Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction.

The effects of oral treatment with coenzyme Q10 (120 mg/d) were compared for 28 days in 73 (intervention group A) and 71 (placebo group B) patients with acute myocardial infarction (AMI). After treatment, angina pectoris (9.5 vs. 28.1), total arrhythmias (9.5% vs. 25.3%), and poor left ventricular function (8.2% vs. 22.5%) were significantly (P < 0.05) reduced in the coenzyme Q group than placebo group. Total cardiac events, including cardiac deaths and nonfatal infarction, were also significantly reduced in the coenzyme Q10 group compared with the placebo group (15.0% vs. 30.9%, P < 0.02). The extent of cardiac disease, elevation in cardiac enzymes, and oxidative stress at entry to the study were comparable between the two groups. Lipid peroxides, diene conjugates, and malondialdehyde, which are indicators of oxidative stress, showed a greater reduction in the treatment group than in the placebo group. The antioxidants vitamin A, E, and C and beta-carotene, which were lower initially after AMI, increased more in the coenzyme Q10 group than in the placebo group. These findings suggest that coenzyme Q10 can provide rapid protective effects in patients with AMI if administered within 3 days of the onset of symptoms. More studies in a larger number of patients and long-term follow-up are needed to confirm our results.

Cardiovasc Drugs Ther. 1998 Sep;12(4):347-53.

Effect of coenzyme Q10 on risk of atherosclerosis in patients with recent myocardial infarction.

In a randomized, double-blind, controlled trial, the effects of oral treatment with coenzyme Q10 (CoQ10, 120 mg/day), a bioenergetic and antioxidant cytoprotective agent, were compared for 1 year, on the risk factors of atherosclerosis, in 73 (CoQ, group A) and 71 (B vitamin group B) patients after acute myocardial infarction (AMI). After 1 year, total cardiac events (24.6 vs. 45.0%, p < 0.02) including non-fatal infarction (13.7 vs. 25.3%, p < 0.05) and cardiac deaths were significantly lower in the intervention group compared to control group. The extent of cardiac disease, elevation in cardiac enzymes, left ventricular enlargement, previous coronary artery disease and elapsed time from symptom onset to infarction at entry to study showed no significant differences between the two groups. Plasma level of vitamin E (32.4 +/- 4.3 vs. 22.1 +/- 3.6 umol/L) and high density lipoprotein cholesterol (1.26 +/- 0.43 vs. 1.12 +/- 0.32 mmol/L) showed significant (p < 0.05) increase whereas thiobarbituric acid reactive substances, malondialdehyde (1.9 + 0.31 vs. 3.1 + 0.32 pmol/L) and diene conjugates showed significant reduction respectively in the CoQ group compared to control group. Approximately half of the patients in each group (n = 36 vs. 31) were receiving lovastatin (10 mg/day) and both groups had a significant reduction in total and low density lipoprotein cholesterol compared to baseline levels. It is possible that treatment with CoQ10 in patients with recent MI may be beneficial in patients with high risk of atherothrombosis, despite optimal lipid lowering therapy during a follow-up of 1 year. Adverse effect of treatments showed that fatigue (40.8 vs. 6.8%, p < 0.01) was more common in the control group than CoQ group.

Mol Cell Biochem. 2003 Apr;246(1-2):75-82.

Evidence for increased catabolism of vitamin B-6 during systemic inflammation.

BACKGROUND: Plasma concentrations of PL 5’-phosphate (PLP), which is the active coenzyme form of vitamin B-6, are reduced during inflammation. The underlying mechanisms may include altered tissue distribution or increased catabolism via pyridoxal (PL) to pyridoxic acid (PA). Recently, we showed that catabolic enzyme activity could be assessed by substrate product ratios measured in plasma. OBJECTIVE: We evaluated the ratios PA:PL, PA:PLP, and PA:(PL + PLP) as possible markers of vitamin B-6 catabolism. DESIGN: Cross-sectional and longitudinal data were derived from the Western Norway B-Vitamin Intervention Trial. We analyzed associations of ratios with inflammatory markers and other clinical variables by using multiple linear regression and partial correlation. In addition, intraclass correlation coefficients (ICCs) were used to assess the ability of plasma indexes to differentiate between subjects. RESULTS: PA:(PL + PLP) had the highest ICC of all vitamin B-6 metabolites and ratios tested. In regression models, the inflammatory markers C-reactive protein, white blood cell count, neopterin, and kynurenine:tryptophan collectively accounted for 28% of the total and > 90% of the explained variation in PA:(PL + PLP). For individual B-6 metabolites, corresponding numbers were 19-25% and 20-44%, respectively, with vitamin supplement intake, smoking, and kidney function (estimated glomerular filtration rate) as additional predictors. In an analysis of receiver operating characteristics, PA:(PL + PLP) discriminated high inflammatory concentrations with an area under the curve (95% CI) of 0.85 (0.81, 0.89). CONCLUSIONS: Broad-specificity enzymes upregulated to reduce oxidative and aldehyde stress could explain increased catabolism of vitamin B-6 during inflammation. The ratio PA:(PL + PLP) may provide novel insights into pathologic processes and potentially predict risk of future disease.

Am J Clin Nutr. 2014 Jul;100(1):250-5.

Vitamin B-6 catabolism and long-term mortality risk in patients with coronary artery disease.

BACKGROUND: Low vitamin B-6 status has been related to increased risk of coronary artery disease (CAD), which is a condition that is associated with inflammation. The most common status marker, plasma pyridoxal 5’-phosphate (PLP), decreases during inflammation; therefore, causal relations are uncertain. OBJECTIVE: We evaluated the vitamin B-6 biomarkers PLP, pyridoxal, and pyridoxic acid (PA) and the pyridoxic acid:(pyridoxal + PLP) ratio (PAr), a proposed marker of vitamin B-6 catabolism during activated cellular immunity, as predictors of mortality. DESIGN: Associations with risks of long-term all-cause mortality and cardiovascular mortality were evaluated with the use of Cox regression in patients who were undergoing elective coronary angiography for suspected stable angina pectoris (SAP) (n = 4131) and an independent cohort of patients who were hospitalized for acute myocardial infarction (AMI) (n = 3665). RESULTS: Plasma PLP (AMI patients only) and PA predicted all-cause mortality in models that were adjusted for established risk predictors, but associations were attenuated or nonsignificant after additional adjustment for inflammatory markers. PAr was correlated with biomarkers of inflammation (Pearson’s r ≥ 0.37) and predicted all-cause mortality and cardiovascular mortality after adjustment for established risk predictors. In SAP patients, PAr had greater predictive strength than did current smoking, diabetes, hypertension, apolipoproteins, or C-reactive protein. PAr provided multiadjusted HRs per SD of 1.45 (95% CI: 1.30, 1.63) and 1.31 (95% CI: 1.21, 1.41) in SAP and AMI patients, respectively. In both cohorts, PAr was a particularly strong predictor of all-cause mortality for patients with no previous CAD history (P-interaction ≤ 0.04). CONCLUSION: PAr may capture unique aspects of inflammatory activation and thus provide new insights into disease mechanisms that may aid in identifying patients at increased risk of future fatal events.

Am J Clin Nutr. 2016 Jun;103(6):1417-25

Effects of coenzyme Q10 supplementation (300 mg/day) on antioxidation and anti-inflammation in coronary artery disease patients during statins therapy: a randomized, placebo-controlled trial.

BACKGROUND: High oxidative stress and chronic inflammation can contribute to the pathogenesis of coronary artery disease (CAD). Coenzyme Q10 is an endogenous lipid-soluble antioxidant. Statins therapy can reduce the biosynthesis of coenzyme Q10. The purpose of this study was to investigate the effects of a coenzyme Q10 supplement (300 mg/d; 150 mg/b.i.d) on antioxidation and anti-inflammation in patients who have CAD during statins therapy. METHODS: Patients who were identified by cardiac catheterization as having at least 50% stenosis of one major coronary artery and who were treated with statins for at least one month were enrolled in this study. The subjects (n = 51) were randomly assigned to the placebo (n = 24) and coenzyme Q10 groups (Q10-300 group, n = 27). The intervention was administered for 12 weeks. The concentrations of coenzyme Q10, vitamin E, antioxidant enzymes activities (superoxide dismutase, catalase, and glutathione peroxidase), and inflammatory markers [C-reactive protein (CRP), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6)] were measured in the 42 subjects (placebo, n = 19; Q10-300, n = 23) who completed the study. RESULTS: The levels of the plasma coenzyme Q10 (P < 0.001) and antioxidant enzymes activities (P < 0.05) were significantly higher after coenzyme Q10 supplementation. The levels of inflammatory markers (TNF-a, P = 0.039) were significantly lower after coenzyme Q10 supplementation. The subjects in the Q10-300 group had significantly higher vitamin E (P = 0.043) and the antioxidant enzymes activities (P < 0.05) than the placebo group at week 12. The level of plasma coenzyme Q10 was significantly positively correlated with vitamin E (P = 0.008) and antioxidant enzymes activities (P < 0.05) and was negatively correlated with TNF-a (P = 0.034) and IL-6 (P = 0.027) after coenzyme Q10 supplementation. CONCLUSION: Coenzyme Q10 supplementation at 300 mg/d significantly enhances antioxidant enzymes activities and lowers inflammation in patients who have CAD during statins therapy.

Nutr J. 2013 Nov 6;12(1):142

Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with coronary artery disease.

OBJECTIVE: The purpose of this study was to investigate the effect of coenzyme Q10 supplementation on oxidative stress and antioxidant enzyme activity in patients with coronary artery disease (CAD). METHODS: This was an intervention study. Patients who were identified by cardiac catheterization as having at least 50% stenosis of one major coronary artery or receiving percutaneous transluminal coronary angioplasty (n = 51) were randomly assigned to the placebo group (n = 14) or one of the two coenzyme Q10-supplemented groups (60 mg/d, n = 19 [Q10-60 group]; 150 mg/d, n = 18 [Q10-150 group]). Intervention was administered for 12 wk. Patients’ blood samples were analyzed every 4 wk for plasma coenzyme Q10 concentrations, malondialdehyde (MDA), and antioxidant enzyme (catalase [CAT], superoxide dismutase [SOD], glutathione peroxidase) activity. RESULTS: Forty-three subjects with CAD completed intervention study. Plasma coenzyme Q10 concentration increased significantly after coenzyme the Q10-150 intervention (P < 0.01). The MDA levels were significantly lower than baseline in the Q10-150 group at week 4 (P = 0.03). The Q10-150 group had significantly lower MDA levels than the placebo group at week 8 (P = 0.03). With respect to antioxidant enzyme activity, subjects in the Q10-150 group had significantly higher CAT (P = 0.03) and SOD (P = 0.03) activity than the placebo group at week 12. The plasma coenzyme Q10 concentration was significantly correlated with MDA levels (r = -0.35, P = 0.02) and CAT (r = 0.43, P = 0.01) and SOD activity (r = 0.39, P = 0.01). The ratio of plasma coenzyme Q10 to total cholesterol was significantly correlated with SOD activity (r = 0.39, P = 0.02). The ratio of plasma coenzyme Q10 to low-density lipoprotein was significantly correlated with CAT (r = 0.35, P = 0.04) and SOD (r = 0.45, P = 0.01) activity. However, there was no relation between coenzyme Q10 concentration and glutathione peroxidase activity. CONCLUSION: Coenzyme Q10 supplements at a dose of 150 mg can decrease oxidative stress and increase antioxidant enzyme activity in patients with CAD. A higher dose of coenzyme Q10 supplements (>150 mg/d) might promote rapid and sustainable antioxidation in patients with CAD.

Nutrition. 2012 Mar;28(3):250-5.

Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial.

AIMS: Coronary artery disease (CAD) is associated with endothelial dysfunction and mitochondrial dysfunction (MD). The aim of this study was to investigate whether co-enzyme Q10 (CoQ) supplementation, which is an obligatory coenzyme in the mitochondrial respiratory transport chain, can reverse MD and improve endothelial function in patients with ischaemic left ventricular systolic dysfunction (LVSD). METHODS AND RESULTS: We performed a randomized, double-blind, placebo-controlled trial to determine the effects of CoQ supplement (300 mg/day, n=28) vs. placebo (controls, n=28) for 8 weeks on brachial flow-mediated dilation (FMD) in patients with ischaemic LVSD(left ventricular ejection fraction <45%). Mitochondrial function was determined by plasma lactate/pyruvate ratio (LP ratio). After 8 weeks, CoQ-treated patients had significant increases in plasma CoQ concentration (treatment effect 2.20 µg/mL, P<0.001) and FMD (treatment effect 1.51%, P=0.03); and decrease in LP ratio (treatment effect -2.46, P=0.03) compared with controls. However, CoQ treatment did not alter nitroglycerin-mediated dilation, blood pressure, blood levels of fasting glucose, haemoglobin A1c, lipid profile, high-sensitivity C-reactive protein and oxidative stress as determined by serum superoxide dismutase and 8-isoprostane (all P>0.05). Furthermore, the reduction in LP ratio significantly correlated with improvement in FMD (r=-0.29, P=0.047). CONCLUSION: In patients with ischaemic LVSD, 8 weeks supplement of CoQ improved mitochondrial function and FMD; and the improvement of FMD correlated with the change in mitochondrial function, suggesting that CoQ improved endothelial function via reversal of mitochondrial dysfunction in patients with ischaemic LVSD.

Atherosclerosis. 2011 Jun;216(2):395-401.

The activities of coenzyme Q10 and vitamin B6 for immune responses.

Coenzyme Q10 (CoQ10) and vitamin B6 (pyridoxine) have been administered together and separately to three groups of human subjects. The blood levels of CoQ10 increased (p < 0.001) when CoQ10 and pyridoxine were administered together and when CoQ10 was given alone. The blood levels of IgG increased when CoQ10 and pyridoxine were administered together (p < 0.01) and when CoQ10 was administered alone (p < 0.05). The blood levels of T4-lymphocytes increased when CoQ10 and pyridoxine were administered together (p < 0.01) and separately (p < 0.001). The ratio of T4/T8 lymphocytes increased when CoQ10 and pyridoxine were administered together (p < 0.001) and separately (p < 0.05). These increases in IgG and T4-lymphocytes with CoQ10 and vitamin B6 are clinically important for trials on AIDS, other infectious diseases, and on cancer.

Biochem Biophys Res Commun. 1993 May 28;193(1):88-92.

Effects of folic acid supplementation on cognitive function and Ab-related biomarkers in mild cognitive impairment: a randomized controlled trail.

PURPOSE: Observational studies have frequently reported that low blood folate concentrations are associated with poor cognitive performance. Our previous studies have shown the potential beneficial effect on the metabolite levels of methionine cycle and peripheral blood inflammatory cytokines from 6- and 12-month folic acid supplementation on cognitive function in mild cognitive impairment (MCI). This study aims to continue exploring the effect of 24-month folic acid supplementation on cognitive function and pathological mechanism in MCI. METHODS: 180 individuals with MCI were identified and randomly divided into intervention (folic acid 400 µg/day, n = 90) and convention (n = 90) groups. Cognitive function (WAIS-RC) and blood Ab-related biomarkers were measured at baseline and at 6, 12, 18, and 24 months. Data were analyzed using generalized estimating equation. This trial has been registered with Trial Number: ChiCTR-TRC-13003227. RESULTS: During the follow-up, scores of full scale IQ, verbal IQ, and subdomains of Information and Digit Span were significantly higher in the intervention group than those in the convention group (P < 0.05). In the intervention group, blood homocysteine, S-adenosylhomocysteine (SAH), Ab-42, and the expression of APP-mRNA were decreased (P < 0.05), while S-adenosylmethionine (SAM), SAM/SAH ratio, and the expression of DNA methyltransferase mRNA were increased (P < 0.05). CONCLUSION: Folic acid supplementation appears to improve cognitive function and reduce blood levels of Ab-related biomarkers in MCI. Larger-scale double-blind placebo-controlled randomized trials of longer duration are needed.

Eur J Nutr. 2017 Dec 18.

Folic acid supplementation improves cognitive function by reducing the levels of peripheral inflammatory cytokines in elderly Chinese subjects with MCI.

This study aimed to evaluate whether folic acid supplementation would improve cognitive performance by reducing serum inflammatory cytokine concentrations. This RCT was performed in Tianjin, China. Participants with mild cognitive impairment (MCI) were randomly assigned to the folic acid (400 µg/day) or conventional treatment groups. Neuropsychological tests were administered, and folate, homocysteine, vitamin B₁₂, IL-6, TNF-a, Ab-42, and Ab-40 were measured at baseline and at 6- and 12-month time points.152 participants (folic acid: 77, conventional: 75) completed the trial. Significant improvements in folate (hp2 = 0.703, P = 0.011), homocysteine (hp2 = 0.644, P = 0.009), Ab-42 (hp2 = 0.687, P = 0.013), peripheral IL-6 (hp2 = 0.477, P = 0.025), TNF-a (hp2 = 0.709, P = 0.009) levels were observed in folic acid group compared with conventional group. Folic acid supplementation improved the Full Scale Intelligence Quotient (P = 0.028; effect size d = 0.153), Information (P = 0.031; d = 0.157) and Digit Span (P = 0.009; d = 0.172) scores at 12 months compared with conventional treatment. Based on these findings, daily oral administration of a 400-µg folic acid supplement to MCI subjects for 12 months can significantly improve cognitive performance and reduce peripheral inflammatory cytokine levels.

Sci Rep. 2016 Nov 23;6:37486.

Effects of 6-Month Folic Acid Supplementation on Cognitive Function and Blood Biomarkers in Mild Cognitive Impairment: A Randomized Controlled Trial in China.

BACKGROUND: This study is to examine the effects of folic acid supplementation on cognitive function in Chinese older adults with mild cognitive impairment who are unexposed to folic acid fortification and assess cognitive functioning in relation to folate, homocysteine, and vitamin B12 values at baseline. METHODS: This was a single-center, randomized, controlled trial in Tianjin, China; 180 individuals aged 65 years and older who had mild cognitive impairment were assigned randomly to one of two groups: (a) those treated with oral folic acid (400 µg/day) and (b) those treated via conventional treatment. Tests of cognitive performance and biomarkers were measured at baseline, 3 months, and 6 months. Analysis was by intention-to-treat. Changes in cognitive or clinical function were analyzed by repeated-measure analysis of variance or mixed-effects models. This trial has been registered with the trial number ChiCTR-TRC-13003227. RESULTS: Total of 159 participants (intervention group: 80; control group: 79) completed the trial. Repeated-measure analysis of variance showed significant improvements in serum folate (hp (2) = 0.712, p = .009), homocysteine (hp (2) = 0.119, p = .017), serum vitamin B12 (hp (2) = 0.144, p = .022), and S-adenosylmethionine (hp (2) = 0.117, p = .033) in the intervention group over the control group. Folic acid supplementation improved Full Scale IQ (p = .031; effect size d = 0.168), Digit Span (p = .009; d = 0.176), and Block Design (p = .036; effect size d = 0.146) scores at 6 months in comparison to the control. There were no significant findings for all other cognitive measures. CONCLUSION: There was a beneficial effect from relatively short-term folate supplementation on cognitive functioning in later life. Larger-scale, randomized, controlled trials of longer duration in selected age groups are needed.

J Gerontol A Biol Sci Med Sci. 2016 Oct;71(10):1376-83

A cross-sectional study to find out the relationship of methylenetetrahydrofolate reductase (MTHFR) C677T genotype with plasma levels of folate and total homocysteine by daily folate intake in Japanese.

In those with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, enzyme activity is lowered. Therefore, these individuals might require an increased intake of folate to maintain or control blood levels of plasma folate or total homocysteine (tHcy). We examined associations of dietary folate intake with fasting plasma folate and total homocysteine (tHcy) according to genotype among 554 Japanese (207 men and 347 women aged 39-89 y) recruited in 2009. Intake of folate was estimated with a food frequency questionnaire. The MTHFR polymorphism was genotyped by a polymerase chain reaction with confronting two-pair primers. The log-transformed concentration of folate or tHcy was regressed on energy-adjusted folate intake in a linear regression analysis. Higher folate intake was associated with higher plasma folate among those with the CC (b=0.165, p=0.066) or CT (b=0.248, p<0.001) genotypes, and with lower tHcy levels only among those with the CC (b=-0.141, p=0.013) genotype. Plasma folate was significantly and inversely associated with tHcy, irrespective of MTHFR genotype. When the analysis was restricted to those with tHcy levels higher than the reference range (≥13.5 nmol/mL, n=20), these significant associations were not found. The interaction between folate intake or plasma folate and genotype was not significant in any analysis. In conclusion, dietary folate intake was positively associated with plasma folate among those with the CC or CT genotypes and inversely associated with tHcy among those with the CC genotype, but the associations were not clear among those with higher levels of tHcy.

J Nutr Sci Vitaminol (Tokyo). 2014;60(4):231-8.

5, 10-Methylenetetrahydrofolate reductase (MTHFR) 677 C --> T genetic polymorphism in 228 Croatian volunteers.

5, 10-Methylenetetrahydrofolate Reductase (MTHFR) is one of the key enzymes in the metabolism of homocysteine, where it catalyses its remethylation. The autosomal recessive bp 677 C --> T mutation in the MTHFR gene leads to the substitution of valine for alanine. Individuals who are homozygous for this C677T mutation exhibit a decreased specific activity and increased thermolability of this enzyme. This leads to increased plasma levels of homocysteine, which is a known risk factor for atherosclerosis and various manifestations of the atherosclerotic disease. The aim of this study was to find out the distribution and frequency of this mutation in the general Croatian population. A group of 228 volunteers (175 males and 53 females) has been analyzed for the MTHFR polymorphism, which revealed the following distribution: 105 (46.05%) individuals were without mutation (C/C), 102 (44.74%) were heterozygous (C/T) and 21 (9.21%) homozygous (T/T). These findings are within the results of studies on other European populations.

Coll Antropol. 2004 Dec;28(2):647-54.

[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase.

BACKGROUND AND PURPOSE: 5,10-Methylenetetrahydrofolate reductase (MTHFR) is responsible for the synthesis of 5-methyltetrahydrofolate (5-MTHF). The 677C-->T mutation of MTHFR reduces the activity of this enzyme. The aim of this study was, first, to compare pharmacokinetic parameters of [6S]-5-MTHF and folic acid (FA) in women with the homozygous (TT) and wild-type (CC) 677C-->T mutation, and second, to explore genotype differences. The metabolism of [6S]-5-MTHF and FA was evaluated by measuring plasma folate derivatives. EXPERIMENTAL APPROACH: Healthy females (TT, n= 16; CC, n= 8) received a single oral dose of FA (400 microg) and [6S]-5-MTHF (416 microg) in a randomized crossover design. Plasma folate was measured up to 8 h after supplementation. Concentration-time-profile [area under the curve of the plasma folate concentration vs. time (AUC)], maximum concentration (C(max)) and time-to-reach-maximum (t(max)) were calculated. KEY RESULTS: AUC and C(max) were significantly higher, and t(max) significantly shorter for [6S]-5-MTHF compared with FA in both genotypes. A significant difference between the genotypes was observed for t(max) after FA only (P < 0.05). Plasma folate consisted essentially of 5-MTHF irrespective of the folate form given. Unmetabolized FA in plasma occurs regularly following FA supplementation, but rarely with [6S]-5-MTHF. CONCLUSIONS AND IMPLICATIONS: These data suggest that [6S]-5-MTHF increases plasma folate more effectively than FA irrespective of the 677C-->T mutation of the MTHFR. This natural form of folate could be an alternative to FA supplementation or fortification.

Br J Pharmacol. 2009 Dec;158(8):2014-21

Is the prevalence of MTHFR C677T polymorphism associated with ultraviolet radiation in Eurasia?

The methylenetetrahydrofolic acid reductase (MTHFR) C677T polymorphism causes an amino-acid change from alanine to valine and results in the enzyme becoming thermolabile and half decreased activity. Its prevalence varies among global population. We collected data about MTHFR C677T polymorphism prevalence from epidemiology studies, as well as ultraviolet (UV) radiations and some other climatological factors from the internet. The results of the correlation and quadric regression showed that there was inverse U-shape relationship between T allele frequency and UV radiation. The explanatory power of UV radiation was stronger than latitude and all climatological factors. Our results supported the hypothesis that the distribution pattern of MTFHR C677T polymorphism in Eurasia might be the result of interaction of genetic and environmental natural selection, especially the UV radiation.

J Hum Genet. 2012 Dec;57(12):780-6.

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

Women have higher requirements for folate during pregnancy. An optimal folate status must be achieved before conception and in the first trimester when the neural tube closes. Low maternal folate status is causally related to neural tube defects (NTDs). Many NTDs can be prevented by increasing maternal folate intake in the preconceptional period. Dietary folate is protective, but recommending increasing folate intake is ineffective on a population level particularly during periods of high demands. This is because the recommendations are often not followed or because the bioavailability of food folate is variable. Supplemental folate [folic acid (FA) or 5-methyltetrahydrofolate (5-methylTHF)] can effectively increase folate concentrations to the level that is considered to be protective. FA is a synthetic compound that has no biological functions unless it is reduced to dihydrofolate and tetrahydrofolate. Unmetabolized FA appears in the circulation at doses of >200 µg. Individuals show wide variations in their ability to reduce FA. Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 5-MethylTHF [also known as (6S)-5-methylTHF] is the predominant natural form that is readily available for transport and metabolism. In contrast to FA, 5-methylTHF has no tolerable upper intake level and does not mask vitamin B12 deficiency. Supplementation of the natural form, 5-methylTHF, is a better alternative to supplementation of FA, especially in countries not applying a fortification program. Supplemental 5-methylTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs.

J Perinat Med. 2013 Sep 1;41(5):469-83.

Does 5-methyltetrahydrofolate offer any advantage over folic acid?

Almost half of the women do not follow the guidelines around folate suppletion before and during pregnancy, despite the proven benefit in the prevention of neural tube defects, miscarriages and premature births. The Belgian Superior Health Council recommends a minimum of 400 micrograms of folic acid or folate suppletion per day from 4 weeks before conception to 8 weeks thereafter. Many studies point to the importance of a wider intake period, more particularly at least 3 months before conception and throughout pregnancy and lactation. In high-risk women 4 mg is recommended until after the first 3 months of pregnancy. Afterwards the usual dose of 400 micrograms is sufficient. About half of the European population appears to have a gene mutation on the gene coding for the production of methylenetetrahydrofolate reductase, the enzyme that is involved in the formation of 5-methyltetrahydrofolate, which is, in his turn, responsible for the conversion of the toxic homocysteine in methionine. Women with such a gene polymorphism have a significantly higher risk to have a miscarriage or a baby with neural tube defects. For this reason, a search for an alternative form of synthetic folic acid supplement “pteroylmonoglutamic acid (PMG)” was conducted, particularly the calcium salt of 5-methyltetrahydrofolate (Metafolin). This offers the possibility to deliver the reduced folate immediately, which no longer needs to be converted by the reductase enzyme. Furthermore, this avoids free PMG in the circulation, lowers the risk for drug interactions and a vitamin B2 deficiency will not be masked. Despite clear guidelines regarding dietary supplements before and during pregnancy, their implementation is poor. Not only gynecologists but also GPs and pharmacists, should make more efforts to provide women of childbearing age with personal information. Especially risk groups such as adolescents, low-skilled or less well-off women and immigrants deserve special attention.

J Pharm Belg. 2012 Dec;(4):16-22.

An abnormality of plasma amyloid protein precursor in Alzheimer’s disease.

beta A4 amyloid deposition in the brain, which is characteristic of Alzheimer’s disease (AD), may result from either overexpression of the amyloid protein precursor (APP) or failure of APP to be correctly processed. A blood marker reflecting this abnormal metabolism would be of diagnostic value and would provide a means of monitoring the efficacy of therapeutic interventions. We analyzed immunoblots of plasma APP enriched by heparin-Sepharose chromatography from patients with moderate to severe AD dementia (n = 34) and control subjects (n = 77) and found an approximately 50% increase in the proportion of 130-kd APP species in patients with AD (p less than 0.001), no difference in the 110-kd form, a 15 to 30% decrease in the 65-kd form (p less than 0.001), and a 20 to 35% decrease in the proportion of 42-kd APP (p less than 0.001). These species of APP were soluble, lacked the carboxyl terminus, and the 110- and 42-kd species were shown to be consistent with degradation products derived from the 130-kd species. A comparison of levels of 130-kd plasma APP from moderately to severely demented patients with AD and control subjects distinguished the two groups with a specificity of 87.0% and a sensitivity of 79.4%.

Ann Neurol. 1992 Jul;32(1):57-65.

A long-term study on the use of evening primrose oil (Efamol) in atopic children.

The effect of essential fatty acids on atopic eczema is controversial. Some workers have reported that patients with atopic eczema improved following oral treatment with evening primrose oil (an oil with a high concentration of gamma-linolenic acid), but others have disputed this. This study was designed to look at the effect of evening primrose oil as a long-term oral supplementation for children with atopic eczema. Treated children dramatically improved their clinical condition after 4 weeks of therapy, and this improvement was maintained during the whole period of treatment (20 weeks). At the same time, modifications in plasma, neutrophil and lymphocyte fatty acid composition were detected.

Drugs Exp Clin Res. 1988;14(4):285-90.

Evening primrose oil (Efamol) in the treatment of children with atopic eczema.

It has been reported that essential fatty acid levels may be low and that there may be reduced levels of delta-6-desaturase metabolites of linoleic acid in patients with atopic eczema. Good therapeutic results have been reported on the use of evening primrose oil (Efamol) in adults but not in children. Efamol contains gamma-linolenic acid, the delta-6-desaturase metabolite of linoleic acid. The authors have studied 24 children with atopic eczema: 12 of them were treated with a higher dose of evening primrose oil than in previous studies and 12 with placebo olive oil. The clinical status and plasma, neutrophil and lymphocyte fatty acid composition in these children have been evaluated. After 4 weeks the eczema of essential fatty acid-treated children significantly improved in comparison with that of placebo-treated children (p less than 0.01). There were significant changes in plasma fatty acid composition between the basal values and the end of active treatment, and between the placebo and actively treated children. Neutrophil and lymphocyte fatty acid composition did not seem to be related to disease activity.

Drugs Exp Clin Res. 1988;14(4):291-7.

Sesamin is a potent and specific inhibitor of delta 5 desaturase in polyunsaturated fatty acid biosynthesis.

Incubation with sesame oil increases the mycelial dihomo-gamma-linolenic acid content of an arachidonic acid-producing fungus, Mortierella alpina, but decreases its arachidonic acid content [Shimizu, S., K. Akimoto, H. Kawashima, Y. Shinmen and H. Yamada (1989) J. Am. Oil Chem. Soc. 66, 237-241]. The factor causing these effects was isolated and identified to be (+)-sesamin. The results obtained in experiments with both a cell-free extract of the fungus and with rat liver microsomes demonstrated that (+)-sesamin specifically inhibits delta 5 desaturase at low concentrations, but does not inhibit delta 6, delta 9 and delta 12 desaturases. Kinetic analysis showed that (+)-sesamin is a noncompetitive inhibitor (Ki for rat liver delta 5 desaturase, 155 microM). (+)-Sesamolin, (+)-sesaminol and (+)-episesamin also inhibited only delta 5 desaturases of the fungus and liver. These results demonstrate that (+)-sesamin and related lignan compounds present in sesame seeds or its oil are specific inhibitors of delta 5 desaturase in polyunsaturated fatty acid biosynthesis in both microorganisms and animals.

Lipids. 1991 Jul;26(7):512-6.

Effects of sesamin on the fatty acid composition of the liver of rats fed N-6 and N-3 fatty acid-rich diet.

Sesamin is known as a specific inhibitor of delta 5-desaturation, the conversion from dihomo-gamma-linolenic acid (20:3(n=6)) to arachidonic acid (20:4(n-6)). In the previous paper, we reported that sesamin inhibited delta 5-desaturation of n-6 fatty acids in rat hepatocytes but not that of n-3 fatty acids, from 20:4(n-3) to 20:5(n-3). Then, we studied the effects of sesamin on delta 5-desaturation of n-6 and n-3 fatty acids in vivo. Rats were fed two types of diets containing sesamin (0.5% w/w) for 4 weeks as follows: in experiment 1 (Exp. 1) gamma-linolenic acid-rich diet and in experiment 2 (Exp. 2) alpha-linolenic acid-rich diet. The fatty acid composition of liver lipids was compared to those of control groups without sesamin. In both Exps. 1 and 2, sesamin increased the liver weight and phospholipid contents in liver. In Exp. 2, sesamin increased n-6 fatty acids and decreased n-3 fatty acids even though the diet was rich in n-3 fatty acids. Sesamin enhanced the composition ratio of 20:3(n-6) in both Exps. 1 and 2. Decrease of delta 5-desaturation index of n-6 fatty acid, the ratio of 20:4(n-6)/20:3(n-6), by the administration of sesamin suggested that sesamin inhibited the delta 5-desaturation of n-6 fatty acids in the liver. On the contrary, the delta 5-desaturation index of n-3 fatty acids, the ratio of 20:5(n-3) to 18:3(n-3), was increased by sesamin administration in the liver of rats fed alpha-linolenic acid-rich diet (Exp. 2).(ABSTRACT TRUNCATED AT 250 WORDS).

J Nutr Sci Vitaminol (Tokyo). 1995 Apr;41(2):217-25.

Dietary alpha-linolenic acid increases TNF-alpha, and decreases IL-6, IL-10 in response to LPS: effects of sesamin on the delta-5 desaturation of omega6 and omega3 fatty acids in mice.

Sesamin (a non-fat portion of sesame seed oil) inhibits delta-5 desaturase activity resulting in an accumulation of dihomo-gamma-linolenic acid (DGLA) which can displace arachidonic acid (AA) and decrease the formation of pro-inflammatory mediators. We investigated the effects of consumption of diets containing 0.25wt% sesamin and 15 wt% safflower oil (SO) (providing 12% of the added fat as linoleic acid) or a 15 wt% 2:1 mixture of linseed oil and SO (LOSO) (providing 6% alpha-linolenic acid and 6% linoleic acid) for 3 weeks on the liver membrane fatty acid composition and on the production of prostaglandin (PG) E2, TNF-alpha, IL-6 and IL10 in mice. Consumption of sesamin-supplemented SO and LOSO diets resulted in a significant increase in the levels of 20:3omega6 (DGLA), suggesting that sesamin inhibited delta-5 desaturation of omega6 fatty acids. In animals fed LOSO diets, the levels of alpha-linolenic acid, eicosapentaenoic acid (EPA) and of docosahexaenoic acid (DHA) were elevated with a concomitant decrease of arachidonic acid (AA) in the liver membrane phospholipids. Further, in animals fed LOSO diets with or without sesamin, an increase in the circulating levels of TNF-alpha was associated with a concomitant decrease in PGE2. Despite a lack of differences in the levels of AA, the PGE2 levels were significantly lower in mice fed sesamin-supplemented SO compared to those fed SO alone. Thus, these data suggest that irrespective of the availability of a specific fatty acid as a substrate, through regulating the PGE2 synthesis, the production of TNF-alpha could be modulated.

Prostaglandins Leukot Essent Fatty Acids. 1998 Mar;58(3):185-91.

Protective effects of sesamin against liver damage caused by alcohol or carbon tetrachloride in rodents.

The effects of sesamin, a potent inhibitor of delta 5-desaturase in polyunsaturated fatty acid biosynthesis, on the fatty acid compositions of tissue lipids and liver functions were examined in rodents. When a mixture of sesamin and episesamin (51.1:48.2, w/w) was given to rats at a dietary level of 0.5% for 13 days, the proportions of dihomo-gamma-linolenic acid significantly increased not only in the liver but also in plasma and hemocytes, suggesting an interference with delta 5-desaturation by these lignans. The sesamin preparation at the dietary level of 1% improved changes in various blood parameters of the mouse, such as aspartate aminotransferase and alanine aminotransferase activities, and the concentrations of total cholesterol, triglyceride and total bilirubin, caused by continuous inhalation of ethanol. In addition, sesamin showed a significant protective effect against the accumulation of fat droplets and vacuolar degeneration in the mouse liver, as confirmed on histological examination. Sesamin, at the level of 100 mg/kg body weight, also tended to prevent liver lipid accumulation by carbon tetrachloride in mice. These results indicate that sesamin and a related lignan compound have an ability to improve liver function.

Ann Nutr Metab. 1993;37(4):218-24.

Intravesical meglumine gamma-linolenic acid in superficial bladder cancer: an efficacy study.

OBJECTIVES: Gamma-linolenic acid (GLA) is known to be cytotoxic to malignant cells. We assessed the efficacy of the novel intravesical formulation, meglumine gamma-linolenic acid (MeGLA), in a phase II trial, in patients with recurrent, superficial bladder cancer. PATIENTS AND METHODS: Thirty patients with recurrent, superficial transitional cell carcinoma (TCC) were recruited. The tumour pattern was recorded at flexible cystoscopy. Patients received a single intravesical instillation of 50ml of either 50mg (1mg/ml) (15 patients), or 125mg (2.5mg/ml) (15 patients) of MeGLA in water, retained for one hour. At subsequent cystoscopy, the tumour patterns were recorded, prior to undertaking routine cystodiathermy. Biopsies were obtained for histological assessment. Responses were divided into complete, partial or none. RESULTS: All 30 patients retained the drug for 1 hour without significant local or systemic side effects. There were 4 (13%) complete responses, 9 (30%) partial responses, and 17 (57%) non-responders. Histology showed no evidence of damage to surrounding urothelium. CONCLUSIONS: Our data confirms the safety and tolerability of MeGLA, which is consistent with findings from a previous phase I trial. A response rate of 43% also indicates that MeGLA has a significant cytotoxic effect against TCC and the results are similar to those obtained using standard, single-dose, intravesical regimens.

Eur Urol. 2002 Jul;42(1):39-42.

Gamma linolenic acid with tamoxifen as primary therapy in breast cancer.

Gamma linolenic acid (GLA) has been proposed as a valuable new cancer therapy having selective anti-tumour properties with negligible systemic toxicity. Proposed mechanisms of action include modulation of steroid hormone receptors. We have investigated the effects of GLA with primary hormone therapy in an endocrine-sensitive cancer. Thirty-eight breast cancer patients (20 elderly Stage I-II, 14 locally advanced, 4 metastatic) took 8 capsules of oral GLA/day (total = 2.8 g) in addition to tamoxifen 20 mg od (T+GLA). Quality and duration of response were compared with matched controls receiving tamoxifen 20 mg od alone (n = 47). Serial tumour biopsies were taken to assess changes in oestrogen receptor (ER) and bcl-2 expression during treatment. GLA was well tolerated with no major side effects. T+GLA cases achieved a significantly faster clinical response (objective response vs. static disease) than tamoxifen controls, evident by 6 weeks on treatment (p = 0.010). There was significant reduction in ER expression in both treatment arms with T+GLA objective responders sustaining greater ER fall than tamoxifen counterparts (6-week biopsy p = 0.026; 6-month biopsy p = 0.019). We propose GLA as a useful adjunct to primary tamoxifen in endocrine-sensitive breast cancer. The effects of GLA on ER function and the apparent enhancement of tamoxifen-induced ER down-regulation by GLA require further investigation.

Int J Cancer. 2000 Mar 1;85(5):643-8.

Gamma-linolenic acid therapy of human gliomas.

OBJECTIVES: We investigated the effect of intratumoral administration of gamma-linolenic acid (GLA) in human gliomas. METHODS: We evaluated the effect of the administration of 1 mg of GLA for 7 d via a cerebral reservoir placed into the tumor bed or by direct intratumoral delivery in nine patients who had grade 4 disease and recurrent glioma after surgery, radiation, or chemotherapy. RESULTS: There was some, but not dramatic, improvement in patients’ survival. No significant prolongation of life span was expected considering the advanced nature of the disease. Nevertheless, it was encouraging that GLA produced no significant side effects in any patient. Regression of the cerebral gliomas was visualized on computed tomography and magnetic resonance imaging. CONCLUSIONS: Based on results of the present and previous studies, we believe that GLA is a safe antitumor agent and that higher doses of GLA should be investigated in future studies.

Nutrition. 2003 Apr;19(4):305-9.

Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid-Producing Microbiota in the Gut.

OBJECTIVE: Recent studies suggest the beneficial effects of metformin on glucose metabolism may be microbially mediated. We examined the association of type 2 diabetes, metformin, and gut microbiota in community-dwelling Colombian adults. On the basis of previous research, we hypothesized that metformin is associated with higher levels of short-chain fatty acid (SCFA)-producing and mucin-degrading microbiota. RESEARCH DESIGN AND METHODS: Participants were selected from a larger cohort of 459 participants. The present analyses focus on the 28 participants diagnosed with diabetes-14 taking metformin- and the 84 participants without diabetes who were matched (3-to-1) to participants with diabetes by sex, age, and BMI. We measured demographic information, anthropometry, and blood biochemical parameters and collected fecal samples from which we performed 16S rRNA gene sequencing to analyze the composition and structure of the gut microbiota. RESULTS: We found an association between diabetes and gut microbiota that was modified by metformin use. Compared with participants without diabetes, participants with diabetes taking metformin had higher relative abundance of Akkermansia muciniphila, a microbiota known for mucin degradation, and several gut microbiota known for production of SCFAs, including Butyrivibrio, Bifidobacterium bifidum, Megasphaera, and an operational taxonomic unit of Prevotella. In contrast, compared with participants without diabetes, participants with diabetes not taking metformin had higher relative abundance of Clostridiaceae 02d06 and a distinct operational taxonomic unit of Prevotella and a lower abundance of Enterococcus casseliflavus. CONCLUSIONS: Our results support the hypothesis that metformin shifts gut microbiota composition through the enrichment of mucin-degrading A. muciniphila as well as several SCFA-producing microbiota. Future studies are needed to determine if these shifts mediate metformin’s glycemic and anti-inflammatory properties.

Diabetes Care. 2017 Jan;40(1):54-62.

An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice.

BACKGROUND: Recent evidence indicates that the composition of the gut microbiota contributes to the development of metabolic disorders by affecting the physiology and metabolism of the host. Metformin is one of the most widely prescribed type 2 diabetes (T2D) therapeutic agents. OBJECTIVE: To determine whether the antidiabetic effect of metformin is related to alterations of intestinal microbial composition. DESIGN: C57BL/6 mice, fed either a normal-chow diet or a high-fat diet (HFD), were treated with metformin for 6 weeks. The effect of metformin on the composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. Adipose tissue inflammation was examined by flow cytometric analysis of the immune cells present in visceral adipose tissue (VAT). RESULTS: Metformin treatment significantly improved the glycaemic profile of HFD-fed mice. HFD-fed mice treated with metformin showed a higher abundance of the mucin-degrading bacterium Akkermansia than HFD-fed control mice. In addition, the number of mucin-producing goblet cells was significantly increased by metformin treatment (p<0.0001). Oral administration of Akkermansia muciniphila to HFD-fed mice without metformin significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by inducing Foxp3 regulatory T cells (Tregs) in the VAT. CONCLUSIONS: Modulation of the gut microbiota (by an increase in the Akkermansia spp. population) may contribute to the antidiabetic effects of metformin, thereby providing a new mechanism for the therapeutic effect of metformin in patients with T2D. This suggests that pharmacological manipulation of the gut microbiota in favour of Akkermansia may be a potential treatment for T2D.

Gut. 2014 May;63(5):727-35.

Metformin; a review of its history and future: from lilac to longevity.

Metformin is a widely prescribed medication that has been used to treat children with type 2 diabetes in the United States for the past 15 years. Metformin now has a variety of clinical applications in pediatrics, and its potential clinical uses continue to expand. In addition to reviewing the current understanding of its mechanisms of action including the newly discovered effects on the gastrointestinal tract, we will also discuss current clinical uses in pediatrics, including in type 1 diabetes. Finally, we examine the existing state of monitoring for metformin efficacy and side effects and discuss prospective future clinical uses.

Pediatr Diabetes. 2017 Feb;18(1):10-16.

Metformin: historical overview.

Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega officinalis (also known as goat’s rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Guanidine derivatives, including metformin, were synthesised and some (not metformin) were used to treat diabetes in the 1920s and 1930s but were discontinued due to toxicity and the increased availability of insulin. Metformin was rediscovered in the search for antimalarial agents in the 1940s and, during clinical tests, proved useful to treat influenza when it sometimes lowered blood glucose. This property was pursued by the French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. However, metformin received limited attention as it was less potent than other glucose-lowering biguanides (phenformin and buformin), which were generally discontinued in the late 1970s due to high risk of lactic acidosis. Metformin’s future was precarious, its reputation tarnished by association with other biguanides despite evident differences. The ability of metformin to counter insulin resistance and address adult-onset hyperglycaemia without weight gain or increased risk of hypoglycaemia gradually gathered credence in Europe, and after intensive scrutiny metformin was introduced into the USA in 1995. Long-term cardiovascular benefits of metformin were identified by the UK Prospective Diabetes Study (UKPDS) in 1998, providing a new rationale to adopt metformin as initial therapy to manage hyperglycaemia in type 2 diabetes. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications.

Diabetologia. 2017 Sep;60(9):1566-1576.

Dietary xylooligosaccharide downregulates IFN-γ and the low-grade inflammatory cytokine IL-1β systemically in mice.

Dietary carbohydrates improve growth conditions for distinct populations of bacteria that may affect mucosal and systemic immunity. In this study, we fed in a parallel experiment a 10% xylooligosaccharide (XOS)-supplemented diet or a control diet to 2 groups of male C57BL/6NTac mice for 10 wk from weaning. We found that the XOS diet significantly increased Bifidobacterium throughout the intestine compared with control-fed mice, with the highest proportions found in the ileum after XOS feeding (P < 0.001). In the intestinal epithelium, most innate immune-related genes were unaffected by XOS feeding, whereas expression of interleukin 1b (Il1b) (P < 0.01) and interferon g (Ifng) (P < 0.05) was significantly less in blood from XOS-fed mice than from control-fed mice. In vitro treatment of blood with propionate significantly decreased Il1b (P < 0.01), Ifng (P < 0.01), and interleukin 18 (Il18) (P < 0.001) expression, supporting our hypothesis that increased production of short-chain fatty acids (SCFAs) in the gut, which are transported across the intestine and into the systemic compartments, results in downregulation of low-grade inflammatory cytokines. The defensin regenerating islet-derived protein 3g (RegIIIg) was significantly more highly expressed in the small intestine (P < 0.01) in XOS-fed mice compared with control-fed mice, suggesting only minor contact between bifidobacteria and epithelial cells. In support of this, the SCFA-induced sodium/hydrogen exchanger isoform 3 expression tended to be greater in the XOS group than in the control group (P = 0.06), indicating an indirect SCFA-mediated antiinflammatory effect of XOS. In conclusion, XOS feeding decreases systemic inflammation, and this effect is most likely caused by higher SCFA concentrations as a result of an increased bifidobacterial saccharolytic fermentation in the entire gut and not only in the large intestine.

J Nutr. 2013 Apr;143(4):533-40.

The role of diet on gut microbiota composition.

Gut microbiota is characterized by an inter-individual variability due to genetic and environmental factors. Among the environmental ones, dietary habits play a key role in the modulation of gut microbiota composition. There are main differences between the intestinal microbiota of subjects fed with prevalent Western diet and that of subjects with a diet rich in fibers. Specific changes in the composition of gut microbiota have been demonstrated among subjects according to a different dietary intake. A particular diet may promote the growth of specific bacterial strains, driving hosts to a consequent alteration of fermentative metabolism, with a direct effect on intestinal pH, which can be responsible for the development of a pathogenic flora. Moreover, a high-fat diet can promote the development of a pro-inflammatory gut microbiota, with a consequent increase of intestinal permeability and, consequently, of circulating levels of lipopolysaccharides. In this review, we discuss the direct role of the diet in the composition of gut microbiota and about the possible clinical consequences.

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Eur Rev Med Pharmacol Sci. 2016 Nov;20(22):4742-4749.