Clustering according to urolithin metabotype explains the interindividual variability in the improvement of cardiovascular risk biomarkers in overweight-obese individuals consuming pomegranate: A randomized clinical trial

Scope: The pomegranate lipid-lowering properties remain controversial, probably due to the interindividual variability in polyphenol (ellagitannins) metabolism. Objective: We aimed at investigating whether the microbially derived ellagitannin-metabolizing phenotypes, i.e. urolithin metabotypes A, (UM-A), B (UM-B), and 0 (UM-0), influence the effects of pomegranate extract (PE) consumption on 18 cardiovascular risk biomarkers in healthy overweight-obese individuals. Methods and results: A double-blind, crossover, dose-response, randomized, placebo-controlled trial was conducted. The study (POMEcardio) consisted of two test phases (dose-1 and dose-2, lasting 3 weeks each) and a 3-week washout period between each phase. Forty-nine participants (BMI > 27 kg/m(2)) daily consumed one (dose-1, 160 mg phenolics/day) or four (dose-2, 640 mg phenolics/day) PE or placebo capsules. Notably, UM-B individuals showed the highest baseline cardiovascular risk. After dose-2, total cholesterol (-15.5 +/- 3.7%), LDL-cholesterol (-14.9 +/- 2.1%), small LDL-cholesterol (-47 +/- 7%), non-HDL-cholesterol (-11.3 +/- 2.5%), apolipoprotein-B (-12 +/- 2.2%), and oxidized LDL-cholesterol -24 +/- 2.5%) dose dependently decreased (P < 0.05) but only in UM-B subjects. These effects were partially correlated with urolithin production and the increase in Gordonibacter levels. Three (50%) nonproducers (UM-0) became producers following PE consumption. Conclusions: UM clustering suggests a personalized effect of ellagitannin-containing foods and could explain the controversial pomegranate benefits. Research on the specific role of urolithins and the microbiota associated with each UM is warranted.