Gut microbiome plays a key role in metabolizing flavonoids to enhance their cardioprotective effects

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Flavonoid-rich foods, including berries, apples, pears and wine, appear to have a positive effect on blood pressure levels, an association that is partially explained by characteristics of the gut microbiome, according to new research published today in Hypertension, an American Heart Association journal.

“Our gut microbiome plays a key role in metabolizing flavonoids to enhance their cardioprotective effects, and this study provides evidence to suggest these blood pressure-lowering effects are achievable with simple changes to the daily diet,” said lead investigator of the study Aedín Cassidy, Ph.D., chair and professor in nutrition and preventive medicine at the Institute for Global Food Security at Queen’s University in Belfast, Northern Ireland.

Flavonoids are compounds found naturally in fruits, vegetables and plant-based foods such as tea, chocolate and wine, and have been shown in previous research to offer a variety of health benefits to the body. Flavonoids are broken down by the body’s gut microbiome – the bacteria found in the digestive tract.

Recent studies found a link between gut microbiota, the microorganisms in the human digestive tract, and cardiovascular disease (CVD), which is the leading cause of death worldwide. Gut microbiota is highly variable between individuals, and there are reported differences in gut microbial compositions among people with and without CVD.

With increased research suggesting flavonoids may reduce heart disease risk, this study assessed the role of the gut microbiome on the process. Researchers examined the association between eating flavonoid-rich foods with blood pressure and gut microbiome diversity.

The study also investigated how much variance within the gut microbiome could explain the association between intake of flavonoid-rich foods and blood pressure.

A group of 904 adults between the ages of 25 and 82, 57% men from Germany’s PopGen biobank were recruited for this study. (The PopGen biobank includes participants from a network of seven biobanks in Northern Germany.)

Researchers evaluated the participants’ food intake, gut microbiome and blood pressure levels together with other clinical and molecular phenotyping at regular follow-up examinations.

Participants’ intake of flavonoid-rich foods during the previous year was calculated from a self-reported food questionnaire detailing the frequency and quantity eaten of 112 foods. Flavonoid values were assigned to foods according to United States Department of Agriculture data on flavonoid content in food.

Gut microbiome for participants was assessed by fecal bacterial DNA extracted from stool samples. After an overnight fast, participants’ blood pressure levels were measured three times in three-minute intervals after an initial five-minute rest period.

Researchers also collected participants’ lifestyle information, including sex, age, smoking status, medication use and physical activity, as well as family history of coronary artery disease, the number of daily calories and fiber consumed, and each participant’s height and weight was measured to calculate BMI (body mass index).

The analysis of regular flavonoid intake with gut microbiome and blood pressure levels found:

  • Study participants who had the highest intake of flavonoid-rich foods, including berries, red wine, apples and pears, had lower systolic blood pressure levels, as well as greater diversity in their gut microbiome than the participants who consumed the lowest levels of flavonoid-rich foods.
  • Up to 15.2% of the association between flavonoid-rich foods and systolic blood pressure could be explained by the diversity found in participants’ gut microbiome.
  • Eating 1.6 servings of berries per day (one serving equals 80 grams, or 1 cup) was associated with an average reduction in systolic blood pressure levels of 4.1 mm Hg, and about 12% of the association was explained by gut microbiome factors.
  • Drinking 2.8 glasses (125 ml of wine per glass) of red wine a week was associated with an average of 3.7 mm Hg lower systolic blood pressure level, of which 15% could be explained by the gut microbiome.

“Our findings indicate future trials should look at participants according to metabolic profile in order to more accurately study the roles of metabolism and the gut microbiome in regulating the effects of flavonoids on blood pressure,” said Cassidy.

“A better understanding of the highly individual variability of flavonoid metabolism could very well explain why some people have greater cardiovascular protection benefits from flavonoid-rich foods than others.”

While this study suggests potential benefits to consuming red wine, the American Heart Association suggests that if you don’t drink alcohol already, you shouldn’t start. If you do drink, talk with your doctor about the benefits and risks of consuming alcohol in moderation.

According to a statement on dietary health by the American Heart Association, alcohol intake can be a component of a healthy diet if consumed in moderation (no more than one alcoholic drink per day for women and 2 alcohol drinks per day for men) and only by nonpregnant women and adults when there is no risk to existing health conditions, medication-alcohol interaction, or personal safety and work situations.

The authors note that participants for the study were from the general population, and the participants were unaware of the hypothesis. However, residual or unmeasured confounding factors (such as other health conditions or genetics) can lead to bias, thus these findings cannot prove a direct cause and effect, although the researchers did conduct a detailed adjustment in their analyses for a wide range of diet and lifestyle factors. The authors noted the focus of this study was on specific foods rich in flavonoids, not all food and beverages with flavonoids.

Co-authors are first author Amy Jennings, Ph.D.; Manja Koch, Ph.D.; Corinna Bang, Ph.D.; Andre Franke, Ph.D.; and Wolfgang Lieb, M.D., M.Sc. The authors’ disclosures are listed in the manuscript.


Flavonoids, which are exclusively plant secondary metabolites, are considered to bear many beneficial effects on health [1–5] and are assumed to contribute especially to a lower cardiovascular disease and cancer-related mortality [6,7]. Most flavonoids are taken up as a part of the human diet mainly as glycosides.

A portion of dietary flavonoids is absorbed in the small intestine following O-deglycosylation by epithelial enzymes. Flavonoid aglycons then undergo phase I/II transformation [8–10]. The major part of dietary flavonoids (or their phase I/II metabolites) reach the large intestine, where they are subject to transfor- mation by gut bacteria which can enhance or lower their bioavailability and biological activtity [11–14].

In particular, members of the genera Bifidobacterium and Lactobacillus were observed to O-deglycosylate, e.g., flavanone and isoflavone glycosides [11]. While O-deglycosylation was the most extensively described flavonoid deglycosylation, with many glycosides from flavonols (e.g., rutin in several vegetables), flavanones (often found in citrus fruits) and isoflavones (present mainly in soy products) as substrates, several bacteria also mediate C-deglycosylation from compounds such as isovitexin, e.g., from buckwheat. Additional flavonoid transformations involve demethylation, dehydroxylation, reduction, and C-ring cleavage [11].
Many described gut bacterial flavonoid-converting activities lack biochemical or ge- netic analyses and, therefore, sequences of the involved enzymes. Of the O-deglycosylating enzymes, six beta-galactosidases [15–17] and a set of flavonoid-active rhamnosidases [18] that cleave the terminal rhamnose subunit of flavonoid rhamnosides (e.g., rutin or naringin), resulting in the corresponding flavonoid glucosides [19–24], have been characterized (Table 1).

The more complex C-deglycosylating enzyme systems were studied in fewer gut bacteria [25–27] (Table 1). The C-deglycosylation system described in strain PUE is dependent on at least three enzymes, DgpABC, which are part of a large gene cluster including transporters and other accessory genes whose function in C-deglycosylation is unclear [26,27]. The C-deglycosylating enzyme system of Eubacterium cellulosolvens includes the five enzymes DfgABCDE [25].

Both corresponding enzyme complexes include at least one glycosyltransferase and an oxidoreductase. Phloretin hydrolysis as carried out by phloretin hydrolase [28,29] and the three-step conversion of daidzein to equol [30–32] are relatively well studied, while the gut bacterial enzymes involved in dehydroxylation and O-demethylation of flavonoids are not yet described. However, an O-demethylase from Eubacterium limosum ZL-II demethylates polyphenolic lignans, [33].

As with other character- ized O-demethylases [34,35], this enzyme system consisted of two methyltransferases (MT), a corroinoid protein (CP) and an activating enzyme (AE), and might also be responsible for the O-demethylation of flavonoid carried out by E. limosum and E. ramulus [36,37].

The enzymes involved in daidzein-to-equol conversion and their encoding genes have been characterized in Slackia eggerthella and Lactococcus strains [30,32,38,39]. At least three enzymes are involved in the complete conversion of daidzein to equol. All three were proposed to be reductases [30,32], although one of them was recently suggested to be a dismutase [38].

In addition, a dihydrodaidzein (DHD) racemase is employed for stereochemical conversion of DHD in some bacteria [30]. Besides the complete conversion from daidzein to equol estimated to occur in about half of the population [40–42], a large number of individuals carry bacteria catalyzing only the reduction of daidzein to DHD or O-desmethylangolensin [42,43].

Phloretin hydrolase (Phy) hydrolytically cleaves the C-C bond adjacent to the aromatic A-ring of phloretin and thereby produces phloroglucinol and 3-(4-hydroxyphenyl)propionic acid. The first Phy was discovered in E. ramulus [28,44]. The only other Phy has been found in the intestinal pathogenic Mycobacterium abscessis, showing a 30% amino acid sequence identity to that of E. ramulus [27].

The flavanone- and flavanol-cleaving reductase (Fcr), cleaving the heterocyclic C-ring of flavanones and flavanonols, was recently characterized in detail [45]. Earlier suggested to be an enoate reductase and to act in a concerted pathway together with a chalcone isomerase (CHI, [46]), the Fcr of E. ramulus was described to catalyze the conversion of, e.g., naringenin to phloretin also without CHI. Still, as CHIs [46–49] are responsible for the production of auronol from flavanonols [47], they could play a substantial role in flavonoid transformation in the human gut. Very recently, the characterization of an ene-reductase (Flr), catalyzing the reduction of the C ring double bond of flavones and flavonols, was published [50].

All of the above studies were performed with few flavonoid-modifying bacteria and the corresponding enzymes originate from a limited number of bacterial species. Isolation of these strains from fecal samples could be biased because of selective enrichment of cul- turable bacteria. Therefore, the research on gut-bacterial flavonoid modification published up to now does not display a complete picture of flavonoid transformation in the human gut: phenotypic studies on human fecal samples rely mainly on (partial) 16S rRNA gene sequencing and do not resolve bacterial species.

Thus, flavonoid-converting species might be missed. In addition, quantitative studies of flavonoid-converting bacteria are scarce. A recent study on the quantification of daidzein-to-equol-converting bacteria relied on primers targeting genes of involved reductases [52].

With the advent of metagenomic stud- ies, a closer look into the gene catalog of the human gut microbiome became feasible [53], but still, quantification and especially taxonomic affiliation of the genes of interest are challenging. Current bioinformatic methods offered the opportunity to assemble genomes from metagenomic data [54], which were also recently applied to human gut metagenome studies [55–57], opening up new ways to reveal flavonoid modification in the human gut.

Here, we aim to identify and quantify flavonoid-modifying bacteria in the human gut microbiota. For this, we screened the most recent combined human gut MAGs collec- tion, the Unified Human Gastrointestinal Protein or Genome (UHGP/UHGG) catalog of more than 280,000 assembled genomes, with a BLAST search using protein sequences of characterized flavonoid-modifying enzymes (Table 1) as queries. In addition, the presence, prevalence and abundance of bacterial species described to modify flavonoids was investi- gated. Based on the obtained data, a possible scenario of flavonoid modification by the identified human gut bacteria is presented.

reference link : https:// doi.org/10.3390/nu13082688


More information: Microbial Diversity and Abundance of Parabacteroides Mediate the Associations Between Higher Intake of Flavonoid-Rich Foods and Lower Blood Pressure, Hypertension (2021). www.ahajournals.org/doi/10.116 … TENSIONAHA.121.17441

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