Management of chronic low-grade inflammation through plant sterol supplementation: A randomized trial in subjects with obesity

Introduction: Obesity is linked to chronic low-grade inflammation. Although plant sterols (PS) can exert anti-inflammatory effects, evidence in obesity remains scarce. To date, the only trial in this population reported non-significant changes in pro-inflammatory cytokines after PS supplementation. Methodology: A randomized, double-blind, placebo-controlled crossover trial included 23 subjects with overweight/class I–III obesity (BMI: 36.4 ± 4.2 kg/m²) and mild hypercholesterolemia (LDL > 115 mg/dL) (NCT06481020). Participants received 2 g/day of PS or placebo for 8 weeks (6-week washout). Inflammatory cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12p70, TNF-α) and endothelial markers (ICAM-1, VCAM-1, E-selectin, endothelin-1, PAI-1, nitric oxide, fibrinogen) were measured in serum at baseline and after each treatment. Pearson and Spearman correlations with serum PS were computed. Results and Discussion: Endothelin-1 and fibrinogen were excluded (>30% of patients below the detection limit or with pre-analytical issues, respectively). No significant changes (p > 0.05) were observed in the remaining markers after PS supplementation. However, substantial inverse correlations were found between serum PS and IL-1β, IL-12p70 and ICAM-1 (r = ‒0.56 to ‒0.37). These findings support an absorption-dependent anti-inflammatory effect of PS, consistent with inverse correlations between serum PS and IL-6 or endothelin-1 reported in normal-weight hypercholesterolemic subjects. IL-1β and IL-12p70 are mainly macrophage-derived following NLRP3 inflammasome activation and M1 polarization, processes linked to intracellular cholesterol handling and triggered by cholesterol crystals forming in sterol-rich membrane microdomains. Once absorbed, PS can incorporate into macrophage membranes, modifying these microdomains by displacing cholesterol, which may reduce IL-1β and IL-12p70 secretion. In contrast, IL-6 and IL-8 in obesity are largely adipose-tissue-derived and NF-κB-regulated, possibly explaining the absence of correlations for these cytokines. Conclusions: PS supplementation could exert an absorption-dependent anti-inflammatory effect in subjects with overweight or class I–III obesity. Further studies are needed to confirm these findings.