(P26-009-25) Enterococcus faecalis Metabolizes Matairesinol to Enterolactone, Which Promotes E. faecalis Growth and Glut4-Dependent Glucose Uptake in Adipocytes

Objectives: 1) Assess the impact of matairesinol (MA) and enterolactone (ENL) on Enterococcus faecalis proliferation; 2) Determine whether E. faecalis metabolizes MA to ENL; 3) Evaluate the effects of MA and ENL on glucose uptake in 3T3-L1 differentiated adipocytes; 4) Investigate the underlying mechanisms driving these effects.

Methods: E. faecalis was exposed to either MA or ENL in a dose-dependent manner. Relative bacterial growth was measured by using spectrophotometry. The presence of ENL, in MA-treated cells, was analyzed via ELISA. 3T3-L1 differentiated adipocytes were exposed to ENL in the presence of selective chemical inhibitors of Glut4 and PI3K. Glucose uptake was measured by using the fluorescent glucose analog, 2-NBDG. Lysates from ENL-exposed cells were analyzed via ELISA for, IRS-1, Akt, GSK3, and AMPK phosphorylation.

Results: MA inhibited E. faecalis growth while ENL promoted its proliferation. Interestingly, E. faecalis metabolized MA to ENL and further metabolized ENL though the product has not yet been described. ENL significantly induced glucose uptake and Akt phosphorylation in 3T3-L1 adipocytes. These effects were blunted by selective chemical inhibitors of Glut4 and PI3K. ENL also inhibited GSK3, thus further supporting its role in promoting Akt-mediated glucose uptake. ENL did not affect IRS-1 nor AMPK phosphorylation, suggesting that ENL promotes glucose uptake via an Akt/Glut4-dependent mechanism.

Conclusions: In this study, we demonstrated that E. faecalis metabolizes MA into ENL, which promotes glucose uptake in 3T3-L1 adipocytes via an Akt/Glut4-dependent mechanism. The inhibition of GSK3 by ENL further supports the rationale that ENL promotes Akt-mediated glucose uptake, thus highlighting its potential therapeutic applications in regulating glucose homeostasis and attenuating the pathogenesis of metabolic disorders including obesity and T2D.

Funding Sources: This work was funded by the Virginia Academy of Science and the Liberty University School of Health Sciences and Department of Biology and Chemistry.