(PTFS15-05-26) Urolithin A Production After Daily Walnut Intake Is Associated with Increased Esterified ALA-Derived Oxylipins and Lower LDL-Cholesterol Levels

Objectives: Walnuts provide essential fatty acids and ellagitannins, whose microbial derived metabolites, the urolithins (Uro) may positively alter lipid metabolism. We hypothesized that 12 weeks (wk) of daily walnut intake improves vascular function by increasing esterified epoxides and Uro A production in healthy postmenopausal women.

Methods: Twenty healthy postmenopausal women (age 57 ± 3.9 years) were enrolled into an 18 wk study, with data collection after an overnight fast scheduled before and after 6 wk of no walnut intake followed by 6 and 12 wk of daily walnut intake (40g/day). The primary endpoint was the reactive hyperemia index (RHI; EndoPAT2000). Secondary outcome measures included plasma cholesterol, along with plasma Uro and lipoprotein-esterified oxylipins assessed by liquid chromatography–mass spectrometry. Each participant’s walnut supplemental period was compared to 6 wk of no walnut intake, using standard least squares regression with treatment and time as factors, participant as a random effect and weight as a covariate. Statistical significance was set at p< 0.05 with a false discovery rate < 0.2.

Results: Walnut intake did not significantly change RHI (p=0.58). Low density lipoprotein-cholesterol (LDLc) was significantly lower during the walnut intake period compared to no walnut intake (127 ± 30 versus 134 ± 34, respectively; p = 0.01). Walnut intake significantly increased esterified alpha linoleic acid (ALA) levels (p < 0.0001) by 12%, with a corresponding increase in the ALA-derived epoxide 15,16 epoxyoctadecadienoic acid (15,16 EpODE; p< 0.0001), and its associated diol (15,16-DiHODE; p< 0.0001). Plasma levels of Uro A, Uro A-glucuronide, Iso-Uro A and Uro B were significantly increased with walnut intake, but not Uro B-glucuronide. In principle components analysis, the sum of Uro A metabolites was positively associated with 15,16-DiHODE and negatively associated with LDLc.

Conclusions: Daily walnut intake increases esterification of ALA fatty acids and 15,16-EpODE and -DiHODE; with the later positively associated with fasting plasma UroA levels while negatively associated with LDLc. The relationship between UroA and esterified ALA-derived epoxide metabolism warrants further exploration.

Funding Sources: California Walnut Commission