Research News

Eating a plant-based diet full of flavonoid-rich “superfoods” has been associated with beneficial effects in combating diseases like obesity, Type II diabetes, cardiovascular disease, inflammatory bowel diseases and colon cancer.

Cleveland Clinic researchers are digging deeper to discover why flavonoids – which are abundant in foods like berries, citrus fruits, legumes and teas – seem so beneficial. Their findings highlight the complexity of the gut microbiome and explain why a diet rich in these foods might not provide the same effects for everyone.

When bacteria in the gut break down these components into a substance called 4-HPAA, it alters how our body metabolizes energy, according to results published in the Proceedings of the National Academy of Sciences.

These changes allow the body to more readily process fat. 4-HPAA was associated with reducing obesity and reversing fatty liver disease in preclinical models. The catch: the research showed about only one in a hundred people have all the bacterial enzymes necessary to process flavonoids and produce 4-HPAA.

The findings reinforce that flavonoids can be useful for health conditions like obesity, but provide evidence that supporting a healthy gut microbiome is key to unlocking these benefits.

Jan Claesen, PhD, Cardiovascular and Metabolic Sciences, says that the results could shift focus in the flavonoid research field from the flavonoids themselves to metabolites, the bacterial enzymes in the gut that are responsible for breaking down flavonoids.

“The flavonoid research field is huge, but with this study we begin to chip away at understanding the molecular processes by which they provide health benefits,” Dr. Claesen says. “We can then potentially take advantage of these pathways to personalize nutrition interventions or introduce probiotics to replace missing enzymes that provide these benefits.”

There are four bacterial enzymes necessary to produce 4-HPAA. These enzymes are encoded by specific bacterial genes. Dr. Claesen’s team analyzed genetic data to find out how often these genes occur. The genes were only found in the gut microbes of 7% of healthy people and the full, four-gene pathway required for 4-HPAA production only occurred in about 1% of the population.

Genetics and other factors, like diet, influence the bacteria in the gut. To translate into medical interventions, researchers in Dr. Claesen’s lab are investigating how to cultivate and maintain bacteria in the gut that would produce the necessary enzymes to break down flavonoids.

Clarifying what types of flavonoids break down in response to different enzymes could lead to doctors being able to recommend foods based on the patient’s microbiome. Probiotics are also an avenue for reintroducing and maintaining bacteria populations that could produce these enzymes, but basic research is fundamental to understanding the complex gut microbiome to produce these effects.

 “While others have alluded to the importance of the gut microbiota in this process, our study was the first to directly show this involvement and demonstrates the effects for 4-HPAA as a microbial metabolite,” Dr. Claesen says. “Overall, I expect this will lead to a shift of focus in the field, away from studying the flavonoids themselves, and instead focusing on the gut microbial metabolites.”

Medical interventions need to focus on the enzymes the bacteria produce, not just the name of the species, according to the study. Two bacteria within the same species, like F. plautii, can have different genetic configurations. This would affect the bacteria’s ability to produce the enzymes to break down flavonoids into 4-HPAA.

“The implication for medical interventions is that it’s not sufficient to look for bacteria called F. plautii in someone’s microbiome, because only a subset of F. plautii have the genes to produce relevant enzymes,” Dr. Claesen says. “Two bacteria can both be named F. plautii because of their evolutionary relation, yet they can have distinct metabolic capabilities.”