What is already known on this topic
Flavonoids are molecules found in chocolate, fruit, tea and other foods, which have been shown to help prevent or treat conditions such as type-2 diabetes and obesity. How these compounds exert their beneficial activities is unclear, as their oral bioavailability is limited.
What this research adds
One hypothesis is that bacterial metabolites produced from flavonoid precursors may be responsible for the anti-diabetic effects of flavonoids. To test this hypothesis, the researchers have studied the activity of a flavonoid precursor and its bacterial metabolites on β-cell function as well as skeletal muscle glucose utilization and respiration.
Flavonoid microbial metabolites stimulate insulin secretion in β-cells, increase skeletal muscle glucose utilization and protect skeletal mitochondrial function from oxidative injury. Although further investigation of flavonoid activity is needed, this study supports the hypothesis that dietary flavonoids could exert anti-diabetic effects through their microbial metabolites.
Bacterial metabolites produced from flavonoid precursors could contribute to the anti-diabetic effects associated with dietary flavonoids. That’s the conclusion of a study by Benjamin Bitner and his colleagues at Brigham Young University in Provo, Utah, published in Journal of Nutritional Biochemistry.
Type-2 diabetes and obesity are on the rise worldwide. Flavonoids – compounds found in foods such as chocolate and fruit – have been shown to help prevent or treat these conditions. But the bioavailability of many flavonoids is limited when the compounds are administered orally, leading to low circulating concentrations, so it’s unclear how they exert their beneficial activities.
Unabsorbed flavonoids reach the gut, where they are metabolized by the resident microbiota to smaller metabolites that are more bioavailable than the native compounds. Because these metabolites are detected in the blood at higher concentrations than their flavonoid precursors, it is possible that bacterial metabolites may contribute to the positive health outcome associated with dietary flavonoids.
To investigate the anti-diabetic effects of these metabolites, the researchers examined the anti-diabetic activities of three classes of flavonoid metabolites in insulin-producing cells and skeletal muscle cells, and then compared these activities to those of a flavonoid precursor.
Microbial metabolites enhance glucose utilization in skeletal muscle
First, the researchers tested the ability of the native flavonoid (epicatechin, EC) and the three metabolites (hippuric acid, HA, homovanillic acid, HVA, and 5-phenylvaleric acid, 5PVA) to affect fatty acid and glucose uptake and metabolism in primary human skeletal muscle cells. Although the compounds had almost no effect on fatty acid oxidation, they did alter glucose oxidation. In particular:
- EC proved to be the most potent stimulator of glucose oxidation, increasing glucose metabolism at concentrations of 10 and 25 μM
- 5PVA and HA were able to increase glucose utilization at 25 μM, while HA had no effect
Although EC is more effective than its metabolites, these compounds are found in the blood at higher levels than the native compound, suggesting that they could have positive effects on glucose levels in vivo.
Microbial metabolites protect skeletal mitochondrial function from injury
Next, the researchers studied the effects of EC and the three metabolites on respiration in C2C12 cells. The compounds did not change skeletal muscle respiration at low doses in uninjured cells. But in cells treated with peroxide to induce mitochondrial injury, most of the compounds had protective effects at 5 μM, reducing leak respiration and maintaining maximal respiration at levels comparable to those of uninjured cells.
Microbial metabolites stimulate insulin secretion in β-cells
The team also investigated the effects of EC and the three flavonoid metabolites on glucose-stimulated insulin secretion (GSIS) in β-cells. EC improved GSIS only at high, non physiologically-relevant concentrations (100 μM), while HA, 5PVA, and HA induced GSIS at lower doses, ranging from 5 to 100 μM.
To test the impact of these compounds on β-cells, the researchers looked at the cellular insulin content in the presence of glucose.
- EC caused small increases in insulin content, but with inconsistent effects across concentrations
- 5PVA and HVA resulted in bigger increase of insulin content, especially at lower doses (5-10 μM)
- HA caused only a slight increase in insulin content at 50 μM
Then, the researchers tested the effect of EC and its metabolites on β-cell mitochondrial respiration in the presence of low or high glucose. In both cases, EC increased basal respiration rate, whereas the metabolites had no significant effect.
The results suggest that flavonoid microbial metabolites could enhance β-cell function by stimulating insulin production and secretion, but their mechanism of action doesn’t involve the alteration of mitochondrial respiration. The metabolites didn’t change the expression of electron-transport chain components either, suggesting that they increase GSIS through extra-mitochondrial modifications.
The study shows that flavonoid microbial metabolites have beneficial effects on β-cell function as well as skeletal muscle glucose utilization and respiration. This is in line with the hypothesis that dietary flavonoids could exert anti-diabetic effects through their microbial metabolites.
The results also suggest that native flavonoids and their metabolites act through distinct mechanisms, therefore more work is needed to elucidate the impact of these compounds on health outcomes.