(PTFS15-04-26) Tocotrienol Supplementation Modulates Adipose MAPK10 Expression and Plasma Lipid Mediator Profiles Without Altering Gut Microbiome Composition in a 24 Week RCT Trial

Objectives: This study is (i) to evaluate the effects of 24‑week tocotrienol supplementation on gut microbiome composition and targeted plasma endocannabinoids and oxylipins, and (ii) to explore non‑targeted RNA sequencing profiles in adipose tissue of obese adults.

Methods: Forty‑nine obese adults were randomized to tocotrienol group (TT group; n=26; annatto tocotrienol softgel 430 mg, 70% purity, daily) or placebo group (n=23; 430 mg olive oil softgel, daily) for 24 weeks. Stool, fasting plasma (sub-group), and visceral adipose tissue (sub‑group) were collected at baseline and week 24. Fasted plasma was analyzed for endocannabinoids (eCB) and oxylipins (OxL) using targeted metabolomic methods. Gut microbiome was assessed via 16S rRNA amplicon sequencing of fecal DNA for analysis. Non‑targeted Poly(A) mRNA sequencing of adipose tissue was performed and analyzed statistically.

Results: After the 24‑week intervention, no statistical differences in gut microbiome profiles, including measures of community diversity and composition, were observed between the placebo and TT groups. Non‑targeted mRNA sequencing analysis revealed reduced MAPK10 expression in the TT group, compared with the placebo group. After 24 weeks, the TT group demonstrated reduced circulating levels of eCBs (1-AG, 2-AG) and arachidonic acid-derived oxylipins (5-HETE, 9-HETE, 15-HETE) compared to the placebo group. For the OxL and eCB, some significant time (20-HETE and N-C20:4n6-EA) and interactions (time x treatment) effects were found (5,6-DiHETE, 15-keto-PGE2, 9(10)-EpOME).

Conclusions: In obese adults, 24-week tocotrienol supplementation did not alter gut microbiome composition but was associated with reduced adipose MAPK10 expression and modulation of plasma eCB and OxL profiles. These coordinated molecular shifts indicate that tocotrienols may suppress obesity related, lipid driven inflammatory stress signaling independent of detectable microbiome changes, providing a mechanistic basis for their potential as a targeted metabolic and inflammatory intervention.

Funding Sources: School of Medicine Seed Grant, Texas Tech University Health Sciences Center. American River Nutrition, LLC, Hadley, MA. Laura W. Bush Institute for Women’s Health, Texas Tech University Health Sciences Center, Amarillo, TX.