A-079 Investigation of gut microbial flavonoid catabolites in metabolic diseases
Authors: Alqudah S 
Published: October 2024

Abstract

Background
Flavonoids, a secondary metabolite found in plant-based diets, have gained attention in the last decade for their antioxidative properties in high-fat diet induced obesity animal models and human studies. Previous work showed that certain gut microbiota members can metabolize flavonoids into monophenolic acids (MPAs), and some of these MPAs have similar effects to insulin when administered orally. Our objective is to explore the microbiome connection between flavonoid-rich diets and improved metabolic parameters in obesity. We hypothesize that flavonoid-supplemented diets are most effective in the presence of gut microbiota capable of MPA formation and that these bacterial metabolites are the main bioactive compounds responsible for the improved 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% berry extract for 12 weeks. Each group was further divided into subgroups that received regular drinking water (RW) or antibiotic water (ABW) to suppress gut microbial communities. A range of metabolic parameters, such as body weight, lean and fat mass, glucose and insulin tolerance, histological assessment of liver cells, quantification of liver injury biomarkers, transcriptional changes in metabolically active tissues, and glucose and lipid metabolism pathways, were monitored. Additionally, 16s sequencing was performed on the cecal microbial composition of each group.

Results
Mice on HFD control with RW or ABW showed prominent hepatic steatosis and an increase in liver lipids accumulation demonstrated by a significant decrease in the activation of lipid metabolism pathways. Similarly, mice on HFD with 1% MPA and RW or ABW exhibited a significant reduction in hepatic steatosis and an increase in the activation of the lipid metabolism pathways, regardless of gut microbiota presence. In line with our hypothesis, mice on HFD with 1% berry extract and RW showed a similar reduction in hepatic steatosis to both 1% MPA groups. However, mice on HFD with 1% berry extract and ABW displayed noticeable hepatic steatosis, indicating the loss of the positive effect provided by berry extract metabolites once gut microbiota was depleted by antibiotics. Insulin tolerance test revealed a gut microbial effect as well in the HFD with 1% berry extract, illustrated by a significant 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 insulin resistance. Although there were notable decreases in fasting blood glucose, there were no significant effects on fat and lean mass, insulin, glucagon, or liver injury marker levels. Finally, the mice on HFD with 1% berry extract had significantly more diverse cecal microbial communities than those fed HFD or HFD with 1% MPA.

Conclusions
Feeding mice a flavonoid-rich diet in the presence of intact gut microbiome can improve metabolic parameters associated with metabolic diseases, potentially preventing, or reversing these diseases. Our findings suggest promising avenues for treatment, such as dietary flavonoid supplementation with concurrent gut microbial probiotic therapy.