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The effect of polyphenols on DNA methylation-assessed biological age attenuation: the DIRECT PLUS randomized controlled trial.
Yaskolka Meir, A, Keller, M, Hoffmann, A, Rinott, E, Tsaban, G, Kaplan, A, Zelicha, H, Hagemann, T, Ceglarek, U, Isermann, B, et al
BMC medicine. 2023;21(1):364
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Biological age differs from chronological age and is determined by assessing our DNA, this is known as mAge. A healthy lifestyle and weight loss have been shown to be of benefit to mAge. The Mediterranean (MED) diet includes ingredients such as vitamins and naturally occurring chemicals, known as polyphenols, which may alter biological age. This randomised control trial of 256 aimed to determine the effects of a MED diet richer in green vegetables and lower in meat (Green-MED) compared to the MED diet and recommendations for healthy eating. The results showed that after 18 months of healthy eating and weight loss, none of the diets was able to lower the biological age, however the Green-MED diet and in particular the intake of green tea and the vegetable Mankai were associated with slower biological ageing compared to the other two diets. The polyphenol tyrosol was also associated with slower biological ageing. It was concluded that the diets were unable to reverse biological ageing, but a GreenMed diet rich in polyphenols, may be able to slow it. This study could be used by healthcare professionals to understand that as higher biological age is associated with poorer health outcomes, a diet rich in polyphenols may have additional benefits beyond just weight loss.
Abstract
BACKGROUND Epigenetic age is an estimator of biological age based on DNA methylation; its discrepancy from chronologic age warrants further investigation. We recently reported that greater polyphenol intake benefitted ectopic fats, brain function, and gut microbiota profile, corresponding with elevated urine polyphenols. The effect of polyphenol-rich dietary interventions on biological aging is yet to be determined. METHODS We calculated different biological aging epigenetic clocks of different generations (Horvath2013, Hannum2013, Li2018, Horvath skin and blood2018, PhenoAge2018, PCGrimAge2022), their corresponding age and intrinsic age accelerations, and DunedinPACE, all based on DNA methylation (Illumina EPIC array; pre-specified secondary outcome) for 256 participants with abdominal obesity or dyslipidemia, before and after the 18-month DIRECT PLUS randomized controlled trial. Three interventions were assigned: healthy dietary guidelines, a Mediterranean (MED) diet, and a polyphenol-rich, low-red/processed meat Green-MED diet. Both MED groups consumed 28 g walnuts/day (+ 440 mg/day polyphenols). The Green-MED group consumed green tea (3-4 cups/day) and Mankai (Wolffia globosa strain) 500-ml green shake (+ 800 mg/day polyphenols). Adherence to the Green-MED diet was assessed by questionnaire and urine polyphenols metabolomics (high-performance liquid chromatography quadrupole time of flight). RESULTS Baseline chronological age (51.3 ± 10.6 years) was significantly correlated with all methylation age (mAge) clocks with correlations ranging from 0.83 to 0.95; p < 2.2e - 16 for all. While all interventions did not differ in terms of changes between mAge clocks, greater Green-Med diet adherence was associated with a lower 18-month relative change (i.e., greater mAge attenuation) in Li and Hannum mAge (beta = - 0.41, p = 0.004 and beta = - 0.38, p = 0.03, respectively; multivariate models). Greater Li mAge attenuation (multivariate models adjusted for age, sex, baseline mAge, and weight loss) was mostly affected by higher intake of Mankai (beta = - 1.8; p = 0.061) and green tea (beta = - 1.57; p = 0.0016) and corresponded with elevated urine polyphenols: hydroxytyrosol, tyrosol, and urolithin C (p < 0.05 for all) and urolithin A (p = 0.08), highly common in green plants. Overall, participants undergoing either MED-style diet had ~ 8.9 months favorable difference between the observed and expected Li mAge at the end of the intervention (p = 0.02). CONCLUSIONS This study showed that MED and green-MED diets with increased polyphenols intake, such as green tea and Mankai, are inversely associated with biological aging. To the best of our knowledge, this is the first clinical trial to indicate a potential link between polyphenol intake, urine polyphenols, and biological aging. TRIAL REGISTRATION ClinicalTrials.gov, NCT03020186.
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Dietary polyphenols, metabolic syndrome and cardiometabolic risk factors: An observational study based on the DCH-NG subcohort.
Lanuza, F, Zamora-Ros, R, Bondonno, NP, Meroño, T, Rostgaard-Hansen, AL, Riccardi, G, Tjønneland, A, Landberg, R, Halkjær, J, Andres-Lacueva, C
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2023;33(6):1167-1178
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Metabolic syndrome (MetS) is a cluster of metabolic disorders that increases the risk of developing chronic diseases. Cardiometabolic risk factors include high waist circumference (WC), insulin resistance, hypertension, dysglycaemia, dyslipidaemia, and altered inflammatory markers. The aim of this study was to investigate the associations between intakes of polyphenols (total polyphenols and their main classes) and the prevalence of MetS and cardiometabolic risk factors. This study is an observational sub-cohort study of 676 Danish participants of the MAX study from the Danish Diet, Cancer and Health - Next Generations (DCH-NG) cohort. Results showed that individuals with higher total polyphenol and phenolic acid intakes, were less likely to have MetS. Furthermore, for cardiovascular risk factors, intakes of total polyphenols, flavonoids and phenolic acids were associated with a lower risk of higher systolic blood pressure and lower high-density lipoprotein cholesterol. Authors conclude by suggesting that intervention studies should be undertaken to establish whether a polyphenol-rich diet can improve some cardiometabolic risk factors and can reduce or delay the onset of cardiometabolic diseases in free-living populations.
Abstract
BACKGROUND AND AIMS Polyphenol-rich foods have beneficial properties that may lower cardiometabolic risk. We aimed to prospectively investigate the relationship between intakes of dietary polyphenols, and metabolic syndrome (MetS) and its components, in 676 Danish residents from the MAX study, a subcohort of the Danish Diet, Cancer and Health-Next Generations (DCH-NG) cohort. METHODS AND RESULTS Dietary data were collected using web-based 24-h dietary recalls over one year (at baseline, and at 6 and 12 months). The Phenol-Explorer database was used to estimate dietary polyphenol intake. Clinical variables were also collected at the same time point. Generalized linear mixed models were used to investigate relationships between polyphenol intake and MetS. Participants had a mean age of 43.9y, a mean total polyphenol intake of 1368 mg/day, and 75 (11.6%) had MetS at baseline. Compared to individuals with MetS in Q1 and after adjusting for age, sex, lifestyle and dietary confounders, those in Q4 - for total polyphenols, flavonoids and phenolic acids-had a 50% [OR (95% CI): 0.50 (0.27, 0.91)], 51% [0.49 (0.26, 0.91)] and 45% [0.55 (0.30, 1.00)] lower odds of MetS, respectively. Higher total polyphenols, flavonoids and phenolic acids intakes as continuous variable were associated with lower risk for elevated systolic blood pressure (SBP) and low high-density lipoprotein cholesterol (HDL-c) (p < 0.05). CONCLUSIONS Total polyphenol, flavonoid and phenolic acid intakes were associated with lower odds of MetS. These intakes were also consistently and significantly associated with a lower risk for higher SBP and lower HDL-c concentrations.
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Wild blueberry (poly)phenols can improve vascular function and cognitive performance in healthy older individuals: a double-blind randomized controlled trial.
Wood, E, Hein, S, Mesnage, R, Fernandes, F, Abhayaratne, N, Xu, Y, Zhang, Z, Bell, L, Williams, C, Rodriguez-Mateos, A
The American journal of clinical nutrition. 2023;117(6):1306-1319
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The risk of developing both cardiovascular and neurodegenerative diseases increases with aging. Growing evidence from epidemiological and human intervention trials indicates that (poly)phenols may have cardioprotective properties as well as the ability to improve cognitive function. The aim of this study was to investigate the effects of daily wild blueberry (WBB) (poly)phenol consumption on vascular function and cognitive performance in healthy older individuals. This study was a randomised, double-blinded, placebo-controlled parallel design study. A total of 61 healthy older individuals were recruited and randomly assigned to one of the two arms; placebo intervention or blueberry intervention group. Results showed that long-term consumption of a dietary achievable amount of WBB enhanced vascular and cognitive function in older adults. Authors conclude that gut microbiota and vascular blood flow may play important roles in mediating the cognitive benefits shown by the consumption of (poly)phenol-rich foods.
Abstract
BACKGROUND Evidence suggests that the intake of blueberry (poly)phenols is associated with improvements in vascular function and cognitive performance. Whether these cognitive effects are linked to increases in cerebral and vascular blood flow or changes in the gut microbiota is currently unknown. METHODS A double-blind, parallel randomized controlled trial was conducted in 61 healthy older individuals aged 65-80 y. Participants received either 26 g of freeze-dried wild blueberry (WBB) powder (302 mg anthocyanins) or a matched placebo (0 mg anthocyanins). Endothelial function measured by flow-mediated dilation (FMD), cognitive function, arterial stiffness, blood pressure (BP), cerebral blood flow (CBF), gut microbiome, and blood parameters were measured at baseline and 12 wk following daily consumption. Plasma and urinary (poly)phenol metabolites were analyzed using microelution solid-phase extraction coupled with liquid chromatography-mass spectrometry. RESULTS A significant increase in FMD and reduction in 24 h ambulatory systolic BP were found in the WBB group compared with the placebo group (0.86%; 95% CI: 0.56, 1.17, P < 0.001; -3.59 mmHg; 95% CI: -6.95, -0.23, P = 0.037; respectively). Enhanced immediate recall on the auditory verbal learning task, alongside better accuracy on a task-switch task was also found following WBB treatment compared with placebo (P < 0.05). Total 24 h urinary (poly)phenol excretion increased significantly in the WBB group compared with placebo. No changes in the CBF or gut microbiota composition were found. CONCLUSIONS Daily intake of WBB powder, equivalent to 178 g fresh weight, improves vascular and cognitive function and decreases 24 h ambulatory systolic BP in healthy older individuals. This suggests that WBB (poly)phenols may reduce future CVD risk in an older population and may improve episodic memory processes and executive functioning in older adults at risk for cognitive decline. Clinical Trial Registration number in clinicaltrials.gov: NCT04084457.
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Consumption of flavonoids and risk of hormone-related cancers: a systematic review and meta-analysis of observational studies.
Liu, F, Peng, Y, Qiao, Y, Huang, Y, Song, F, Zhang, M, Song, F
Nutrition journal. 2022;21(1):27
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Hormone-related cancers (HRCs) are greatly influenced by hormone levels and generally respond to hormone regulation, which plays an indispensable role in tumour growth. Encouragingly, diets rich in vegetables, fruits and tea are found to reduce the cancer risk, having the potential to exert chemo-preventive effects with the presence of anticarcinogenic phytochemicals. The aim of this study was to elucidate the association between flavonoids intake and HRCs risk. This study is a meta-analysis of fifty-one studies. It consisted of 22 prospective cohort studies, 1 nested case–control study, 18 population-based case–control studies and 10 hospital-based case–control studies. Results show that higher consumption of total flavonoids was only associated with an increased risk of men-specific cancers, mainly prostate cancer. Furthermore, the subclasses, flavanols, flavones, and isoflavones, and the three main individual compounds of isoflavones (daidzein, genistein and glycitein) may have protective effects on women-specific cancers, whereas flavones and flavanones have been found to cause potentially dangerous effects in thyroid cancer. Additionally, there was no evidence in support of any role for anthocyanidins in HRCs. Authors conclude that there is a small amount of evidence that total flavonoids, flavanols, flavones, flavanones, flavan-3-ols and isoflavones may be associated with a lower or higher risk of certain HRCs, which may provide guidance for dietary guidelines to a certain extent in the future.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Dietary flavonoids are widely available in plant-based foods such as vegetables, citrus fruits, green tea and berries
- Menopausal status may be an important consideration for flavonoid intake when considering breast cancer risk
- Differences in results for Asians and non-Asians need to be considered for the use of flavonoids in women-specific hormonal cancers and prostate cancer in men
- Caution should be exercised when considering flavones and flavanones and thyroid cancer risk until further research is available
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Background
Hormone-related cancers (HRCs) are the most frequently diagnosed cancers globally , accounting for more than a quarter of new cancer cases worldwide in 2018. They include breast, ovarian, endometrial, prostate, testicular and thyroid cancer which share a similar carcinogenic mechanism. Diets rich in vegetables, fruit, legumes and tea may reduce cancer risk due to anticarcinogenic phytochemicals, such as flavonoids. Flavonoids are claimed to have many different physiological and pathological functions in the cancer process, including tumour cell proliferation, inflammation, angiogenesis, invasion and metastasis.. This study aimed to summarise the relationships between consumption of flavonoids with the risk of HRC.
Methods:
The meta-analysis was carried out following PRISMA guidelines and registered on PROSPERO. A literature search in PubMed and Embase was conducted using the keywords flavonoids, flavanols and isoflavones and breast, ovarian, endometrial, prostate, testicular and thyroid cancer. 51 studies published between 1999 and 2022 consisted of 22 prospective cohort, 18 population-based and 10 hospital-based case-control studies. On the Newcastle-Ottawa Scale assessment all studies were of medium or high methodological quality.
Results:
Results were analysed using Stata 15.1 software and ORs with 95% CIs used to measure the association between flavonoid intake and HRCs risk. Statistical I2 evaluated heterogeneity among the studies.
Funnel plots were inspected for publication bias and calculated by Begg’s/Egger’s regression tests. Sensitivity analyses were performed to explore the source of heterogeneity. Subgroup analysis was performed on study design and region, as well as menopausal status.
Higher consumption of flavonoids was associated with a decreased risk of women-specific cancers but a significant elevated risk of prostate cancer as seen below.
Women specific cancers:
For flavonoid sub-classes, higher consumption of flavanols (OR=0.85; 95% CI, 0.76–0.94; I2=75.5%; p<0.001), flavones (OR=0.85; 95% CI, 0.77–0.95; I2=76.3%; p<0.001) and isoflavones (OR=0.87; 95% CI, 0.82–0.92; I2=73.8%; p<0.001) was associated with a decreased risk of women-specific cancers (breast, ovarian and endometrial), especially among the case–control studies. Similar results were seen in the main compounds of isoflavones: daidzen, genistein and glycitein. There were differences in the association between isoflavones in Asian and non-Asian regions.
Men-specific cancers:
The higher consumption of total flavonoids (OR=1.11; 95% CI, 1.02–1.21; I2 = 0%; p = 0.484) was associated with an increased risk of prostate cancer and this was only found in non-Asian populations.
Conclusion:
Despite limitations of the meta-analysis, such as the use of observational studies and small sample sizes of the included studies, this systematic review may provide some preliminary dietary evidence for the use of flavonoids in HRCs.
Clinical practice applications:
- The promotion of a plant-based diet, rich in vegetables, fruits, green tea and legumes may have protective effects on women-specific cancers due to the rich presence of flavanols, flavones and isoflavones, as well as the compounds genistein, glycitein and daidzein.
- Results show no associations between total flavonoids intake and women-specific cancer however, the sub-groups of flavanols, flavones and isoflavones were associated with a decreased risk in women-specific cancers. Similar results were seen in the individual compounds of isoflavones: genistein, glycitein and daidzein. These results may guide decision-making when recommending the inclusion of these compounds for protective benefits in women-specific cancers.
- The positive association between total flavonoids and prostate cancer risk was only seen in non-Asians, and between higher consumption of flavones and flavanones and thyroid cancer risk albeit in limited studies (n=3) may provide important guidelines when considering which foods to include from a plant-based diet.
Considerations for future research:
- Further meta-analysis of prospective studies with larger sample sizes
- The use of a validated and reliable questionnaire for measuring flavonoid intake
- Intervention studies evaluating flavonoid subclasses
- Comparisons between Asian and non-Asian populations
- Consideration of menopausal status as an effect modifier
Abstract
BACKGROUND Flavonoids seem to have hormone-like and anti-hormone properties so that the consumption of flavonoids may have potential effects on hormone-related cancers (HRCs), but the findings have been inconsistent so far. This meta-analysis was aimed to explore the association between flavonoids intake and HRCs risk among observational studies. METHODS Qualified articles, published on PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) from January 1999 to March 2022 and focused on relationships between flavonoids (total, subclass of and individual flavonoids) and HRCs (breast, ovarian, endometrial, thyroid, prostate and testicular cancer), were retrieved for pooled analysis. Random effects models were performed to calculate the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Funnel plots and Begg's/Egger's test were used to evaluate the publication bias. Subgroup analyses and sensitivity analyses were conducted to explore the origins of heterogeneity. RESULTS All included studies were rated as medium or high quality. Higher consumption of flavonols (OR = 0.85, 95% CI: 0.76-0.94), flavones (OR = 0.85, 95% CI: 0.77-0.95) and isoflavones (OR = 0.87, 95% CI: 0.82-0.92) was associated with a decreased risk of women-specific cancers (breast, ovarian and endometrial cancer), while the higher intake of total flavonoids was linked to a significantly elevated risk of prostate cancer (OR = 1.11, 95% CI: 1.02-1.21). A little evidence implied that thyroid cancer risk was augmented with the higher intake of flavones (OR = 1.24, 95% CI: 1.03-1.50) and flavanones (OR = 1.31, 95% CI: 1.09-1.57). CONCLUSIONS The present study suggests evidence that intake of total flavonoids, flavonols, flavones, flavanones, flavan-3-ols and isoflavones would be associated with a lower or higher risk of HRCs, which perhaps provides guidance for diet guidelines to a certain extent. TRIAL REGISTRATION This protocol has been registered on PROSPERO with registration number CRD42020200720 .
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The effect of high-polyphenol Mediterranean diet on visceral adiposity: the DIRECT PLUS randomized controlled trial.
Zelicha, H, Kloting, N, Kaplan, A, Yaskolka Meir, A, Rinott, E, Tsaban, G, Chassidim, Y, Bluher, M, Ceglarek, U, Isermann, B, et al
BMC medicine. 2022;20(1):327
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Visceral adipose tissue (VAT) accumulation is one of the main key factors that differentiate between metabolic healthy and unhealthy obese individuals. VAT is closely related to the development of multiple cardiovascular risk factors. The Mediterranean (MED) diet, high in polyphenol content and rich in plant food sources, was shown to have an enhanced effect on VAT reduction in combination with physical activity (PA), regardless of weight loss The aim of this study was to assess the effect of the MED diet, further enriched with polyphenols, and lower in red and processed meat (“green-MED diet”) on visceral adiposity in the 18-month Dietary Intervention Randomized Controlled Trial-Polyphenols, Unprocessed trial. This study is a randomised controlled trial. Participants were randomly assigned to one of three intervention groups (1:1:1 ratio): healthy dietary guidelines, MED diet, or green-MED diet, all included PA recommendations, with a free gym membership and educational sessions promoting moderate-intensity PA. Results show that participants following the green-MED diet achieved more than twice the degree of VAT reduction compared to those following the MED diet, despite similar weight loss. In fact, VAT loss was specifically related to lower red meat intake and increased walnuts, green tea, Wolfa globosa, and dietary fibre (this was reflected by higher plasma polyphenol and serum folate levels). Authors conclude that a green-MED diet enriched with polyphenols and decreased red meat consumption might serve as an improved version of the MED diet for targeted VAT reduction.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The positive health effects of the traditional MED diet, moderately high in PUFAs and MUFAs and low in red meat, are well-established
- Higher levels of total plasma polyphenol and serum folate may reflect higher consumption of “green” dietary components, which were significantly associated with greater VAT loss
- The green-MED diet, richer in dietary polyphenols and green plant-based proteins and lower in red meat, might be a more effective strategy for VAT loss than the traditional healthy MED diet, achieving more than twice the degree of VAT reduction, despite similar weight loss.
- VAT loss was specifically related to lower red meat intake and increased walnuts, green tea, Wolffia globosa, and dietary fibre and was reflected by higher plasma polyphenol and serum folate levels.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
A mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. Visceral adipose tissue (VAT) accumulation is one of the main factors that differentiate between metabolic healthy and unhealthy obese individuals.
In this Dietary Intervention Randomised Controlled Trial PoLyphenols UnproceSsed (DIRECT‐ PLUS) weight‐loss trial, 294 participants were randomised to: (A) healthy dietary guidelines (HDG), (B) MED, or (C) green‐MED diets, all combined with physical activity. The study duration was 18‐months.
This study explored the effect of the green‐MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT) and used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues.
Both isocaloric (with the same calorific value) MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green‐MED group further consumed green tea (3–4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake.
The mean weight loss (HDG: −0.4% (5.0), MED: −2.7% (5.6), green-MED: −3.9% (6.5)) and WC loss (HDG: −3.6% (5.1), MED: −4.7% (5.0), green-MED: −5.7%(5.7)) after 18 months were similar between the two MED diets (p > 0.05 for all) and higher as compared to the HDG (weight: HDG vs. MED: p = 0.02; HDG vs. green+MED: p < 0.001; WC: HDG vs. MED: p = 0.33, HDG vs. green+MED: p = 0.02).
All three abdominal fat depots decreased over 18 months of intervention (p < 0.05 vs. baseline for all). The green-MED group achieved a greater reduction in VAT than the other intervention groups (HDG: −4.2% (22.5), MED: −6.0%(31.3), green-MED: −14.1%(27.7); p < 0.05 green-MED vs. MED or vs. HDG groups). These differences in VAT loss across the groups remained significant after adjusting for age, sex, and 18-month WC change (green-MED vs. MED p = 0.023; green-MED vs. HDG p = 0.002) (Fig. 1)
Limitations of the study included a low proportion of women, and different VAT proportions at baseline across groups limit the generalisability of findings to women.
The authors of the study did not identify the exact components responsible for the dietary effects when they compared dietary regimens and not specific nutrients.
Adherence was by a validated, self-reported dietary intake assessment tool, which the authors acknowledge is subject to error
Strengths of the study included the relatively large sample size, high retention rate, and use of 3-T MRI measurements (considered one of the gold standards tools for the quantification of specific fat depots
Clinical practice applications:
- This trial shows that, when combined with a Mediterranean diet, higher dietary consumption of green tea, walnuts, and dietary fibre and reduced red meat consumption were significantly associated with greater %VAT loss
- The authors observed a significant synergistic interaction effect between decreased red meat consumption and increased serum folate on VAT loss
- A reduction in VAT accumulation, known as a key risk factor in CVD development, may reduce metabolic complications, improve the lipid profile, and decrease cardiometabolic risk.
Considerations for future research:
- Future studies are needed to explore the exact mechanisms of specific polyphenol-rich foods on visceral adiposity.
- Future studies could explore whether the results are replicable in both male and female participants, as this sample was largely male.
Abstract
BACKGROUND Mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. We explored the effect of the green-MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT). METHODS In the 18-month Dietary Intervention Randomized Controlled Trial PoLyphenols UnproceSsed (DIRECT-PLUS) weight-loss trial, 294 participants were randomized to (A) healthy dietary guidelines (HDG), (B) MED, or (C) green-MED diets, all combined with physical activity. Both isocaloric MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green-MED group further consumed green tea (3-4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake. We used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues. RESULTS Participants (age = 51 years; 88% men; body mass index = 31.2 kg/m2; 29% VAT) had an 89.8% retention rate and 79.3% completed eligible MRIs. While both MED diets reached similar moderate weight (MED: - 2.7%, green-MED: - 3.9%) and waist circumference (MED: - 4.7%, green-MED: - 5.7%) loss, the green-MED dieters doubled the VAT loss (HDG: - 4.2%, MED: - 6.0%, green-MED: - 14.1%; p < 0.05, independent of age, sex, waist circumference, or weight loss). Higher dietary consumption of green tea, walnuts, and Wolffia globosa; lower red meat intake; higher total plasma polyphenols (mainly hippuric acid), and elevated urine urolithin A polyphenol were significantly related to greater VAT loss (p < 0.05, multivariate models). CONCLUSIONS A green-MED diet, enriched with plant-based polyphenols and lower in red/processed meat, may be a potent intervention to promote visceral adiposity regression. TRIAL REGISTRATION ClinicalTrials.gov , NCT03020186.
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Efficacy and safety of dietary polyphenol supplementation in the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis.
Yang, K, Chen, J, Zhang, T, Yuan, X, Ge, A, Wang, S, Xu, H, Zeng, L, Ge, J
Frontiers in immunology. 2022;13:949746
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Non-alcoholic fatty liver disease (NAFLD) is characterised by fat accumulation in the liver that can result in liver damage. NAFLD affects approximately 25% of the global population. There is evidence that dietary polyphenols can improve metabolism and insulin resistance and reduce inflammation and oxidative stress, which are the mechanisms that lead to liver damage in NAFLD. This systematic review and meta-analysis aimed to assess the effectiveness of dietary polyphenols in the treatment of non-alcoholic fatty liver disease (NAFLD). Eight dietary polyphenols, such as curcumin, resveratrol, naringenin, anthocyanin, hesperidin, catechin, silymarin, and genistein, were evaluated for their efficacy and safety. The administration of 80-3,000 mg of Curcumin for an 8-12 week duration is effective and safe for reducing body mass index, aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides (TG), total cholesterol (TC), and insulin resistance (HOMA-IR). Compared with the placebo, Naringenin reduced the percentage of NAFLD grade, TG, TC, and low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol. Hesperidin may potentially decrease body mass index (BMI), AST, ALT, TG, TC, and HOMA-IR. Catechin is safe, and 500-1000 mg supplementation for 12 weeks may reduce BMI, HOMA-IR, and TG. NAFLD patients who received silymarin showed improvements in ALT and AST, as well as reductions in hepatic fat accumulation and liver stiffness. 94–2100 mg of Silymarin supplementation for 8–48 weeks may reduce liver enzyme levels. Researchers can use the results of this study to understand the clinical utility of different polyphenol supplements in the treatment of NAFLD. Because the current evidence is highly heterogeneous in nature and limited in scope, further robust research is required on various classes of polyphenols and their effectiveness in reducing the severity of NAFLD.
Abstract
Background: Dietary polyphenol treatment of non-alcoholic fatty liver disease (NAFLD) is a novel direction, and the existing clinical studies have little effective evidence for its therapeutic effect, and some studies have inconsistent results. The effectiveness of dietary polyphenols in the treatment of NAFLD is still controversial. The aim of this study was to evaluate the therapeutic efficacy of oral dietary polyphenols in patients with NAFLD. Methods: The literature (both Chinese and English) published before 30 April 2022 in PubMed, Cochrane, Medline, CNKI, and other databases on the treatment of NAFLD with dietary polyphenols was searched. Manual screening, quality assessment, and data extraction of search results were conducted strictly according to the inclusion and exclusion criteria. RevMan 5.3 software was used to perform the meta-analysis. Results: The RCTs included in this study involved dietary supplementation with eight polyphenols (curcumin, resveratrol, naringenin, anthocyanin, hesperidin, catechin, silymarin, and genistein) and 2,173 participants. This systematic review and meta-analysis found that 1) curcumin may decrease body mass index (BMI), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Triglycerides (TG) total cholesterol (TC), and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) compared to placebo; and curcumin does not increase the occurrence of adverse events. 2) Although the meta-analysis results of all randomized controlled trials (RCTs) did not reveal significant positive changes, individual RCTs showed meaningful results. 3) Naringenin significantly decreased the percentage of NAFLD grade, TG, TC, and low-density lipoprotein cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C) but had no significant effect on AST and ALT, and it is a safe supplementation. 4) Only one team presents a protocol about anthocyanin (from Cornus mas L. fruit extract) in the treatment of NAFLD. 5) Hesperidin may decrease BMI, AST, ALT, TG, TC, HOMA-IR, and so on. 6) Catechin may decrease BMI, HOMA-IR, and TG level, and it was well tolerated by the patients. 7) Silymarin was effective in improving ALT and AST and reducing hepatic fat accumulation and liver stiffness in NAFLD patients. Conclusion: Based on current evidence, curcumin can reduce BMI, TG, TC, liver enzymes, and insulin resistance; catechin can reduce BMI, insulin resistance, and TG effectively; silymarin can reduce liver enzymes. For resveratrol, naringenin, anthocyanin, hesperidin, and catechin, more RCTs are needed to further evaluate their efficacy and safety.
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The effects of Aronia berry (poly)phenol supplementation on arterial function and the gut microbiome in middle aged men and women: Results from a randomized controlled trial.
Le Sayec, M, Xu, Y, Laiola, M, Gallego, FA, Katsikioti, D, Durbidge, C, Kivisild, U, Armes, S, Lecomte, M, Fança-Berthon, P, et al
Clinical nutrition (Edinburgh, Scotland). 2022;41(11):2549-2561
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Over the last decades, Aronia melanocarpa, or black chokeberry, has gained increased attention for its high content of (poly)phenols, and potential protection against chronic diseases such as cardiovascular disease and diabetes. The aim of this study was to investigate the effects of 12-week aronia berry (poly)phenol consumption on cardiometabolic health and gut microbiome composition in prehypertensive middle-aged adults. This study was a 2-arm, double-blind, parallel randomised controlled trial. Participants (n = 102; 47 men and 55 women) were assigned randomly to Aronia or control groups. Results showed that there were no significant effects in blood pressure (primary outcome), endothelial function or blood lipids. However, there was a significant improvement in 24-hour ambulatory arterial indices and significant changes in gut microbiome richness, functions and composition between Aronia and control groups. Authors conclude that future studies should be conducted to investigate whether aronia supplementation may be effective in other at-risk populations such as hypertensives or people with cardiovascular disease risk.
Abstract
BACKGROUND AND AIMS Berry (poly)phenol consumption has been associated with cardioprotective benefits, however little is known on the role the gut microbiome may play on such health benefits. Our objective was to investigate the effects of aronia berry (poly)phenol consumption on cardiometabolic health and gut microbiome richness and composition in prehypertensive middle-aged men and women. METHODS A total of 102 prehypertensive participants were included in a parallel 12-week randomized double-blind placebo-controlled trial. Volunteers were randomly allocated to daily consume an encapsulated (poly)phenol-rich aronia berry extract (Aronia, n = 51) or a matched maltodextrin placebo (Control, n = 51). Blood pressure (BP) and arterial function (office and 24 h), endothelial function (measured as flow-mediated dilation), serum biochemistry (including blood lipids), plasma and urine (poly)phenol metabolites as well as gut microbiome composition through shotgun metagenomic sequencing were monitored over the study period. Relationships between vascular outcomes, (poly)phenol metabolites and gut microbiome were investigated using an integrated multi-levels approach. RESULTS A significant improvement in arterial indices measured as augmentation index (AIx) and pulse wave velocity (PWV) was found in the Aronia compared to Control group (awake Δ PWV = -0.24 m/s; 95% CI: -0.79, -0.01 m/s, P < 0.05; 24 h peripheral Δ AIx = -6.8; -11.2, -2.3, %, P = 0.003; 24 h central Δ AIx = -3.3; -5.5, -1.0, %, P = 0.006). No changes in BP, endothelial function or blood lipids were found following the intervention. Consumption of aronia (poly)phenols led to a significant increase in gut microbiome gene richness and in the abundance of butyrate-producing species such as Lawsonibacter asaccharolyticus and Intestinimonas butyriciproducens species, compared to Control group. Results from an approach including metabolomic, metagenomic and clinical outcomes highlighted associations between aronia-derived phenolic metabolites, arterial stiffness, and gut microbiome. CONCLUSIONS Aronia berry (poly)phenol consumption improved arterial function in prehypertensive middle-aged individuals, possibly via modulation of gut microbiome richness and composition based on the associations observed between these parameters. CLINICAL TRIAL REGISTRY The National Institutes of Health (NIH)-randomized trial records held on the NIH ClinicalTrials.gov website (NCT03434574). Aronia Berry Consumption on Blood Pressure.
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Dietary macronutrients and the gut microbiome: a precision nutrition approach to improve cardiometabolic health.
Jardon, KM, Canfora, EE, Goossens, GH, Blaak, EE
Gut. 2022;71(6):1214-1226
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The global rise in the prevalence of obesity is strongly associated with an increase in the incidence and prevalence of cardiometabolic diseases, including insulin resistance (IR) and type 2 diabetes mellitus. In recent years, advancements have been made in understanding the involvement of the gut microbiome in obesity and related cardiometabolic complications as regulator of host energy and substrate metabolism. This study is a review that discusses the latest research describing interactions between dietary composition, the gut microbiome and host metabolism. Results show that current evidence for developing optimal dietary interventions targeting bodyweight control and IR via the gut microbiota is still in its infancy and does not capture the complexity of the integration of a whole-diet approach, the microbial and the host’s metabolic phenotype. Furthermore, implementation of targeted, precision nutrition intervention strategies or dietary guidelines for individuals or subgroups in public health requires further insight in the mechanisms involved in (non-)response to dietary intervention. Authors conclude that future studies are needed and these should focus on assessing detailed individual phenotyping and gaining insight into the balance between carbohydrate and protein fermentation by the gut microbiota as well as the site of fermentation in the colon.
Abstract
Accumulating evidence indicates that the gut microbiome is an important regulator of body weight, glucose and lipid metabolism, and inflammatory processes, and may thereby play a key role in the aetiology of obesity, insulin resistance and type 2 diabetes. Interindividual responsiveness to specific dietary interventions may be partially determined by differences in baseline gut microbiota composition and functionality between individuals with distinct metabolic phenotypes. However, the relationship between an individual's diet, gut microbiome and host metabolic phenotype is multidirectional and complex, yielding a challenge for practical implementation of targeted dietary guidelines. In this review, we discuss the latest research describing interactions between dietary composition, the gut microbiome and host metabolism. Furthermore, we describe how this knowledge can be integrated to develop precision-based nutritional strategies to improve bodyweight control and metabolic health in humans. Specifically, we will address that (1) insight in the role of the baseline gut microbial and metabolic phenotype in dietary intervention response may provide leads for precision-based nutritional strategies; that (2) the balance between carbohydrate and protein fermentation by the gut microbiota, as well as the site of fermentation in the colon, seems important determinants of host metabolism; and that (3) 'big data', including multiple omics and advanced modelling, are of undeniable importance in predicting (non-)response to dietary interventions. Clearly, detailed metabolic and microbial phenotyping in humans is necessary to better understand the link between diet, the gut microbiome and host metabolism, which is required to develop targeted dietary strategies and guidelines for different subgroups of the population.
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A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.
Basak, SK, Bera, A, Yoon, AJ, Morselli, M, Jeong, C, Tosevska, A, Dong, TS, Eklund, M, Russ, E, Nasser, H, et al
Cancer. 2020;126(8):1668-1682
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APG-157 is a botanical drug containing multiple polyphenols that delivers the active components to oromucosal tissues near the tumour target. APG-157 slowly disintegrates in the oral cavity over 15 to 20 minutes to release the drug substance. The drug substance is a precise, rational combination of multiple molecules derived from Curcuma longa wherein curcumin is the principal component. The main aim of this study was to determine the pharmacokinetics and safety of the orally delivered pastille (APG-157) when used by normal subjects and patients with cancer. This study is a randomised, double-blind, placebo-controlled trial. A total of 32 subjects were enrolled, and 25 completed the study (13 normal individuals and 12 patients with oral cancer). Results demonstrated that transoral APG-157 treatment leads to systemic absorption of curcumin and its analogs. There was a statistically significant concentration reduction in inflammatory cytokines and Bacteroides species noted in the salivary cells. Pre-treatment and post-treatment tumour samples from patients with cancer demonstrated T-cell recruitment to the tumour microenvironment. Authors conclude that APG-157 is absorbed well, reduces inflammation, and attracts T-cells to the tumour thus, it can be potentially used in combination with immunotherapy drugs. Furthermore, a long-term evaluation of immune checkpoint blockade with and without APG-157 could provide a clear understanding of the usefulness of APG-157 as either an adjuvant or neoadjuvant therapeutic agent for patients with advanced or recurrent head and neck cancer.
Abstract
BACKGROUND Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target. METHODS A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity. RESULTS Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment. CONCLUSIONS The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy. LAY SUMMARY Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.
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Green tea (Camellia sinensis) for the prevention of cancer.
Filippini, T, Malavolti, M, Borrelli, F, Izzo, AA, Fairweather-Tait, SJ, Horneber, M, Vinceti, M
The Cochrane database of systematic reviews. 2020;3(3):CD005004
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Brewed tea is obtained from the infusion of leaves and buds of Camellia sinensis. The most consumed types of tea are green and black tea. Due to the high content of antioxidant compounds, a great deal of attention has been given to green tea regarding the possible prevention of chronic diseases and cancer, as well as possible beneficial effects on cardiovascular disease, insulin sensitivity and lipid profiles. The main aim of this review was to assess the association between green tea consumption and the risk of developing cancer in epidemiologic studies. This study is an update of a previously published Cochrane review based on studies in which participants consumed green tea orally, either as drinkable tea or as extracts. One hundred and forty-two epidemiological studies of experimental and nonexperimental design were included with a total of 1,100,000 participants. Findings yielded inconsistent results for the effect of green tea consumption on cancer risk, despite some indications of a beneficial effect of green tea on a few site-specific cancers. Authors conclude that the epidemiological evidence appears to be still inadequate to support a beneficial effect of green tea on cancer risk.
Abstract
BACKGROUND This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (2009, Issue 3).Tea is one of the most commonly consumed beverages worldwide. Teas from the plant Camellia sinensis can be grouped into green, black and oolong tea, and drinking habits vary cross-culturally. C sinensis contains polyphenols, one subgroup being catechins. Catechins are powerful antioxidants, and laboratory studies have suggested that these compounds may inhibit cancer cell proliferation. Some experimental and nonexperimental epidemiological studies have suggested that green tea may have cancer-preventative effects. OBJECTIVES To assess possible associations between green tea consumption and the risk of cancer incidence and mortality as primary outcomes, and safety data and quality of life as secondary outcomes. SEARCH METHODS We searched eligible studies up to January 2019 in CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and reference lists of previous reviews and included studies. SELECTION CRITERIA We included all epidemiological studies, experimental (i.e. randomised controlled trials (RCTs)) and nonexperimental (non-randomised studies, i.e. observational studies with both cohort and case-control design) that investigated the association of green tea consumption with cancer risk or quality of life, or both. DATA COLLECTION AND ANALYSIS Two or more review authors independently applied the study criteria, extracted data and assessed methodological quality of studies. We summarised the results according to diagnosis of cancer type. MAIN RESULTS In this review update, we included in total 142 completed studies (11 experimental and 131 nonexperimental) and two ongoing studies. This is an additional 10 experimental and 85 nonexperimental studies from those included in the previous version of the review. Eleven experimental studies allocated a total of 1795 participants to either green tea extract or placebo, all demonstrating an overall high methodological quality based on 'Risk of bias' assessment. For incident prostate cancer, the summary risk ratio (RR) in the green tea-supplemented participants was 0.50 (95% confidence interval (CI) 0.18 to 1.36), based on three studies and involving 201 participants (low-certainty evidence). The summary RR for gynaecological cancer was 1.50 (95% CI 0.41 to 5.48; 2 studies, 1157 participants; low-certainty evidence). No evidence of effect of non-melanoma skin cancer emerged (summary RR 1.00, 95% CI 0.06 to 15.92; 1 study, 1075 participants; low-certainty evidence). In addition, adverse effects of green tea extract intake were reported, including gastrointestinal disorders, elevation of liver enzymes, and, more rarely, insomnia, raised blood pressure and skin/subcutaneous reactions. Consumption of green tea extracts induced a slight improvement in quality of life, compared with placebo, based on three experimental studies. In nonexperimental studies, we included over 1,100,000 participants from 46 cohort studies and 85 case-control studies, which were on average of intermediate to high methodological quality based on Newcastle-Ottawa Scale 'Risk of bias' assessment. When comparing the highest intake of green tea with the lowest, we found a lower overall cancer incidence (summary RR 0.83, 95% CI 0.65 to 1.07), based on three studies, involving 52,479 participants (low-certainty evidence). Conversely, we found no association between green tea consumption and cancer-related mortality (summary RR 0.99, 95% CI 0.91 to 1.07), based on eight studies and 504,366 participants (low-certainty evidence). For most of the site-specific cancers we observed a decreased RR in the highest category of green tea consumption compared with the lowest one. After stratifying the analysis according to study design, we found strongly conflicting results for some cancer sites: oesophageal, prostate and urinary tract cancer, and leukaemia showed an increased RR in cohort studies and a decreased RR or no difference in case-control studies. AUTHORS' CONCLUSIONS Overall, findings from experimental and nonexperimental epidemiological studies yielded inconsistent results, thus providing limited evidence for the beneficial effect of green tea consumption on the overall risk of cancer or on specific cancer sites. Some evidence of a beneficial effect of green tea at some cancer sites emerged from the RCTs and from case-control studies, but their methodological limitations, such as the low number and size of the studies, and the inconsistencies with the results of cohort studies, limit the interpretability of the RR estimates. The studies also indicated the occurrence of several side effects associated with high intakes of green tea. In addition, the majority of included studies were carried out in Asian populations characterised by a high intake of green tea, thus limiting the generalisability of the findings to other populations. Well conducted and adequately powered RCTs would be needed to draw conclusions on the possible beneficial effects of green tea consumption on cancer risk.