By Mercy Kagoda, MD
Private Practitioner, Pasadena, CA
SUMMARY POINTS
- High dietary intake of flavonoids (berries, red wine, apples/pears) is associated with increased gut microbial biodiversity, lower Parabacteroides, increased unclassified Ruminococcaceae, up to 4 mmHg lower systolic blood pressure, and lower pulse pressure.
- Up to 15% of the association between systolic blood pressure and dietary flavonoids is explained by the changes in the gut microbiome.
SYNOPSIS: Participants from the Population-Based Recruitment for Genetic Research (PopGen) control cohort who consumed the highest intake of dietary flavonoids (berries [1.6 portions per day]), red wine [250 mL per week], and apples/pears [1.6 portions per day]) had greater gut microbial biodiversity and up to 4 mmHg lower systolic blood pressure and pulse pressure compared to those with the lowest intakes.
SOURCE: Jennings A, Koch M, Bang C, et al. Microbial diversity and abundance of Parabacteroides mediate the associations between higher intake of flavonoid-rich foods and lower blood pressure. Hypertension 2021;78:1016-1026.
Flavonoids may be obtained from dietary sources, including tea, chocolate, red wine, and specific fruits, such as berries. Once ingested, flavonoids are metabolized in the liver and gastrointestinal tract, and various factors, such as age and sex, may affect the metabolic processes and bioavailability.1 During digestion, flavonoids reach the colon, where they are exposed to colonic microbiomes and interact with and modulate the microbiome.
Both human and animal studies have shown an increase in Bifidobacterium with increased dietary intake of anthocyanin-rich berries. High levels of Bifidobacterium are associated with increased metabolites of anthocyanin in urine, such as homovanillic acid, p-coumaric acid, syringic acid, and 4-hydroxybenzoic acid. These metabolites of anthocyanin have been shown to improve lipid profiles and offer a cardioprotective effect. Anthocyanin metabolites upregulate the antioxidant protein heme oxygenase-1, which is associated with a decrease in vascular resistance and a consequent decrease in blood pressure.
This study provides additional information on the gut microbiome’s mediating effect on dietary flavonoid intake association with systolic and diastolic blood pressure. This is a cross-sectional study, with the study population recruited from the Population-Based Recruitment for Genetic Research (PopGen) control cohort in Germany.
PopGen is internationally recognized as a large-scale genetic epidemiological project.2 Nine hundred four participants from PopGen aged 25 to 82 years were included in this study.
Data collection included participant characteristics (including age, sex, medication use, smoking status, and self-reported physical activity), systolic and diastolic blood pressure measurement (three times within 15 minutes), gut microbiome composition analysis using fecal bacterial deoxyribonucleic acid, and retrospective dietary intake of the previous year using a 112-item validated Food Frequency Questionnaire (validation using doubly labeled water, urinary nitrogen, and repeated 24-hour dietary recall method).
Characteristics of the participants included sex, age, self-reported physical activity, smoking status, body mass index (BMI), use of blood pressure medication, family history of coronary heart disease, systolic and diastolic blood pressure, pulse pressure, proportions of foods consumed (apples/pears, berries, strawberries, grapes, red wine, tea, peppers, daily caloric and fiber intake), and total flavonoid intake. The flavonoid intake was further stratified into the six categories: flavanones, anthocyanins, flavan-3-ols, flavanols, flavones and polymers (specifically proanthocyanidins).
Statistical analysis included use of independent t tests for continuous variables, chi-square tests for categorical variables, analysis of covariance (ANCOVA) for evaluation of the associations of categorical variables on the continuous variables, and conducting a stratified analysis to check for effect modification. Shannon index and Bray-Curtis dissimilarity measure were used to define the microbial diversity. The Shannon index is a mathematical measure used to quantify diversity; it provides information about the commonness of a species or the rarity of a species. The Bray-Curtis dissimilarity measure is used to quantify differences in species between different sites. For sites that share the same species, the measure is 0, and for those that do not share any species, the measure is 1. Sometimes this measure is represented as a percentage.
Linear discriminant analysis effect size, per the Huttenhower Lab at the Harvard School of Public Health, “determines the features (organisms, clades, operational taxonomic units, genes, or functions) most likely to explain differences between classes by coupling standard tests for statistical significance with additional tests encoding biological consistency and effect relevance.”3 Structural equation modeling helps to qualify the relationship among variables and also to take into account the measurement of error to accurately assess effects, and the Benjamini-Hochberg method avoids false positives.
Results showed that higher dietary intake of total flavonoids, specifically anthocyanins and proanthocyanidins polymers, were associated with statistically significant lower systolic blood pressure and pulse pressure. Higher dietary intake of flavan-3-ols was associated with statistically significant lower systolic blood pressure, but not pulse pressure. Higher dietary intake of flavonols and flavones were associated with statistically significant lower pulse pressure. None of the flavonoids categories were associated with statistically significant lower diastolic blood pressure.
Higher dietary intake of apples/pears (Q4 - Q1 = -0.3 [95% confidence interval (CI), -0.4 to -0.1]) and berries (Q4 - Q1= -0.2 [95% CI, -0.4 to -0.1]) were significantly associated with lower Parabacteroides abundance. Higher dietary intake of only berries was significantly associated with lower Clostridium XIVa Q4 - Q1= -0.1 (95% CI, -0.2 to -0.01) and significantly higher Roseburia abundance (Q4 - Q1 = 0.1 [95% CI, 0.03 to 0.3]).
Parabacteroides abundance was associated with significantly higher systolic blood pressure, while higher abundance of unclassified Ruminococcaceae was associated with lower systolic blood pressure and pulse pressure. Up to 15.2% of the association between systolic blood pressure and flavonoid foods could be explained by the gut microbiome. Specifically, 7.9% of the association between systolic blood pressure and dietary berry intake could be explained by Parabacteroides and 9.6% by unclassified Ruminococcaceae. For a more comprehensive look at the results and data, visit https://bit.ly/30yaWOP and see Tables 1 and 2.
COMMENTARY
Hypertension is one of the major modifiable risk factors for cardiovascular diseases. There are pharmacological and nonpharmacological approaches to managing hypertension. Effective lifestyle modification can lower blood pressure by at least as much as a single antihypertensive drug.4 Most lifestyle interventions lead to a reduction in diastolic blood pressure. Although this study did not show any statistically significant effect on diastolic blood pressure, there was a 3.7-4.8 mmHg decrease in systolic blood pressure. As noted in the discussion, a reduction of systolic blood pressure of 3.7-4.8 mmHg likely has some clinical benefit, since prior studies have shown that systolic blood pressure reduction of 5 mmHg reduces the risk of stroke by 13% over almost 300,000 patient years.
This study was not using diet as an intervention; therefore, one could hypothesize that, with the use of flavonoid-rich dietary intake as an intervention to manage hypertension, an even greater significant change in systolic blood pressure could be expected. The main strength of this study was that different categories of flavonoids and their effects on different bacteria was highlighted — neither the gut microbiome nor flavonoids were lumped in one category.
Fecal transplantation already is being used for treatment of recurrent Clostridium difficile colitis. Various human and animal model studies have implicated the gut microbiome in metabolic syndrome and obesity.5 Another strength of this study is that it described the effect of modulating gut microbiome to control blood pressure with a validated food questionnaire.
Possible questions for future studies include: Are there synergistic foods that increase the bioavailability of these cardioprotective compounds? Could there be a dose response to blood pressure change with increasing servings of specific flavonoid-rich foods? At what quantity of flavonoid-rich food intake could diastolic blood pressure be decreased significantly?
In summary, this study showed that a high dietary intake of 1.6 portions a day of berries and apples/pears, and 2.8 glasses (250 mL) per week of red wine is associated with increased gut microbial biodiversity, lower Parabacteroides, increased unclassified Ruminococcaceae, and up to 4 mmHg lower systolic blood pressure. Clinicians may recommend berries, apples, and pears to patients with hypertension to help them decide which fruits to consume. There are other well-known dietary and lifestyle interventions (such as Dietary Approaches to Stop Hypertension, the Mediterranean diet, increasing physical activity, and weight loss) that should be maximized for those patients open to nonpharmacological approaches to controlling hypertension.
REFERENCES
- Cassidy A, Minihane AM. The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. Am J Clin Nutr 2017;105:10-22.
- Krawczak M, Nikolaus S, von Eberstein H, et al. PopGen: Population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships. Community Genet 2006;9:55-61.
- The Huttenhower Lab. LefSe. https://huttenhower.sph.harvard.edu/lefse/
- Nicoll R, Henein MY. Hypertension and lifestyle modification: How useful are the guidelines? Br J Gen Pract 2010;60:879-880.
- John GK, Mullin GE. The gut microbiome and obesity. Curr Oncol Rep 2016;18:45.
Results showed that higher dietary intake of total flavonoids, specifically anthocyanins and proanthocyanidins polymers, were associated with statistically significant lower systolic blood pressure and pulse pressure.
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