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Feed your microbes to deal with stress: a psychobiotic diet impacts microbial stability and perceived stress in a healthy adult population.
Berding, K, Bastiaanssen, TFS, Moloney, GM, Boscaini, S, Strain, CR, Anesi, A, Long-Smith, C, Mattivi, F, Stanton, C, Clarke, G, et al
Molecular psychiatry. 2022
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Psychobiotic describe any exogenous intervention that leads to a bacterially mediated impact on the brain. Probiotics and prebiotics have shown promising results as psychobiotic agents in both animal and human studies. The aim of this study was to investigate the potential of a whole diet psychobiotic approach to modulate the microbiota composition and function, affect responses to and feelings of stress and improve mood in a healthy population. This study is a single-blind, randomized, controlled study which recruited healthy adult (male and female) participants with poor dietary habits, aged 18–59 years. Participants were block randomized (block of 4, stratified by gender) into either intervention or control group using randomly permuted blocks and were instructed to follow their respective diet for 4 weeks. Results show that a short term psychobiotic dietary intervention improved perceived stress in a healthy population, while eliciting specific metabolic changes in the gut microbiota. Authors conclude that underlying microbial influences need to be investigated and future preclinical experiments are required to explore causality and decipher mechanistic pathways.
Expert Review
Conflicts of interest:
None
Take Home Message:
Eating foods known to have a positive influence on gut microbial composition could elicit benefits in terms of reducing perceived stress and improving sleep quality.
Evidence Category:
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X
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:
This RCT explored the impact of a psychobiotic diet, compared to a control diet, on perceived stress, sleep and gut microbiota.
A high psychobiotic diet is one high in prebiotic and fermented foods. In this study, a psychobiotic diet included daily recommended consumption and servings of the following:
- High prebiotic fruit & veg (6-8)
- Grains (5-8)
- Fermented foods (2-3)
- Legumes (3-4 per week)
Methodology:
- A single-blind, randomised, controlled study
- 45 healthy adults (18-59 years) with poor dietary habits
- Sample size determined by previous microbiome research - target not reached due to introduction of covid restrictrictions
- Active intervention (n=24) received dietitian advice to follow psychobitoic diet
- Control intervention (n=21) received dietitian advice largely based on the Irish Healthy Eating Guidelines food pyramid
- Intervention duration 4 weeks.
- Assessed on questionnaire measures of perceived stress and sleep, pre and post-intervention (no primary outcome defined)
- Shotgun microbiome analysis on stool samples, pre and post-intervention
Results:
- Perceived stress improved in the psychobiotic diet group
- Subjective sleep quality improved in the psychobiotic diet group
- Only subtle changes in microbial composition and function
- More stable microbiota throughout the study (regardless of diet) was correlated with greater changes in perceived stress
- Neither cortisol awakening response nor measured immune markers were affected by dietary intervention
Conclusions:
- Using a diet targeted to positively modulate gut-brain communication may have the potential for reducing stress and improving sleep
- Although improvements in stress were only observed for the intervention group – the post-intervention stress levels were not significantly different between the groups.
- Thus, we should interpret the results with some caution
Clinical practice applications:
- Providing advice on dietary intake of foods known to positively impact gut microbiota may be helpful for individuals affected by stress or sleep problems
- The inclusion of the following foods may be helpful:
- High prebiotic fruit & veg (6-8 per day)
- Grains (5-8 per day)
- Fermented foods (2-3 per day)
- Legumes (3-4 per week)
Considerations for future research:
- Important to replicate these results in a larger sample
- It might be helpful to investigate individual aspects of the diet separately, to assess their individual impact
- Objective measures of sleep (such as actigraphy recordings) might provide additionally useful findings
- It would be interesting to explore the effect of the psychobiotic diet in other conditions
- Chronobiology or chrononutrition - i.e. looking at timing of the foods proposed in the section above
Abstract
The impact of diet on the microbiota composition and the role of diet in supporting optimal mental health have received much attention in the last decade. However, whether whole dietary approaches can exert psychobiotic effects is largely understudied. Thus, we investigated the influence of a psychobiotic diet (high in prebiotic and fermented foods) on the microbial profile and function as well as on mental health outcomes in a healthy human population. Forty-five adults were randomized into either a psychobiotic (n = 24) or control (n = 21) diet for 4 weeks. Fecal microbiota composition and function was characterized using shotgun sequencing. Stress, overall health and diet were assessed using validated questionnaires. Metabolic profiling of plasma, urine and fecal samples was performed. Intervention with a psychobiotic diet resulted in reductions of perceived stress (32% in diet vs. 17% in control group), but not between groups. Similarly, biological marker of stress were not affected. Additionally, higher adherence to the diet resulted in stronger decreases in perceived stress. While the dietary intervention elicited only subtle changes in microbial composition and function, significant changes in the level of 40 specific fecal lipids and urinary tryptophan metabolites were observed. Lastly, microbial volatility was linked to greater changes in perceived stress scores in those on the psychobiotic diet. These results highlight that dietary approaches can be used to reduce perceived stress in a human cohort. Using microbiota-targeted diets to positively modulate gut-brain communication holds possibilities for the reduction of stress and stress-associated disorders, but additional research is warranted to investigate underlying mechanisms, including the role of the microbiota.
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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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X
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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Broccoli consumption affects the human gastrointestinal microbiota.
Kaczmarek, JL, Liu, X, Charron, CS, Novotny, JA, Jeffery, EH, Seifried, HE, Ross, SA, Miller, MJ, Swanson, KS, Holscher, HD
The Journal of nutritional biochemistry. 2019;63:27-34
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Diet affects metabolic and gastrointestinal diseases, with the microbiome considered to be a mediating factor. Broccoli is a good source of fibre and phytochemicals including glucosinolates. The aim of this investigator-blinded, controlled feeding, randomised, crossover study was to evaluate the effects of broccoli on the composition and function of the microbiome. 18 healthy adults received 200 g cooked broccoli and 20 g raw daikon radish per day for 18 days in addition to a controlled, brassica-free diet or the same diet without the broccoli and daikon radish, with a 24-day washout period. A statistically significant increase in the ratio of Bacteroidetes to Firmicutes was observed following the broccoli intervention. When stratified by BMI above or below 25, this increase was only seen in those with a lower BMI whilst those with a higher BMI displayed a decrease in the ratio, although the latter was not statistically significant. In those with the lower BMI, there was also a correlation between the changes in the microbiota composition and glucosinolate metabolites. It was predicted that the involved changes would affect the functions of the endocrine system, transport and catabolism and energy metabolism. The authors concluded that eating broccoli may affect both the composition and the function of the microbiome.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Broccoli consumption at dosages of 200g per day were shown to change the composition of gastrointestinal microbiota, increasing Bacteroidetes and decreasing Firmicutes, and impact their function
- The observed results were strongest in those with a BMI of less than 26
- While interesting, the study only included 18 participants and therefore the results should be further confirmed.
Evidence Category:
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X
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:
Introduction
There is growing evidence linking dysbiosis of the gastrointestinal microbiota and diet-induced gastrointestinal and metabolic diseases. Both long-term and acute dietary changes, fasting, eating frequency, and consumption of specific fibres and food phytochemicals play a role in shaping the composition and function of the microbiota, although evidence is lacking for specific foods. This study aimed to determine the impact of broccoli intake on the number of bacterial strains and their functional capacity.
Methods
This was a single-blind, randomised, crossover, complete feeding intervention. Study participants were healthy adults (n=18, females =10). Participants were requested to not eat Brassica vegetables for 3 weeks before the start of the study.
Subjects participated in two 18-day diet periods separated by a 24-hour washout, during which breakfast and dinner were consumed on site to observe compliance. The control diet was prepared using traditional American foods, excluding all Brassica vegetables. During the broccoli intervention period, participants consumed the same base diet with the addition of 200g of broccoli.
Faecal samples were collected on day 1, and day 16. Quantitative polymerase chain reaction was performed on bacterial strains. On day 17, time series plasma sampling and 24-hour urine collection was done.
Results
There was no difference in alpha diversity (a measure of microbiome diversity within a sample) between the two treatment periods. This indicates that no bacterial species were extinguished by broccoli treatment. Beta diversity analysis (a measure of the (dis)similarity between samples) indicated that bacterial communities were impacted by treatment (P=0.03).
After broccoli consumption, Bacteroidetes increased by 10% (P =0.03), while Firmicutes decreased by 8% (P=0.05). Overall the ratio of Bacteroidetes to Firmicutes increased by 37% (P=0.01) versus a 5% decrease in the control period. The Bacteroides genus increased by 6% (P=0.02) versus a 2% decrease in the control period.
Interestingly, the effects were most strong in those with a lower BMI (< 26 kg/m2) who had an increase in metabolites after broccoli consumption. Algorithms to predict the function of the microbiota showed that broccoli increased endocrine (P=0.05), energy metabolism (P=0.01), transport and catabolism (P=0.04) pathways.
Conclusion
Broccoli intake, at 200g daily, changes the composition and potentially impacts the function of the gut microbiota.
Clinical practice applications:
- Studies like this allow practitioners to focus on specific foods in specific quantities to positively alter the microbiota and their function
- Cruciferous vegetables, like broccoli, kale, cauliflower, cabbage, Brussel sprouts, are an important group as they contain fibre and phytonutrients such as glucosinolates. These compounds can be metabolised by the microbiota into active compounds with health benefits. This study has shown the bidirectional benefit of broccoli consumption in that it can positively impact the function and composition of the microbiota
- Interestingly, the results in this small study were driven by participants with a BMI of less than 26. Sub-group analysis found no statistically significant relationships in participants with BMI >26
- It is worth noting that it is possible that the addition of 5g of fibre from the broccoli is also contributing to the changes observed.
Considerations for future research:
- Larger, controlled feeding studies that isolate specific foods to identify their effects on the microbiota are needed
- Genetic sequencing for only a few bacterial myrosinases has been completed and therefore future studies should aim to assess the metabolic capabilities in faecal samples such as myrosinase activity
- While this study and others have shown changes in the types of bacteria after cruciferous vegetable consumption the consistency of results has been mixed potentially due to differing study designs and treatment dosages. Further studies to clarify and confirm these results would be beneficial
- To assess the function of the microbiota a predictive algorithm was used. This requires experimental confirmation by such methods as metabolite profiling and whole genome shotgun sequencing.
Abstract
The human gastrointestinal microbiota is increasingly linked to health outcomes; however, our understanding of how specific foods alter the microbiota is limited. Cruciferous vegetables such as broccoli are a good source of dietary fiber and phytonutrients, including glucosinolates, which can be metabolized by gastrointestinal microbes. This study aimed to determine the impact of broccoli consumption on the gastrointestinal microbiota of healthy adults. A controlled feeding, randomized, crossover study consisting of two 18-day treatment periods separated by a 24-day washout was conducted in healthy adults (n=18). Participants were fed at weight maintenance with the intervention period diet including 200 g of cooked broccoli and 20 g of raw daikon radish per day. Fecal samples were collected at baseline and at the end of each treatment period for microbial analysis. Beta diversity analysis indicated that bacterial communities were impacted by treatment (P=.03). Broccoli consumption decreased the relative abundance of Firmicutes by 9% compared to control (P=.05), increased the relative abundance of Bacteroidetes by 10% compared to control (P=.03) and increased Bacteroides by 8% relative to control (P=.02). Furthermore, the effects were strongest among participants with body mass index <26 kg/m2, and within this group, there were associations between bacterial relative abundance and glucosinolate metabolites. Functional prediction revealed that broccoli consumption increased the pathways involved in the functions of the endocrine system (P=.05), transport and catabolism (P=.04), and energy metabolism (P=.01). These results reveal that broccoli consumption affects the composition and function of the human gastrointestinal microbiota.
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Effect of a Protein Supplement on the Gut Microbiota of Endurance Athletes: A Randomized, Controlled, Double-Blind Pilot Study.
Moreno-Pérez, D, Bressa, C, Bailén, M, Hamed-Bousdar, S, Naclerio, F, Carmona, M, Pérez, M, González-Soltero, R, Montalvo-Lominchar, MG, Carabaña, C, et al
Nutrients. 2018;10(3)
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Protein supplements are popular among athletes to improve performance and increase muscle mass. However, their effect on other aspects of health is less well known. Dietary changes can affect gut microbiota balance, with beneficial or harmful consequences for the host. This small pilot study was performed on cross-country runners whose diets were complemented with a protein supplement (whey isolate and beef hydrolysate) or maltodextrin (control) for 10 weeks. Microbiota, water content, pH, ammonia, and short-chain fatty acids (SCFAs) were analysed in faecal samples, and oxidative stress markers were measured in blood plasma and urine. Faecal pH, water content, ammonia, and SCFA concentrations did not change, indicating that protein supplementation did not increase the presence of these metabolites of fermentation. Similarly, it had no impact on plasma or urine malondialdehyde levels. Protein supplementation did however increase the abundance of the Bacteroidetes phylum and decrease the presence of health-related taxa including Roseburia, Blautia, and Bifidobacterium longum. The authors concluded that long-term protein supplementation may have a negative impact on gut microbiota. Further research is needed to establish the impact of protein supplements on gut microbiota.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Long-term protein supplementation may have a negative impact on gut microbiota.
- Further research is needed to establish the impact of protein supplements on gut microbiota and whether there is a differential impact between protein from animal and plant sources.
Evidence Category:
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X
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:
This is a very interesting study that is relevant to athletic populations.
Clinical practice applications:
Potentially there is a role for probiotics / prebiotics when increasing protein intake (particularly of animal origin) to maintain microbiota diversity and prevent ensuing health complications.
Considerations for future research:
Further, larger scale, research is needed to understand whether the same effect of protein supplementation would be seen with plant-based proteins or whether this is unique to animal based protein supplementation. For example, is the hydrolysation of the proteins to account for the largest effect or could a whole food protein, i.e. not hydrolysed, elicit the same effects?
Also, is this effect seen in other sports, e.g. non-endurance. What about the effect under different conditions e.g. energy deficit vs. energy excess?
Abstract
Nutritional supplements are popular among athletes to improve performance and physical recovery. Protein supplements fulfill this function by improving performance and increasing muscle mass; however, their effect on other organs or systems is less well known. Diet alterations can induce gut microbiota imbalance, with beneficial or deleterious consequences for the host. To test this, we performed a randomized pilot study in cross-country runners whose diets were complemented with a protein supplement (whey isolate and beef hydrolysate) (n = 12) or maltodextrin (control) (n = 12) for 10 weeks. Microbiota, water content, pH, ammonia, and short-chain fatty acids (SCFAs) were analyzed in fecal samples, whereas malondialdehyde levels (oxidative stress marker) were determined in plasma and urine. Fecal pH, water content, ammonia, and SCFA concentrations did not change, indicating that protein supplementation did not increase the presence of these fermentation-derived metabolites. Similarly, it had no impact on plasma or urine malondialdehyde levels; however, it increased the abundance of the Bacteroidetes phylum and decreased the presence of health-related taxa including Roseburia, Blautia, and Bifidobacterium longum. Thus, long-term protein supplementation may have a negative impact on gut microbiota. Further research is needed to establish the impact of protein supplements on gut microbiota.
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Combined bioavailable isoflavones and probiotics improve bone status and estrogen metabolism in postmenopausal osteopenic women: a randomized controlled trial.
Lambert, MNT, Thybo, CB, Lykkeboe, S, Rasmussen, LM, Frette, X, Christensen, LP, Jeppesen, PB
The American journal of clinical nutrition. 2017;106(3):909-920
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Oestrogens play a vital role in maintaining bone health. The natural decline in oestrogen during menopause negatively impacts bone mineral density and increases the risk of osteoporosis and fractures. Standard interventions offered include calcium and vitamin D supplementation and hormone replacement therapy. As hormone replacement therapy is associated with increased cancer risk, there is a need to find effective treatments that display a suitable safety profile for long-term use. Isoflavones are compounds found in legume plants, many of which are dietary staples in some cultures. Isoflavones are phytoestrogens, substances that can selectively interact with human oestrogen receptors. Initial research on Isoflavones indicated that it reduces bone breakdown whilst showing protective effects for certain cancers. This randomized, double- blind, placebo-controlled trial compared the effectiveness of an lactic acid fermented, probiotic-rich isoflavone product from Red Clover (RCE) or a placebo, when given in addition to Calcium, Magnesium and Vitamin D (CMD) in postmenopausal women with osteopenia. Participants were monitored using blood tests assessing phytoestrogen activity and oestrogen metabolism, DXA scans to observe changes in bone structure and activity and dietary questionnaires. A total of 78 participants completed the study. The results showed that twice a day 60 mg isoflavones from RCE had a significant physiological impact on preventing bone loss associated with oestrogen deficiency, and was more effective in preserving bone density than CDM alone. The authors concluded that RCE was close to effectiveness to conventional bone-preserving treatments like hormone therapy but stood out due to its better safety profile and minimal side effects. Gut bacteria enhance the effectiveness of these isoflavones, which can be metabolised into compounds called equol. While before the study none of the participants could produce equol, in the end, half of the participants in the RCE group were able to produce equol, suggesting that the probiotic presence in the supplement positively influenced the participants' gut bacteria, creating favourable conditions. Additionally, RCE treatment led to favourable changes in urinary oestrogen metabolites associated with less carcinogenic oestrogen metabolism. In conclusion, the probiotic RCE, enhanced the effectiveness of CMD in preventing bone loss, whilst also increasing the ability to produce equol.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Fermented red clover extract, rich in bioavailable isoflavones with selective oestrogen receptor affinity and probiotics, combined with traditional supplementation (calcium, magnesium and vitamin D) improves bone mineral density and bone turnover compared to placebo in post menopausal women with osteopenia.
- Combining probiotics with isoflavones appears to enhance intestinal isoflavone uptake and isoflavone metabolism.
Evidence Category:
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X
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:
Introduction
This was a well-constructed randomised, parallel-design, placebo-controlled, double-blind trial over 12 months. The primary aim was to determine the effectiveness of a novel fermented red clover extract (RCE) containing isoflavones and probiotics combined with traditional calcium/magnesium/vitamin D supplementation, in comparison with traditional calcium/magnesium/vitamin D supplementation alone on bone mineral density (BMD) in postmenopausal women with osteopenia.
Methods
- The trial followed the guidelines of the Declaration of Helsinki and received ethics approval.
- Inclusion criteria: female; >=1 year postmenopause; age 60-85; and bone T score of -1 to -2.25.
- Exclusion criteria: medical treatment for osteopenia or hormone replacement therapy within the past 3 months; diet rich in or supplementation with isoflavones; supplementation with Vitamin K; medical history of stipulated conditions.
- 85 participants were eligible and randomised to either the control or treatment group.
- Treatment group received 95 mL of RCE twice daily, containing 60 mg isoflavone aglycones and probiotics, plus 1040mg calcium, 487mg magnesium and 25μg Vitamin D daily (CMD/d). Control group received masked RCE placebo plus CMD/d.
Results
- The change in BMD (p=0.043) and T score (p=0.045) showed a statistically significant greater decrease in the lumbar spine, femoral neck and hip of the control group than the RCE treatment group after 12 months of treatment.
- A statistically significant reduction in one bone resorption marker was found in the RCE group compared to control (p=0.045). All other bone biomarkers failed to reach significance.
- Plasma isoflavone concentration was elevated in the RCE treatment group compared to control (p=0.0094).
- The concentration ratios of urinary oestrogen metabolites 2-OH:16αOH was significantly increased in the RCE group compared to control (p=0.026).
Conclusion
Fermented RCE with CMD/d slowed oestrogen-deficient BMD loss and improved one marker of bone turnover in postmenopausal osteopenic women. Combining RCE with CMD/d was found to be more effective in preserving bone density than CMD/d alone in this target group. Probiotics in the fermented RCE appear to enhance intestinal isoflavone uptake, metabolism, and therapeutic effect.
Clinical practice applications:
- Healthcare practitioners working with women in post-menopause with osteopenia could consider the addition of fermented RCE with CMD/d for improved bone mineral density and bone turnover over 12 months.
- Given the positive impact of RCE intake over 12 months on 2-OH:16αOH oestrogen metabolite ratios, healthcare practitioners could consider fermented RCE when HRT is not an available option in relation to cancer risk.
- Based on these results, Nutritional Therapists working with post-menopausal women with osteopenia can focus on dietary isoflavone intake and pre and probiotic foods to support BMD, alongside supplementary options.
Considerations for future research:
- Given the length of time taken in bone remodelling cycles, a clinical trial of more than 2 years would strengthen the evidence provided by DXA scan.
- All trial participants were normotensive and healthy weight. Future studies could include women with hypertension and obesity to determine effects of RCE on bone and blood pressure/lipid markers in this group.
- Controlled feeding studies to determine the dietary effects of isoflavones and pre and probiotic foods would provide additional information in this area.
- Other fermented RCE products should be trialled to replicate findings.
Abstract
Background: Female age-related estrogen deficiency increases the risk of osteoporosis, which can be effectively treated with the use of hormone replacement therapy. However, hormone replacement therapy is demonstrated to increase cancer risk. Bioavailable isoflavones with selective estrogen receptor affinity show potential to prevent and treat osteoporosis while minimizing or eliminating carcinogenic side effects.Objective: In this study, we sought to determine the beneficial effects of a bioavailable isoflavone and probiotic treatment against postmenopausal osteopenia.Design: We used a novel red clover extract (RCE) rich in isoflavone aglycones and probiotics to concomitantly promote uptake and a favorable intestinal bacterial profile to enhance isoflavone bioavailability. This was a 12-mo, double-blind, parallel design, placebo-controlled, randomized controlled trial of 78 postmenopausal osteopenic women supplemented with calcium (1200 mg/d), magnesium (550 mg/d), and calcitriol (25 μg/d) given either RCE (60 mg isoflavone aglycones/d and probiotics) or a masked placebo [control (CON)].Results: RCE significantly attenuated bone mineral density (BMD) loss at the L2-L4 lumbar spine vertebra (P < 0.05), femoral neck (P < 0.01), and trochanter (P < 0.01) compared with CON (-0.99% and -2.2%; -1.04% and -3.05%; and -0.67% and -2.79, respectively). Plasma concentrations of collagen type 1 cross-linked C-telopeptide was significantly decreased in the RCE group (P < 0.05) compared with CON (-9.40% and -6.76%, respectively). RCE significantly elevated the plasma isoflavone concentration (P < 0.05), the urinary 2-hydroxyestrone (2-OH) to 16α-hydroxyestrone (16α-OH) ratio (P < 0.05), and equol-producer status (P < 0.05) compared with CON. RCE had no significant effect on other bone turnover biomarkers. Self-reported diet and physical activity were consistent and differences were nonsignificant between groups throughout the study. RCE was well tolerated with no adverse events.Conclusions: Twice daily RCE intake over 1 y potently attenuated BMD loss caused by estrogen deficiency, improved bone turnover, promoted a favorable estrogen metabolite profile (2-OH:16α-OH), and stimulated equol production in postmenopausal women with osteopenia. RCE intake combined with supplementation (calcium, magnesium, and calcitriol) was more effective than supplementation alone. This trial was registered at clinicaltrials.gov as NCT02174666.