Targeted Microbiome Intervention by Microencapsulated Delayed-Release Niacin Beneficially Affects Insulin Sensitivity in Humans
Targeted Microbiome Intervention by Microencapsulated Delayed-Release Niacin Beneficially Affects Insulin Sensitivity in Humans
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DOI：
10.2337/dc17-1967
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发表时间：
2018-03-01
期刊：
影响因子：
16.2
通讯作者：
Laudes, Matthias
中科院分区：
文献类型：
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作者：
Fangmann, Daniela;Theismann, Eva-Maria;Laudes, Matthias
目的微生物区系代表着未来糖尿病前期和2型糖尿病治疗的潜在新靶点。在这方面，烟酸已经被证明在啮齿动物模型中有益地影响宿主-微生物群的相互作用。研究设计和方法我们研究了500多名具有不同代谢表型的受试者的烟酸(烟酸[NA]和烟酰胺[NAM])状态和他们的肠道微生物群。此外，在两项人体干预研究(生物利用度研究和概念验证/安全性研究)中，NA和NAM延迟释放微囊被设计并在体外和体内进行了检测。结果我们发现肥胖受试者微生物群中的α-多样性和类杆菌丰度降低与饮食中烟酸摄入量低有关。因此，我们开发了针对回结肠区域的延迟释放微囊，以向微生物群传递越来越多的NA和NAM，同时防止全身吸收，以避免负面副作用(如面部潮红)。这些缓释微囊的体外研究表明，在pH 1.4、4.5和6.8条件下稳定，然后在pH 7.4下释放化合物，模拟回结肠区域。在活体人体内，肠道靶向延迟释放NA而不是NAM显著增加了拟杆菌的丰度。在没有全身副作用的情况下，微囊化缓释NA诱导的这些有利的微生物群变化与全身胰岛素敏感性和代谢性炎症的生物标志物的改善有关。结论缓释NA靶向微生物群干预可能是未来治疗糖尿病前期和2型糖尿病的一种选择。
OBJECTIVEGut microbiota represent a potential novel target for future prediabetes and type 2 diabetes therapies. In that respect, niacin has been shown to beneficially affect the host-microbiome interaction in rodent models.RESEARCH DESIGN AND METHODSWe characterized more than 500 human subjects with different metabolic phenotypes regarding their niacin (nicotinic acid [NA] and nicotinamide [NAM]) status and their gut microbiome. In addition, NA and NAMdelayed-release microcapsules were engineered and examined in vitro and in vivo in two human intervention studies (bioavailability study and proof-of-concept/safety study).RESULTSWe found a reduced a-diversity and Bacteroidetes abundance in the microbiome of obese human subjects associated with a low dietary niacin intake. We therefore developed delayed-release microcapsules targeting the ileocolonic region to deliver increasing amounts of NA and NAM to the microbiome while preventing systemic resorption to avoid negative side effects (e.g., facial flushing). In vitro studies on these delayed-release microcapsules revealed stable conditions at pH 1.4, 4.5, and 6.8, followed by release of the compounds at pH 7.4, simulating the ileocolonic region. In humans in vivo, gut-targeted delayed-release NA but not NAM produced a significant increase in the abundance of Bacteroidetes. In the absence of systemic side effects, these favorable microbiome changes induced by microencapsulated delayed-release NA were associated with an improvement of biomarkers for systemic insulin sensitivity and metabolic inflammation.CONCLUSIONTargeted microbiome intervention by delayed-release NA might represent a future therapeutic option for prediabetes and type 2 diabetes.