Rationale: Evidence linking saturated fat intake with cardiovascular health is controversial. The associations of unsaturated fats with total and cardiovascular disease (CVD) mortality remain inconsistent, and data about non-CVD mortality are limited. Objective: To assess dietary fat intake in relation to total and cause-specific mortality. Methods and Results: We analyzed data of 521 120 participants aged 50 to 71 years from the National Institutes of Health-American Association of Retired Persons Diet and Health Study with 16 years of follow-up. Intakes of saturated fatty acids (SFAs), trans-fatty acids, monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) were assessed via food frequency questionnaires. Hazard ratios and 95%CIs were estimated using the Cox proportional hazards model. Overall, 129 328 deaths were documented during 7.3 million person-years of follow-up. In the replacement of carbohydrates, multivariable-adjusted hazard ratios of total mortality comparing extreme quintiles were 1.29 (95% CI, 1.25–1.33) for SFAs, 1.03 (1.00–1.05) for trans-fatty acids, 0.98 (0.94–1.02) for MUFAs, 1.09 (1.06–1.13) for animal MUFAs, 0.94 (0.91–0.97) for plant MUFAs, 0.93 (0.91–0.95) for PUFAs, 0.92 (0.90–0.94) for marine omega-3 PUFAs, 1.06 (1.03–1.09) for α-linolenic acid, 0.88 (0.86–0.91) for linoleic acid, and 1.10 (1.08–1.13) for arachidonic acid. CVD mortality was inversely associated with marine omega-3 PUFA intake ( P trend <0.0001), whereas it was positively associated with SFA, trans-fatty acid, and arachidonic acid intake. Isocalorically replacing 5% of the energy from SFAs with plant MUFAs was associated with 15%, 10%, 11%, and 30% lower total mortality, CVD, cancer, and respiratory disease mortality, respectively. Isocaloric replacement of SFA with linoleic acid (2%) was associated with lower total (8%), CVD (6%), cancer (8%), respiratory disease (11%), and diabetes mellitus (9%) mortality. Conclusions: Intakes of SFAs, trans-fatty acids, animal MUFAs, α-linolenic acid, and arachidonic acid were associated with higher mortality. Dietary intake of marine omega-3 PUFAs and replacing SFAs with plant MUFAs or linoleic acid were associated with lower total, CVD, and certain cause-specific mortality. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00340015.

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.

Scope: To assess the individual effects of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on insulin resistance (IR), gut microbiome, and gut metabolites in high-fat-diet-induced obese (DIO) mice. Methods and results: DIO mice are fed an either high-fat diet (HFD), EPA (1% w/w) enriched HFD, or DHA (1% wt/wt) enriched HFD for 15 weeks. Both EPA and DHA supplements reverse hyperglycemia and IR but do not affect body weight in DIO mice while DHA exhibits a more pronounced ameliorative effect in male mice. Both EPA-and DHA-enriched Lactobacillus and short-chain fatty acids (SCFAs)-producing species from Lachnospiraceae while reduced lipopolysaccharide (LPS)-producing Bilophila and Escherichia/Shigella. Compared with EPA, DHA-supplemented mice have more abundant propionic/butyric acid-producing bacteria, including Coprococcus, Butyricimonas synergistica, Bacteroides acidifaciens, and Intestinimonas, and less-abundant LPS-correlated species Streptococcus and p-75-a5.