A water-soluble tomato extract rich in secondary plant metabolites lowers trimethylamine-n-oxide and modulates gut microbiota: a randomized, double-blind, placebo-controlled cross-over study in overweight and obese adults.

BACKGROUND: Natural products rich in polyphenols have been shown to lower plasma trimethylamine-n-oxide (TMAO) known for its proatherogenic effects by modulating the intestinal microbiota. OBJECTIVES: We aimed to determine the impact of Fruitflow, a water-soluble tomato extract, on TMAO, fecal microbiota, and plasma and fecal metabolites. METHODS: Overweight and obese adults (n = 22, BMI 28-35 kg/m2) were included in a double-blind, placebo-controlled, cross-over study receiving 2×150 mg Fruitflow per day or placebo (maltodextrin) for 4 wk with a 6-week wash-out between interventions. Stool, blood, and urine samples were collected to assess changes in plasma TMAO (primary outcome) as well as fecal microbiota, fecal and plasma metabolites, and urine TMAO (secondary outcomes). In a subgroup (n = 9), postprandial TMAO was evaluated following a choline-rich breakfast (∼450 mg). Statistical methods included paired t-tests or Wilcoxon signed rank tests and permutational multivariate analysis of variance. RESULTS: Fruitflow, but not placebo, reduced fasting levels of plasma (-1.5 µM, P ≤ 0.05) and urine (-19.1 µM, P ≤ 0.01) TMAO as well as plasma lipopolysaccharides (-5.3 ng/mL, P ≤ 0.05) from baseline to the end of intervention. However, these changes were significant only for urine TMAO levels when comparing between the groups (P ≤ 0.05). Changes in microbial beta, but not alpha, diversity paralleled this with a significant difference in Jaccard distance-based Principal Component (P ≤ 0.05) as well as decreases in Bacteroides, Ruminococccus, and Hungatella and increases in Alistipes when comparing between and within groups (P ≤ 0.05, respectively). There were no between-group differences in SCFAs and bile acids (BAs) in both faces and plasma but several changes within groups such as an increase in fecal cholic acid or plasma pyruvate with Fruitflow (P ≤ 0.05, respectively). An untargeted metabolomic analysis revealed TMAO as the most discriminant plasma metabolite between groups (P ≤ 0.05). CONCLUSIONS: Our results support earlier findings that polyphenol-rich extracts can lower plasma TMAO in overweight and obese adults related to gut microbiota modulation. This trial was registered at clinicaltrials.gov as NCT04160481 (https://clinicaltrials.gov/ct2/show/NCT04160481?term= Fruitflow&draw= 2&rank= 2).

Evaluation of the equivalence of different intakes of Fruitflow in affecting platelet aggregation and thrombin generation capacity in a randomized, double-blinded pilot study in male subjects.

BACKGROUND: The water-soluble tomato extract, Fruitflow® is a dietary antiplatelet which can be used to lower platelet aggregability in primary preventative settings. We carried out a pilot study to investigate the range of intakes linked to efficacy and to make an initial assessment of variability in response to Fruitflow®. METHODS: Platelet response to adenosine diphosphate (ADP) agonist and thrombin generation capacity were monitored at baseline and 24 h after consuming 0, 30, 75, 150 or 300 mg of Fruitflow® in a randomized, double-blinded crossover study in male subjects 30-65 years of age (N = 12). Results were evaluated for equivalence to the standard 150 mg dose. RESULTS: Results showed that the changes from baseline aggregation and thrombin generation observed after the 75 mg, 150 mg, and 300 mg supplements were equivalent. Aggregation was reduced from baseline by - 12.9 ± 17.7%, - 12.0 ± 13.9% and - 17.7 ± 15.7% respectively, while thrombin generation capacity fell by - 8.6 ± 4.1%, - 9.2 ± 3.1% and - 11.3 ± 2.3% respectively. Effects observed for 0 mg and 30 mg supplements were non-equivalent to 150 mg and not different from baseline (aggregation changed by 3.0 ± 5.0% and - 0.7 ± 10.2% respectively, while thrombin generation changed by 0.8 ± 3.0% and 0.8 ± 3.1% respectively). CONCLUSIONS: The data suggest that the efficacious range for Fruitflow® lies between 75 mg and 300 mg, depending on the individual. It may be pertinent to personalize the daily intake of Fruitflow® depending on individual platelet response. TRIAL REGISTRATION: ISRCTN53447583 , 24/02/2021.

Dietary Antiplatelets: A New Perspective on the Health Benefits of the Water-Soluble Tomato Concentrate Fruitflow®.

Our understanding of platelet functionality has undergone a sea change in the last decade. No longer are platelets viewed simply as regulators of haemostasis; they are now acknowledged to be pivotal in coordinating the inflammatory and immune responses. This expanded role for platelets brings new opportunities for controlling a range of health conditions, targeting platelet activation and their interactions with other vascular cells. Antiplatelet drugs may be of wider utility than ever expected but often cause platelet suppression too strong to be used out of clinical settings. Dietary antiplatelets represent a nutritional approach that can be efficacious while safe for general use. In this review, we discuss potential new uses for dietary antiplatelets outside the field of cardiovascular health, with specific reference to the water-soluble tomato extract Fruitflow®. Its uses in different aspects of inflammation and immune function are discussed, highlighting exercise-induced inflammation, mediating the effects of air pollution, and controlling thrombotic aspects of the immune response. Potential future developments in women's health, erectile dysfunction, and the allergic response indicate how broad the utility of dietary antiplatelets can be.

Effect of Varying Molecular Weight of Oat ß-Glucan Taken just before Eating on Postprandial Glycemic Response in Healthy Humans.

To see if the molecular weight (MW) and viscosity of oat ß-glucan (OBG) when taken before eating determine its effect on postprandial glycemic responses (PPRG), healthy overnight-fasted subjects (n = 16) were studied on eight separate occasions. Subjects consumed 200 mL water alone (Control) or with 4 g OBG varying in MW and viscosity followed, 2-3 min later, by 113 g white-bread. Blood was taken fasting and at 15, 30, 45, 60, 90, and 120 min after starting to eat. None of the OBG treatments differed significantly from the Control for the a-priori primary endpoint of glucose peak-rise or secondary endpoint of incremental area-under-the-curve (iAUC) over 0-120 min. However, significant differences from the Control were seen for glucose iAUC over 0-45 min and time to peak (TTP) glucose. Lower log(MW) and log(viscosity) were associated with higher iAUC 0-45 (p < 0.001) and shorter TTP (p < 0.001). We conclude that when 4 g OBG is taken as a preload, reducing MW does not affect glucose peak rise or iAUC0-120, but rather accelerates the rise in blood glucose and reduces the time it takes glucose to reach the peak. However, this is based on post-hoc calculation of iAUC0-45 and TTP and needs to be confirmed in a subsequent study.

Increasing oat ß-glucan viscosity in a breakfast meal slows gastric emptying and reduces glycemic and insulinemic responses but has no effect on appetite, food intake, or plasma ghrelin and PYY responses in healthy humans: a randomized, placebo-controlled, crossover trial.

BACKGROUND: The viscosity of oat ß-glucan (OBG) determines its effect on serum cholesterol and glycemic responses, but whether OBG viscosity affects gastric emptying, appetite, and ad libitum food intake is unknown. OBJECTIVES: We aimed to determine the effect of altering the amount or molecular weight (MW) and, hence, viscosity of OBG in a breakfast meal on the primary endpoint of food intake at a subsequent meal. METHODS: Overnight-fasted males (n = 16) and nonpregnant females (n = 12) without diabetes, aged 18-60 y, with BMI 20.0-30.0 kg/m² who were unrestrained eaters participated in a double-blind, randomized, crossover study at a contract research organization. Participants consumed, in random order, breakfast meals equivalent in weight, energy, and macronutrients consisting of white-bread, butter, jam, and 2% milk plus hot cereal [Cream of Rice (CR), or instant-oatmeal plus either 3 g oat-bran (2gOBG), 10 g oat-bran (4gOBG), or 10 g oat-bran plus ß-glucanase (4gloMW) to reduce OBG MW and viscosity compared with 4gOBG]. Gastric emptying, subjective appetite, and glucose, insulin, ghrelin, and peptide tyrosine tyrosine (PYY) responses were assessed for 3 h and then subjects were offered an ad libitum lunch (water and pizza). RESULTS: Pizza intakes (n = 28) after CR, 2gOBG, 4gOBG, and 4gloMW (mean ± SEM: 887 ± 64, 831 ± 61, 834 ± 78, and 847 ± 68 kcal, respectively) were similar (nonsignificant). Compared with CR, 4gOBG significantly reduced glucose (78 ± 10 compared with 135 ± 15 mmol × min/L) and insulin (14.0 ± 1.6 compared with 26.8 ± 3.5 nmol × min/L) incremental area-under-the-curve and delayed gastric-emptying half-time (geometric mean: 285; 95% CI: 184, 442, compared with geometric mean: 105; 95% CI: 95, 117 min), effects not seen after 4gloMW. Subjective appetite, PYY, and ghrelin responses after 2gOBG, 4gOBG, and 4gloMW were similar to those after CR. CONCLUSIONS: The results demonstrate that OBG viscosity determines its effect on postprandial glucose, insulin, and gastric emptying. However, we were unable to demonstrate a significant effect of OBG on appetite or food intake, regardless of its viscosity.This trial was registered at clinicaltrials.gov as NCT03490851.

Effect of adding oat bran to instant oatmeal on glycaemic response in humans - a study to establish the minimum effective dose of oat ß-glucan.

Reducing the glycaemic response to carbohydrate-containing foods may have desirable physiological effects for many people. Here, we aimed to determine the minimum amount of oat ß-glucan from oat-bran which, when added to instant-oatmeal, would reduce the glycaemic response by 20% compared to a ß-glucan-free cereal. Therefore, the glycaemic responses elicited by one serving (27 g) instant-oatmeal plus 247 g 2% milk (IO, 28 g available-carbohydrate, 1.2 g ß-glucan) or IO plus 0.2, 0.4, 0.8 or 1.6 g oat ß-glucan (OBG) from oat-bran, or an available-carbohydrate matched portion of cream of rice (CR) plus milk were measured over 2 h in n = 40 subjects using a randomized, cross-over design. The primary endpoint was incremental area under the curve (iAUC). The secondary endpoint was glucose peak-rise. The results showed that grams OBG consumed were significantly correlated with mean iAUC (p = 0.009) and with mean glucose peak-rise (p = 0.002). Each gram of OBG reduced iAUC by 7% and peak-rise by 15%. Thus, to achieve a ≥20% reduction in iAUC relative to CR, 1.6 g OBG had to be added to IO (74 ± 7 vs. 93 ± 6 mmol min L-1, p < 0.05), but, to achieve a 20% reduction in peak-rise, only 0.4 g OBG was required (2.00 ± 0.1 vs. 2.40 ± 0.1 mmol, p < 0.05). We conclude that adding OBG to IO flattened postprandial glycaemic responses in a dose-dependent fashion; 1.6 g OBG was required to reduce iAUC by ≥20% versus CR, but a 20% reduction in peak-rise required only 0.4 g. The greater effect of OGB on peak-rise than iAUC presumably reflects the way viscous dietary fibres modulate glucose absorption kinetics.

Bioactive oat ß-glucan reduces LDL cholesterol in Caucasians and non-Caucasians.

BACKGROUND: There is increasing global acceptance that viscous soluble fibers lower serum LDL cholesterol (LDL-C), but most evidence for this comes from studies in Caucasians. To see if oat ß-glucan lowers LDL-C in Caucasians and non-Caucasians we conducted a post-hoc analysis of the results of a randomized, controlled, double-blind, multi-center clinical trial whose primary aim was to determine if molecular-weight (MW) influenced the LDL-C-lowering effect of oat ß-glucan. RESULTS: Caucasian and non-Caucasian subjects with LDL-C-C ≥ 3.0 and ≤ 5.0 mmol/L (n = 786 screened, n = 400 ineligible, n = 19 refused, n = 367 randomized, n = 345 completed, n = 1 excluded for missing ethnicity) were randomly assigned to consume cereal containing wheat-fiber (Control, n = 74:13 Caucasian:non-Caucasian) or 3 g high-MW (3H, 2,250,000 g/mol, n = 67:19), 4 g medium-MW (4 M, 850,000 g/mol, n = 50:17), 3 g medium-MW (3M, 530,000 g/mol, n = 54:9) or 4 g low-MW (4 L, 210,000 g/mol, n = 51:12) oat ß-glucan daily for 4 weeks. LDL-C after 4 weeks was influenced by baseline LDL-C (p < 0.001) and treatment (p = 0.003), but not ethnicity (p = 0.74). In all subjects, compared to control, 3 H, 4 M and 3 M reduced LDL-C significantly by 4.8 to 6.5%, but 4 L had no effect. Compared to control, the bioactive oat ß-glucan treatments (3H, 4M and 3M) reduced LDL-C by a combined mean (95% CI) of 0.18 (0.06, 0.31) mmol/L (4.8%, n = 171, p = 0.004) in Caucasians, a value not significantly different from the 0.37 (0.09, 0.65) mmol/L (10.3%, n = 45, p = 0.008) reduction in non-Caucasians. CONCLUSION: We conclude that oat ß-glucan reduces LDL-C in both Caucasians and non-Caucasians; there was insufficient power to determine if the magnitude of LDL-C-lowering differed by ethnicity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00981981.

Physicochemical properties of oat ß-glucan influence its ability to reduce serum LDL cholesterol in humans: a randomized clinical trial.

BACKGROUND: Consumption of 3 g oat ß-glucan/d is considered sufficient to lower serum LDL cholesterol, but some studies have shown no effect. LDL cholesterol lowering by oat ß-glucan may depend on viscosity, which is controlled by the molecular weight (MW) and amount of oat ß-glucan solubilized in the intestine (C). OBJECTIVES: Our 2 primary objectives were to determine whether consumption of 3 g high-MW oat ß-glucan/d would reduce LDL cholesterol and whether LDL cholesterol lowering was related to the log(MW × C) of oat ß-glucan. DESIGN: In a double-blind, parallel-design, multicenter clinical trial, subjects with LDL cholesterol ≥3.0 and ≤5.0 mmol/L (n = 786 screened, n = 400 ineligible, n = 19 refused, n = 367 enrolled, and n = 345 completed) were randomly assigned to receive cereal containing wheat fiber (n = 87) or 3 g high-MW (2,210,000 g/mol, n = 86), 4 g medium-MW (850,000 g/mol, n = 67), 3 g medium-MW (530,000 g/mol, n = 64), or 4 g low-MW (210,000 g/mol, n = 63) oat ß-glucan/d (divided doses, twice daily) for 4 wk. RESULTS: LDL cholesterol was significantly less with 3 g high-MW, 4 g medium-MW, and 3 g medium-MW oat ß-glucan cereals than with the wheat-fiber cereal by 0.21 (5.5%; 95% CI: -0.11, -0.30; P = 0.002), 0.26 (6.5%; 95% CI: -0.14, -0.37; P = 0.0007), and 0.19 (4.7%; 95% CI: -0.08, -0.30; P = 0.01) mmol/L, respectively. However, the effect of 4 g low-MW oat ß-glucan/d (0.10 mmol/L) was not significant (2.3%; 95% CI: 0.02, -0.20). By analysis of covariance, log(MW × C) was a significant determinant of LDL cholesterol (P = 0.003). Treatment effects were not significantly influenced by age, sex, study center, or baseline LDL cholesterol. CONCLUSIONS: The physicochemical properties of oat ß-glucan should be considered when assessing the cholesterol-lowering ability of oat-containing products; an extruded breakfast cereal containing 3 g oat ß-glucan/d with a high-MW (2,210,000 g/mol) or a medium-MW (530,000 g/mol) lowered LDL cholesterol similarly by ≈0.2 mmol/L (5%), but efficacy was reduced by 50% when MW was reduced to 210,000 g/mol. This trial was registered at www.clinicaltrials.gov as NCT00981981.

Processing affects the physicochemical properties of beta-glucan in oat bran cereal.

The tendency of mixed linkage oat beta-glucan to form viscous solutions is generally assumed to be related to its ability to lower serum cholesterol levels in humans. However, the association has not been clearly demonstrated. To conduct a clinical trial showing the relationship between LDL-cholesterol levels and viscosity, a series of extruded oat bran cereals were prepared in which the beta-glucan had a range of molecular weights and modified solubility. An extraction protocol using physiological enzymes at 37 degrees C was used to estimate the effect that the cereals would have on gut viscosity. By reducing the molecular weight from 1,930,000 to 251,000 g/mol, the apparent viscosity in the physiological extract dropped from 2900 to 131 mPa.s (at 30 s(-1)). Microscopic examination showed that as the extrusion conditions were made more severe, to cause depolymerization, the integrity of the cell walls was lost and beta-glucan dispersed throughout the cereal. Differences in the hardness and density of the extruded cereals were also evident as the molecular weight was reduced.