Eicosapentaenoic and docosahexaenoic acids attenuate hyperglycemia through the microbiome-gut-organs axis in db/db mice.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been suggested to prevent the development of metabolic disorders. However, their individual role in treating hyperglycemia and the mechanism of action regarding gut microbiome and metabolome in the context of diabetes remain unclear. Supplementation of DHA and EPA attenuated hyperglycemia and insulin resistance without changing body weight in db/db mice while the ameliorative effect appeared to be more pronounced for EPA. DHA/EPA supplementation reduced the abundance of the lipopolysaccharide-containing Enterobacteriaceae whereas elevated the family Coriobacteriaceae negatively correlated with glutamate level, genera Barnesiella and Clostridium XlVa associated with bile acids production, beneficial Bifidobacterium and Lactobacillus, and SCFA-producing species. The gut microbiome alterations co-occurred with the shifts in the metabolome, including glutamate, bile acids, propionic/butyric acid, and lipopolysaccharide, which subsequently relieved β cell apoptosis, suppressed hepatic gluconeogenesis, and promoted GLP-1 secretion, white adipose beiging, and insulin signaling. All these changes appeared to be more evident for EPA. Furthermore, transplantation with DHA/EPA-mediated gut microbiota mimicked the ameliorative effect of DHA/EPA on glucose homeostasis in db/db mice, together with similar changes in gut metabolites. In vitro, DHA/EPA treatment directly inhibited the growth of Escherichia coli (Family Enterobacteriaceae) while promoted Coriobacterium glomerans (Family Coriobacteriaceae), demonstrating a causal effect of DHA/EPA on featured gut microbiota. DHA and EPA dramatically attenuated hyperglycemia and insulin resistance in db/db mice, which was mediated by alterations in gut microbiome and metabolites linking gut to adipose, liver and pancreas. These findings shed light into the gut-organs axis as a promising target for restoring glucose homeostasis and also suggest a better therapeutic effect of EPA for treating diabetes. Video abstract The online version contains supplementary material available at 10.1186/s40168-021-01126-6.

二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）被认为可预防代谢紊乱的发生。然而，它们在治疗高血糖方面的个体作用以及在糖尿病背景下对肠道微生物组和代谢组的作用机制仍不清楚。 在db/db小鼠中，补充DHA和EPA可减轻高血糖和胰岛素抵抗，且不改变体重，而EPA的改善作用似乎更为显著。DHA/EPA补充剂降低了含脂多糖的肠杆菌科的丰度，同时提高了与谷氨酸水平呈负相关的科里杆菌科、与胆汁酸产生相关的巴恩斯氏菌属和梭菌XlVa、有益的双歧杆菌和乳酸杆菌以及产生短链脂肪酸的菌种。肠道微生物组的改变与代谢组的变化同时发生，包括谷氨酸、胆汁酸、丙酸/丁酸和脂多糖，这些变化随后减轻了β细胞凋亡，抑制了肝脏糖异生，促进了胰高血糖素样肽 - 1（GLP - 1）分泌、白色脂肪米色化和胰岛素信号传导。所有这些变化对于EPA似乎更为明显。此外，移植经DHA/EPA调节的肠道微生物群模拟了DHA/EPA对db/db小鼠葡萄糖稳态的改善作用，同时肠道代谢物也有类似变化。在体外，DHA/EPA处理直接抑制大肠杆菌（肠杆菌科）的生长，同时促进肾小球科里杆菌（科里杆菌科）的生长，证明了DHA/EPA对特定肠道微生物群的因果作用。 DHA和EPA显著减轻了db/db小鼠的高血糖和胰岛素抵抗，这是由肠道微生物组和代谢物的改变所介导的，这些改变将肠道与脂肪、肝脏和胰腺联系起来。这些发现揭示了肠道 - 器官轴作为恢复葡萄糖稳态的一个有希望的靶点，也表明EPA在治疗糖尿病方面具有更好的治疗效果。 视频摘要 网络版包含补充材料，可在10.1186/s40168 - 2021 - 01126 - 6获取。