魏泓、陈廷涛：二代工程益生菌通过调控肠-胰岛-肝轴改善2型糖尿病
据世界卫生组织统计，糖尿病并发症高达100多种，是目前已知并发症最多的一种疾病。2型糖尿病（T2DM）是一种慢性代谢疾病，多在35～40岁之后发病，占糖尿病患者90%以上，患者特征为高血糖、相对缺乏胰岛素、胰岛素抵抗等，需要终身药物治疗。虽然注射技术已经达到无针、无痛注射，但人们与生俱来就有对注射的恐惧感，导致对口服将抗药物需求剧增。
与胰岛素相比，GLP-1具有独特的生物学功能，其降糖功效可根据患者血糖水平变化而变化；此外，益生菌本身可对糖尿病有改善效果。基于此，研究者以植物乳杆菌（L. plantarum）为底盘菌，构建一株能够表达潜在糖尿病治疗药物GLP-1的工程益生菌L. plantarum-pMG36e-GLP-1，探索益生菌和GLP-1的共同降糖作用可行性。
研究者分别以高脂饮食联合链脲佐菌素（HFD-STZ）诱导的T2DM（糖尿病）小鼠和自发性T2DM小鼠（db/db）为动物模型，运用组织病理学技术、蛋白质免疫印记（Westernblotting）和微生物组学（16S高通量测序）等方法，探索了L. plantarum-pMG36e-GLP-1在T2DM小鼠中发挥的抗糖作用及其潜在分子机制。
研究结果表明，L. plantarum-pMG36e-GLP-1可以显著降低T2DM小鼠的血糖，抑制体重增长，改善糖耐。同时，L. plantarum-pMG36e-GLP-1可下调胰腺组织炎症相关蛋白（TLR-4、MyD88、NFκB）的表达，并抑制促炎细胞因子（IL-1β、IL-6、TNFα）的表达，从而缓解胰腺炎症。而且，L. plantarum-pMG36e-GLP-1还可下调凋亡相关蛋白Bax/Bcl-2的比值且增加抗凋亡相关蛋白p-AKT/AKT的比值，促进胰岛组织形态修复和胰岛β细胞增殖，从而提高胰岛素的分泌。再者，L. plantarum-pMG36e-GLP-1通过上调脂肪氧化相关基因（Pparα、Cpt-1、Acox-1）的表达同时抑制脂肪合成相关基因（Screbp-1、Fasn、Acaca）的表达进而调控肝脏脂肪脂质代谢。研究者还发现，L. plantarum-pMG36e-GLP-1显著提高了T2DM小鼠肠道菌群丰富度和多样性，并增加了益生菌Akkermansia和Lactobacillus的丰度，减少了致病菌Bacteroides的丰度。
研究开展，为开发新型T2DM口服药物及其临床应用提供了参考依据。
The engineered strain L. plantarum-pMG36e-GLP-1 improves diabetic symptoms and pancreatic inflammation in HFD/STZ-induced T2DM mice. a. Scheme of animal experiment. b. The fasting blood glucose levels during treatment. c. Body weight. d. Blood glucose levels and AUC in GTT test. e. Western blotting results indicated that the expression levels of proinflammatory proteins including TLR-4 and the ratio of p-NFκB/NFκB in pancreas of the engineered strain treated mice were significantly reduced. f. Gene expression levels of IL-1β, IL-6 and TNF-α in pancreas of the engineered strain treated mice were obviously decreased. C: normal mice (n=12); M: T2DM mice (n=12); Lac group: L. plantarum treated T2DM mice (n=12); Lac-G group: L. plantarum-pMG36e-GLP-1 treated T2DM mice (n=12); P group: exenatide treated T2DM mice (n=12). Data are presented as mean ± SD. ∗p < 0.05, ∗∗p < 0.01.
The engineered strain L. plantarum-pMG36e-GLP-1 repairs the pancreas of HFD/STZ-induced T2DM mice. a. Western blot-ting results indicated that the engineered strain markedly lowered the expression ratio of Bax/Bcl-2 and rised the ratio of p-AKT/AKT. b. The H&E staining of the pancreas. Pictures in the second line are the magnification of the red square above (Magnification ×100 and ×400, Scale bar = 200 μm and 50 μm). c. The immunofluorescence analysis of insulin in the pancre-as. Pictures in the fourth line are the magnification of the red square above (Magnification ×100 and ×400, Scale bar = 200 μm and 50 μm). C: normal mice (n=12); M: T2DM mice (n=12); Lac group: L. plantarumtreated T2DM mice (n=12); Lac-G group: L. plantarum-pMG36e-GLP-1 treated T2DM mice (n=12); P group: exenatide treated T2DM mice (n=12). Data are presented as mean ± SD. ∗p < 0.05, ∗∗p < 0.01.
The regulation of L. plantarum-pMG36e-GLP-1 on the liver lipid metabolism in db/db mice. a. The Oil red staining of the liver. Pictures in the second line are the magnification of the red square above (Magnification×100 and ×400, Scale bar = 200 μm and 50 μm). b. The expression of fat oxidation-related gene Pparα, Cpt-1 and Acox-1. c. The expression of fat synthesis-related gene Srebp-1,Fasn andAcaca. C: wild-type mice (n=8); M: db/db mice (n=8); Lac group: L. plantarum treated db/db mice (n=8); Lac-G group: L. plantarum-pMG36e-GLP-1 treated db/db mice (n=8); P group: exenatide treated db/db mice (n=8). Data are presented as mean ± SD. ∗p< 0.05, ∗∗p< 0.01.
The engineered strainL. plantarum-pMG36e-GLP-1 restores the intestinal microbiota in HFD/STZ-induced T2DM mice. The engineered strain increased the Shannon (a) and Chao 1 (b) indices of gut microbiota. c. The total number of core operational taxonomic units (OTUs) shared and unique in a Venn diagram. d. PcoA analysis of different group’s samples. e. LEfSe cladogram. f. LEfSe analysis with linear discriminant analysis. g. Barplots of the relative abundance of gut bacteria at the genus level. C: normal mice (n=12); M: T2DM mice (n=12); Lac group: L. plantarum treated T2DM mice (n=12); Lac-G group: L. plantarum-pMG36e-GLP-1 treated T2DM mice (n=12); P group: exenatide treated T2DM mice (n=12). Data are presented as mean ± SD. ∗p< 0.05, ∗∗p< 0.01.
https://pubs.rsc.org/en/content/articlelanding/2023/fo/d3fo00044c/unauth
陈廷涛，研究员/教授，博士生导师，江西省转化医学工程技术研究中心副主任。累计发表高水平学术论文155篇，授权专利30余件；以第一/通讯作者发表SCI论文108篇，其中IF21>5论文67篇、中科院TOP期刊35篇，工作被Nature、New England Journal of Medicine、Lancet等多家权威期刊正面评述或引用，被《中国肿瘤营养治疗指南2020》引用收录；担任Canadian Journal of Infectious Diseases & Medical Microbiology主编，Frontiers in Immunology/Frontiers in Microbiology副主编，及其他十余家国内外期刊编委、专刊主编。指导本科生获包括互联网+银/铜奖在内的国家级奖项12项，省级奖项1项。
先后获得江西省双千计划（科技创新高端人才项目）、江西省杰出青年、江西省省级优势科技创新团队、江西省新世纪百千万人才、江西省主要学科学术和技术带头人、产学研合作创新奖（省部级，1/1）、发明创业奖-创新奖一等奖（省部级，1/6）等荣誉，担任国家基金委函评专家及8个省/市科技项目评审专家；生物工程药物及其技术国家地方联合工程研究中心、江西省国家科技创新平台培育平台“生物工程药物技术创新中心”微生物方向负责人。主持国家自然科学基金3项，省部级自然基金12项，横向课题24项，总经费逾2100万。
与青岛东海药业、美华生物、杭州远大、中科嘉亿、江西善行、上海医药、博雅生物等公司研发部门合作，共同致力于益生菌的基础研究与产业转化；近5年共给合作企业带来新增销售额10.25亿元，新增利润逾1.48亿元。
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