Background 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. Results 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. Conclusions 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.

Background Whether consumption of egg and cholesterol is detrimental to cardiovascular health and longevity is highly debated. Data from large-scale cohort studies are scarce. This study aimed to examine the associations of egg and cholesterol intakes with mortality from all causes, cardiovascular disease (CVD), and other causes in a US population. Methods and findings Overall, 521,120 participants (aged 50–71 years, mean age = 62.2 years, 41.2% women, and 91.8% non-Hispanic white) were recruited from 6 states and 2 additional cities in the US between 1995 and 1996 and prospectively followed up until the end of 2011. Intakes of whole eggs, egg whites/substitutes, and cholesterol were assessed by a validated food frequency questionnaire. Cause-specific hazard models considering competing risks were used, with the lowest quintile of energy-adjusted intake (per 2,000 kcal per day) as the reference. There were 129,328 deaths including 38,747 deaths from CVD during a median follow-up of 16 years. Whole egg and cholesterol intakes were both positively associated with all-cause, CVD, and cancer mortality. In multivariable-adjusted models, the hazard ratios (95% confidence intervals) associated with each intake of an additional half of a whole egg per day were 1.07 (1.06–1.08) for all-cause mortality, 1.07 (1.06–1.09) for CVD mortality, and 1.07 (1.06–1.09) for cancer mortality. Each intake of an additional 300 mg of dietary cholesterol per day was associated with 19%, 16%, and 24% higher all-cause, CVD, and cancer mortality, respectively. Mediation models estimated that cholesterol intake contributed to 63.2% (95% CI 49.6%–75.0%), 62.3% (95% CI 39.5%–80.7%), and 49.6% (95% CI 31.9%–67.4%) of all-cause, CVD, and cancer mortality associated with whole egg consumption, respectively. Egg white/substitute consumers had lower all-cause mortality and mortality from stroke, cancer, respiratory disease, and Alzheimer disease compared with non-consumers. Hypothetically, replacing half a whole egg with equivalent amounts of egg whites/substitutes, poultry, fish, dairy products, or nuts/legumes was related to lower all-cause, CVD, cancer, and respiratory disease mortality. Study limitations include its observational nature, reliance on participant self-report, and residual confounding despite extensive adjustment for acknowledged dietary and lifestyle risk factors. Conclusions In this study, intakes of eggs and cholesterol were associated with higher all-cause, CVD, and cancer mortality. The increased mortality associated with egg consumption was largely influenced by cholesterol intake. Our findings suggest limiting cholesterol intake and replacing whole eggs with egg whites/substitutes or other alternative protein sources for facilitating cardiovascular health and long-term survival. Trial registration ClinicalTrials.gov NCT00340015.

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