基于肠道菌群宏基因组测序探讨现代服药辟谷逆转/缓解2型糖尿病的代谢性内毒素血症机制

The latest paper in the Lancet showed that 46-86% of type 2 diabetes patients achieved remission for 1 year through caloric restriction, suggesting that lifestyle alteration could be used as a major treatment for diabetes rather than a kind of supplementary method. Similar effects could be achieved by our modern Chinese medication fasting (modified Chinese fasting therapy) which induced a remission period between 3 to 5 months in newly diagnosed type 2 diabetes patients. The development of type 2 diabetes is closely related to lipopolysaccharides (LPS), which is derived from gut microbiota, metabolic endotoxemia, and inflammation. Our pre-experiment showed that Firmicutes abundance, Akkermansia abundance and the diversity of intestinal flora increased in 3 patients after receiving modern Chinese medication fasting, indicating that the mechanism of modern Chinese medication in treating diabetes may lie in gut microbiota regulating. We will evaluate the effects and mechanisms of modern Chinese medication fasting on intestinal flora regulation, metabolic endotoxemia and low inflammatory state in diabetes treatment through detecting changes of gut microbiota, metabolic products of small molecules, endotoxin and inflammatory cytokines, using the combination of metagenomics sequencing of intestinal microbiota and metabonomics. Meanwhile, this project aims to determine the differences in gut microbiota components or specific bacterial species as treating targets, laying the foundation of applying gut microbiota transplantation in type 2 diabetes treatment in the next step and further promoting the application of this effective ancient health preservation method in the prevention and treatment of type 2 diabetes mellitus.

《柳叶刀》最新论文显示，热量限制使46-86%的2型糖尿病获得一年缓解，提示生活方式改变可作为糖尿病治疗逆转/缓解2型糖尿病。我们的现代服药辟谷（改良的中国式禁食疗法）也有类似的功效，实施一次可使新发2型糖尿病患者获得3-5个月的缓解。2型糖尿病与肠道菌群衍生的脂多糖及代谢性内毒素血症、炎症状态有密切关系，我们预实验显示3名接受现代服药辟谷的患者肠道厚壁菌门丰度减少、Akkermansia菌丰度增加、菌群多样性升高，提示现代服药辟谷通过肠道菌群的调节来逆转/缓解糖尿病。本研究采用肠道菌群宏基因组测序及代谢组学相结合，观察肠道菌群、小分子代谢产物、内毒素及炎症因子水平变化，从调节肠道菌群、代谢性内毒素血症、低炎症状态3个方面探讨现代服药辟谷干预2型糖尿病的疗效及机制，找出菌群差异或目标菌群种类，为下一步精准的粪菌移植治疗2型糖尿病打下基础，让传统辟谷养生方法在2型糖尿病防治方面焕发新的生机。

目前2型糖尿病患病人数与日俱增，为个人和社会造成了巨大负担，寻找更加便捷有效的治疗迫在眉睫。现代服药辟谷作为西方热量限制与中医传统辟谷相结合的特殊热量限制方法，已在临床运用13年，既往已初步探究其对2型糖尿病的疗效，但相关机制尚不明确。因此本课题通过临床研究、动物实验两个部分，运用肠道菌群宏基因组测序、非靶向代谢组学、16sRNA高通量测序等方法，发现现代服药辟谷可显著改善超重/肥胖2型糖尿病患者血糖和血脂水平，改善胰岛素抵抗，且效果在6个月内持续，同时可以显著调节其肠道菌群及血清代谢产物的总体结构，降低其中促炎的致病菌种及代谢产物，增加抗炎的有益菌种及代谢产物，调节多条2型糖尿病相关的功能通路。而其中机制可能与增加肠道微生态多样性，降低致病菌属，增加有益菌属，进而改善肠道屏障功能，改善代谢性内毒性血症，抑制肝脏TLR4蛋白表达，降低炎症反应有关。本研究为现代服药辟谷的临床应用提供了更深一步的科学依据，并为2型糖尿病防治提供了更加具备中医特色、更加简便验廉的治疗方法。