presented results identify a novel host-microbe interaction which may ultimately lead to the development of a microbial peptide-based therapeutic for metabolic disease.