A-034 Prevention of Obesity and Metabolic Disorders Through a Gut Microbial Metabolite Derived from Polyphenol Supplementation in a High-Fat Diet

Background Obesity and metabolic disorders are growing problems, with both their prevalence and severity on the rise. However, a promising approach to address these conditions is the consumption of polyphenol-rich foods, such as colorful fruits and vegetables, which provide an accessible and cost-effective option for the prevention and management of metabolic diseases. Despite their health benefits, humans lack the enzymes capable of metabolizing polyphenols into health-improving metabolites, referred to as monophenolic acids (MPA). We hypothesize that the human gut microbiome plays a crucial role in metabolizing these polyphenols into bioactive metabolites, contributing to the observed improvements in metabolic parameters. Methods To investigate our hypothesis, we fed male and female C57BL/6 mice a high-fat control diet (HFD) or the same diet supplemented with 1% MPA or 1% elderberry extract for 12 weeks. Each group was further divided into subgroups; regular drinking water (RW) or antibiotic water (ABW) to suppress gut microbial communities. A range of metabolic parameters were measured, such as body weight, food intake, fasting glucose levels, a panel of gut hormones, glucose, and insulin tolerance, histological assessment of liver cells, and glucose and lipid metabolism pathways. Additionally, we measured MPAs produced by the gut microbiome in portal plasma using targeted liquid chromatography-tandem mass spectrometry. Finally, 16s sequencing was performed on the cecal microbial composition of each group. Results Consistent with our hypothesis, mice on HFD supplemented with 1% elderberry extract on RW showed a reduction in hepatic steatosis and inflammation compared to HFD control group receiving RW or ABW. However, mice on HFD with 1% elderberry extract on ABW exhibited hepatic steatosis, suggesting that the beneficial effects of elderberry extract metabolites were lost when antibiotics depleted the gut microbiota. This improvement in mice on HFD supplemented with 1% elderberry extract on RW is attributed to the increase in the activation of AMPKa, an enzyme known to increase fat oxidation and decrease fat synthesis in liver. Portal plasma samples from these mice were rich in 3-phenylpropionic acid, an MPA able to activate AMPKa in vitro. Furthermore, insulin tolerance tests revealed a gut microbial effect in the HFD with 1% elderberry extract, illustrated by a notable reduction in glucose levels after insulin injection and an increase in insulin sensitivity. In contrast, the HFD control mice experienced an increase in glucose levels after insulin injection and significant insulin resistance. Moreover, an improvement in glucose hemostasis and a marked decrease in fasting blood glucose was observed. Leptin levels were higher in the presence of 1% elderberry with an intact gut microbiome, and glucagon-like peptide-1 (GLP-1) was significantly higher in the ABW mice groups. Notably, the mice on HFD with 1% elderberry extract had significantly more diverse cecal microbial communities compared to the other experimental groups. Conclusion Feeding mice elderberry-supplemented HFD in the presence of an intact gut microbiome can improve and potentially prevent the metabolic parameters associated with metabolic diseases. Our findings suggest promising avenues for treatment, such as dietary polyphenol supplementation with concurrent gut microbial probiotic therapy