Do high-protein diets have the potential to reduce gut barrier function in a sex-dependent manner?

PURPOSE: Impaired gut barrier function is associated with systemic inflammation and many chronic diseases. Undigested dietary proteins are fermented in the colon by the gut microbiota which produces nitrogenous metabolites shown to reduce barrier function in vitro. With growing evidence of sex-based differences in gut microbiotas, we determined whether there were sex by dietary protein interactions which could differentially impact barrier function via microbiota modification. METHODS: Fermentation systems were inoculated with faeces from healthy males (n = 5) and females (n = 5) and supplemented with 0.9 g of non-hydrolysed proteins sourced from whey, fish, milk, soya, egg, pea, or mycoprotein. Microbial populations were quantified using fluorescence in situ hybridisation with flow cytometry. Metabolite concentrations were analysed using gas chromatography, solid phase microextraction coupled with gas chromatography-mass spectrometry and ELISA. RESULTS: Increased protein availability resulted in increased proteolytic Bacteroides spp (p < 0.01) and Clostridium coccoides (p < 0.01), along with increased phenol (p < 0.01), p-cresol (p < 0.01), indole (p = 0.018) and ammonia (p < 0.01), varying by protein type. Counts of Clostridium cluster IX (p = 0.03) and concentration of p-cresol (p = 0.025) increased in males, while females produced more ammonia (p = 0.02), irrespective of protein type. Further, we observed significant sex-protein interactions affecting bacterial populations and metabolites (p < 0.005). CONCLUSIONS: Our findings suggest that protein fermentation by the gut microbiota in vitro is influenced by both protein source and the donor's sex. Should these results be confirmed through human studies, they could have major implications for developing dietary recommendations tailored by sex to prevent chronic illnesses.

Impact of a food-based dietary fat exchange model for replacing dietary saturated with unsaturated fatty acids in healthy men on plasma phospholipids fatty acid profiles and dietary patterns.

PURPOSE: UK guidelines recommend dietary saturated fatty acids (SFAs) should not exceed 10% total energy (%TE) for cardiovascular disease prevention, with benefits observed when SFAs are replaced with unsaturated fatty acids (UFAs). This study aimed to assess the efficacy of a dietary exchange model using commercially available foods to replace SFAs with UFAs. METHODS: Healthy men (n = 109, age 48, SD 11 year) recruited to the Reading, Imperial, Surrey, Saturated fat Cholesterol Intervention-1 (RISSCI-1) study (ClinicalTrials.Gov n°NCT03270527) followed two sequential 4-week isoenergetic moderate-fat (34%TE) diets: high-SFA (18%TE SFAs, 16%TE UFAs) and low-SFA (10%TE SFAs, 24%TE UFAs). Dietary intakes were assessed using 4-day weighed diet diaries. Nutrient intakes were analysed using paired t-tests, fasting plasma phospholipid fatty acid (PL-FA) profiles and dietary patterns were analysed using orthogonal partial least square discriminant analyses. RESULTS: Participants exchanged 10.2%TE (SD 4.1) SFAs for 9.7%TE (SD 3.9) UFAs between the high and low-SFA diets, reaching target intakes with minimal effect on other nutrients or energy intakes. Analyses of dietary patterns confirmed successful incorporation of recommended foods from commercially available sources (e.g. dairy products, snacks, oils, and fats), without affecting participants' overall dietary intakes. Analyses of plasma PL-FAs indicated good compliance to the dietary intervention and foods of varying SFA content. CONCLUSIONS: RISSCI-1 dietary exchange model successfully replaced dietary SFAs with UFAs in free-living healthy men using commercially available foods, and without altering their dietary patterns. Further intervention studies are required to confirm utility and feasibility of such food-based dietary fat replacement models at a population level.

Patient activation and patient-reported outcomes of men from a community pharmacy lifestyle intervention after prostate cancer treatment.

PURPOSE: To report patient activation, which is the knowledge, skills, and confidence in self-managing health conditions, and patient-reported outcomes of men after prostate cancer treatment from a community pharmacy lifestyle intervention. METHODS: The 3-month lifestyle intervention was delivered to 116 men in nine community pharmacies in the UK. Patient Activation Measure (PAM) was assessed at baseline, 3 and 6 months. Prostate cancer-related function and quality of life were assessed using the European Prostate Cancer Index Composite (EPIC-26) and EuroQOL 5-dimension 5-level (EQ5D-5L) questionnaires at baseline and 6 months. Lifestyle assessments included Mediterranean Diet Adherence Screener (MEDAS) at baseline, 3 and 6 months and Godin Leisure Time Exercise Questionnaire (GLTEQ) at baseline and 3 months. RESULTS: PAM score increased from 62 [95% CI 59-65] at baseline to 66 [64-69] after the intervention (p = 0.001) and remained higher at 6 months (p = 0.008). Scores for all the EPIC-26 domains (urinary, bowel and hormonal) were high at both assessments, indicating good function (between 74 [70-78] and 89 [86-91]), except sexual domain, where scores were much lower (21 [17-25] at baseline, increasing to 24 [20-28] at 6 months (p = 0.012)). In EQ5D-5L, 3% of men [1-9] reported self-care problems, while 50% [41-60] reported pain and discomfort, and no significant changes over time. Men who received androgen deprivation therapy, compared with those who did not, reported higher (better) urinary incontinence scores (p < 0.001), but lower (worse) scores in the urinary irritative/obstructive (p = 0.003), bowel (p < 0.001) and hormonal (p < 0.001) domains. Poor sexual function was common across all age groups irrespective of prostate cancer treatment. CONCLUSIONS: The intervention led to significant improvements in patient activation, exercise and diet. Community pharmacy could deliver effective services to address sexual dysfunction, pain and discomfort which are common after prostate cancer.

Responses to a GP survey: current controversies in diet and cardiovascular disease.

BACKGROUND: When advising patients on diet and health, the general practitioner (GP) makes judgements based on the evidence available. Since current evidence on diet and cardiovascular disease is conflicted and confusing, we surveyed the current consensus amongst GPs. The aim of this study was to determine the views of GPs on dietary saturated fat, carbohydrates and long chain omega-3 fatty acids in the management of cardiovascular disease. METHOD: An online questionnaire inviting participants to comment on seven contentious statements on diet and cardiovascular disease. Questionnaire circulated to the 1800 members of South West Thames Faculty of the Royal College of General Practitioners (RCGP). Participants were invited to tick "Agree", "Disagree" or "Not sure" and were encouraged to add comments for each question. The results were analysed with a combination of statistical analysis and thematic analysis of comments. RESULTS: There were 89 responses. Most GPs seem well aware that drug treatment alone is inadequate and that dietary advice is important. However, there was considerable disagreement about the roles of saturated fats and carbohydrates in cardiovascular disease and "Not sure" responses ranged from 12 to 40.7%. The 40.7% related to a statement on long chain omega-3 fatty acids. Analysis of comments revealed more opinions including an awareness of the need to warn patients about trans-fatty acids. CONCLUSIONS: Although the GP response rate was poor, responders do seem to see dietary advice as part of their role but do not consider themselves as experts. Education in this area should have a higher priority.

Impact of liver fat on the differential partitioning of hepatic triacylglycerol into VLDL subclasses on high and low sugar diets.

Dietary sugars are linked to the development of non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia, but it is unknown if NAFLD itself influences the effects of sugars on plasma lipoproteins. To study this further, men with NAFLD (n = 11) and low liver fat 'controls' (n = 14) were fed two iso-energetic diets, high or low in sugars (26% or 6% total energy) for 12 weeks, in a randomised, cross-over design. Fasting plasma lipid and lipoprotein kinetics were measured after each diet by stable isotope trace-labelling.There were significant differences in the production and catabolic rates of VLDL subclasses between men with NAFLD and controls, in response to the high and low sugar diets. Men with NAFLD had higher plasma concentrations of VLDL1-triacylglycerol (TAG) after the high (P<0.02) and low sugar (P<0.0002) diets, a lower VLDL1-TAG fractional catabolic rate after the high sugar diet (P<0.01), and a higher VLDL1-TAG production rate after the low sugar diet (P<0.01), relative to controls. An effect of the high sugar diet, was to channel hepatic TAG into a higher production of VLDL1-TAG (P<0.02) in the controls, but in contrast, a higher production of VLDL2-TAG (P<0.05) in NAFLD. These dietary effects on VLDL subclass kinetics could be explained, in part, by differences in the contribution of fatty acids from intra-hepatic stores, and de novo lipogenesis. The present study provides new evidence that liver fat accumulation leads to a differential partitioning of hepatic TAG into large and small VLDL subclasses, in response to high and low intakes of sugars.

Current and future strategies for the nutritional management of cardiometabolic complications of androgen deprivation therapy for prostate cancer.

Androgen deprivation therapy (ADT) is used widely as part of a combined modality for the treatment of prostate cancer. However, ADT has also been associated with the development of cardiometabolic complications that can increase mortality from cardiovascular events. There is emerging evidence to suggest that ADT-related cardiometabolic risk can be mitigated by diet and lifestyle modification. While the clinical focus for a nutritional approach for achieving this effect is unclear, it may depend upon the timely assessment and targeting of dietary changes to the specific risk phenotype of the patient. The present review aims to address the metabolic origins of ADT-related cardiometabolic risk, existing evidence for the effects of dietary intervention in modifying this risk, and the priorities for future dietary strategies.

Randomised controlled trial of the effect of long-term selenium supplementation on plasma cholesterol in an elderly Danish population.

Although cross-sectional studies have shown a positive association between Se and cholesterol concentrations, a recent randomised controlled trial in 501 elderly UK individuals of relatively low-Se status found that Se supplementation for 6 months lowered total plasma cholesterol. The Danish PRECISE (PREvention of Cancer by Intervention with Selenium) pilot study (ClinicalTrials.gov ID: NCT01819649) was a 5-year randomised, double-blinded, placebo-controlled trial with four groups (allocation ratio 1:1:1:1). Men and women aged 60-74 years (n 491) were randomised to 100 (n 124), 200 (n 122) or 300 (n 119) µg Se-enriched yeast or matching placebo-yeast tablets (n 126) daily for 5 years. A total of 468 participants continued the study for 6 months and 361 participants, equally distributed across treatment groups, continued for 5 years. Plasma samples were analysed for total and HDL-cholesterol and for total Se concentrations at baseline, 6 months and 5 years. The effect of different doses of Se supplementation on plasma lipid and Se concentrations was estimated by using linear mixed models. Plasma Se concentration increased significantly and dose-dependently in the intervention groups after 6 months and 5 years. Total cholesterol decreased significantly both in the intervention groups and in the placebo group after 6 months and 5 years, with small and nonsignificant differences in changes in plasma concentration of total cholesterol, HDL-cholesterol, non-HDL-cholesterol and total:HDL-cholesterol ratio between intervention and placebo groups. The effect of long-term supplementation with Se on plasma cholesterol concentrations or its sub-fractions did not differ significantly from placebo in this elderly population.

HDL and lifestyle interventions.

The main lifestyle interventions to modify serum HDL cholesterol include physical exercise, weight loss with either caloric restriction or specific dietary approaches, and smoking cessation. Moderate alcohol consumption can be permitted in some cases. However, as these interventions exert multiple effects, it is often difficult to discern which is responsible for improvement in HDL outcomes. It is particularly noteworthy that recent data questions the use of HDL cholesterol as a risk factor and therapeutic target since randomised interventions and Mendelian randomisation studies failed to provide evidence for such an approach. Therefore, these current data should be considered when reading and interpreting this review. Further studies are needed to document the effect of lifestyle changes on HDL structure-function and health.

Nonpharmacological approaches for reducing serum low-density lipoprotein cholesterol.

PURPOSE OF REVIEW: To reinforce the key role of diet and lifestyle modification as the first-line treatment for the reduction of raised serum low-density lipoprotein cholesterol (LDL-C) and prevention of cardiovascular disease. Also, to counter recent claims that the current dietary guidelines for the treatment of cardiovascular disease have misplaced emphasis on the importance of removing dietary saturated fat instead of sugar. RECENT FINDINGS: This review provides new insight into the effects of diet and lifestyle factors with established efficacy in lowering serum LDL-C. This includes energy-restricted weight loss and new findings on the effects of alternative day fasting; novel metabolic and molecular effects of replacing palmitic acid with oleic acid; evidence for a dose-response relationship between the intake of dietary stanols and LDL-C; and identification of a unique metabolic pathway for the excretion of cholesterol. SUMMARY: The review reports new evidence for the efficacy of alternate day fasting, reassurance that the current dietary guidelines are not misguided by recommending removal of saturated fat, that a high intake of dietary stanols can achieve a reduction in LDL-C of up to 18%, and describes a pathway of cholesterol excretion that may help to explain variation in the response of serum LDL-C to dietary fat and cholesterol.

Saturated fat and CVD: importance of inter-individual variation in the response of serum low-density lipoprotein cholesterol.

The aim of this review is to provide an overview of the history in support of the role of dietary saturated fatty acids (SFA) in the development of cardiovascular disease (CVD), and the controversy and consensus for the evidence in support of guidelines to remove and replace SFA with unsaturated fatty acids. The review will also examine the existence, origins, and implications for CVD risk of variability in serum LDL-cholesterol in response to these guidelines. While the quality of supporting evidence for the efficacy of restricting SFA on CVD risk has attracted controversy, this has helped to increase understanding of the inter-relationships between SFA, LDL-cholesterol and CVD, and reinforce confidence in this dietary recommendation. Nevertheless, there is significant inter-individual variation in serum LDL-C in response to this dietary change. The origins of this variation are multi-factorial and involve both dietary and metabolic traits. If serum biomarkers of more complex metabolic traits underlying LDL-responsiveness can be identified, this would have major implications for the targeting of these dietary guidelines to LDL-responders, to maximise the benefit to their cardiovascular health.

Separation of the principal HDL subclasses by iodixanol ultracentrifugation.

HDL subclasses detection, in cardiovascular risk, has been limited due to the time-consuming nature of current techniques. We have developed a time-saving and reliable separation of the principal HDL subclasses employing iodixanol density gradient ultracentrifugation (IxDGUC) combined with digital photography. HDL subclasses were separated in 2.5 h from prestained plasma on a three-step iodixanol gradient. HDL subclass profiles were generated by digital photography and gel scan software. Plasma samples (n = 46) were used to optimize the gradient for the resolution of HDL heterogeneity and to compare profiles generated by IxDGUC with gradient gel electrophoresis (GGE); further characterization from participants (n = 548) with a range of lipid profiles was also performed. HDL subclass profiles generated by IxDGUC were comparable to those separated by GGE as indicated by a significant association between areas under the curve for both HDL2 and HDL3 (HDL2, r = 0.896, P < 0.01; HDL3, r = 0.894, P < 0.01). The method was highly reproducible, with intra- and interassay coefficient of variation percentage < 5 for percentage area under the curve HDL2 and HDL3, and < 1% for peak Rf and peak density. The method provides time-saving and cost-effective detection and preparation of the principal HDL subclasses.

The acute and long-term effects of dietary fatty acids on vascular function in health and disease.

PURPOSE OF REVIEW: Vascular function is recognized as an early and integrative marker of cardiovascular disease. While there is consistent evidence that the quantity of dietary fat has significant effects on vascular function, the differential effects of individual fatty acids is less clear. This review summarizes recent evidence from randomly controlled dietary studies on the impact of dietary fatty acids on vascular function, as determined by flow-mediated dilatation (FMD). RECENT FINDINGS: Critical appraisal is given to five intervention studies (one acute, four chronic) which examined the impact of long-chain n-3 polyunsaturated fatty acid [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] on FMD. In the acute setting, a high dose of long-chain n-3 polyunsaturated fatty acid (4.9 g per 70 kg man) improved postprandial FMD significantly, compared with a saturated fatty acid-rich meal in healthy individuals. In longer-term studies, there was limited evidence for a significant effect of EPA/DHA on FMD in diseased groups. SUMMARY: The strongest evidence for the benefits of EPA/DHA on vascular function is in the postprandial state. More evidence from randomly controlled intervention trials with foods will be required to substantiate the long-term effects of EPA/DHA, to inform public health and clinical recommendations.

Variation in the effects of three different breakfast meals on subjective satiety and subsequent intake of energy at lunch and evening meal.

PURPOSE: To determine the relative impact of three iso-caloric breakfast meals, of variable composition, on satiety, hunger and subsequent intake of energy. METHODS: In a three-way, crossover design, 30 healthy men (age of 21.7 ± 1.2 years; BMI, 23.1 ± 2.7 kg/m²) were randomised to one of three test breakfasts, on three separate occasions, separated by 1 week. The breakfasts consisted of eggs on toast, cereal (cornflakes) with milk and toast, or a croissant and orange juice. Subjective ratings of satiety, hunger, fullness and desire to eat were recorded at 30-min intervals by electronic visual analogue scales (VAS). Energy intake was assessed by weighed food intake at an ad libitum lunch and evening meal. RESULTS: Participants showed increased satiety, less hunger and a lower desire to eat after the breakfast containing eggs relative to the cereal (p < 0.02), and croissant-based meals (p < 0.0001). The egg breakfast was also accompanied by a significantly lower intake of energy relative to the croissant- and cereal-based breakfasts at the buffet lunch and evening meal, respectively, 1,284 ± 464 (egg) versus 1,442 ± 426 kcal (croissant), p = 0.03, 1,407 ± 379 (cereal) at lunch and 1,899 ± 729 (egg) versus 2,214 ± 620 kcal (cereal), p = 0.02, 2,047 ± 712 (croissant) at evening meal. The breakfast meal with the greatest effect on satiety and subsequent intake of energy was distinct in having the highest protein and lowest carbohydrate content relative to the other two breakfasts. CONCLUSION: These findings provide evidence to support the importance of food choice at breakfast as a means of increasing satiety in the morning and reducing energy intake at lunch.

Effect of supplementation with high-selenium yeast on plasma lipids: a randomized trial.

BACKGROUND: High selenium status has been linked to elevated blood cholesterol levels in cross-sectional studies. OBJECTIVE: To investigate the effect of selenium supplementation on plasma lipids. DESIGN: Randomized, placebo-controlled, parallel-group study stratified by age and sex. Participants, research nurses, and persons assessing outcomes were blinded to treatment assignment. (International Standard Randomised Controlled Trial Number Register registration number: ISRCTN25193534) SETTING: 4 general practices in the United Kingdom. PARTICIPANTS: 501 volunteers aged 60 to 74 years. INTERVENTION: Participants received selenium, 100 mcg/d (n = 127), 200 mcg/d (n = 127), or 300 mcg/d (n = 126), as high-selenium yeast or a yeast-based placebo (n = 121) for 6 months. MEASUREMENTS: Total and high-density lipoprotein (HDL) cholesterol concentrations were measured in nonfasting plasma samples stored from participants in the UK PRECISE (United Kingdom PREvention of Cancer by Intervention with SElenium) Pilot Study at baseline (n = 454) and at 6 months (n = 394). Non-HDL cholesterol levels were calculated. RESULTS: Mean plasma selenium concentration was 88.8 ng/g (SD, 19.2) at baseline and increased statistically significantly in the treatment groups. The adjusted difference in change in total cholesterol levels for selenium compared with placebo was -0.22 mmol/L (-8.5 mg/dL) (95% CI, -0.42 to -0.03 mmol/L [-16.2 to -1.2 mg/dL]; P = 0.02) for 100 mcg of selenium per day, -0.25 mmol/L (-9.7 mg/dL) (CI, -0.44 to -0.07 mmol/L [-17.0 to -2.7 mg/dL]; P = 0.008) for 200 mcg of selenium per day, and -0.07 mmol/L (-2.7 mg/dL) (CI, -0.26 to 0.12 mmol/L [-10.1 to 4.6 mg/dL]; P = 0.46) for 300 mcg of selenium per day. Similar reductions were observed for non-HDL cholesterol levels. There was no apparent difference in change in HDL cholesterol levels with 100 and 200 mcg of selenium per day, but the difference was an adjusted 0.06 mmol/L (2.3 mg/dL) (CI, 0.00 to 0.11 mmol/L [0.0 to 4.3 mg/dL]; P = 0.045) with 300 mcg of selenium per day. The total-HDL cholesterol ratio decreased progressively with increasing selenium dose (overall P = 0.01). LIMITATION: The duration of supplementation was limited, as was the age range of the participants. CONCLUSION: Selenium supplementation seemed to have modestly beneficial effects on plasma lipid levels in this sample of persons with relatively low selenium status. The clinical significance of the findings is unclear and should not be used to justify the use of selenium supplementation as additional or alternative therapy for dyslipidemia. This is particularly true for persons with higher selenium status, given the limitations of the trial and the potential additional risk in other metabolic dimensions. PRIMARY FUNDING SOURCE: The Cancer Research Campaign (now Cancer Research UK) and the University of Surrey.

Interaction of PPARG Pro12Ala with dietary fat influences plasma lipids in subjects at cardiometabolic risk.

The PPARγ2 gene single nucleotide polymorphism (SNP) Pro12Ala has shown variable association with metabolic syndrome traits in healthy subjects. The RISCK Study investigated the effect of interaction between genotype and the ratio of polyunsaturated:saturated (P:S) fatty acid intake on plasma lipids in 367 white subjects (ages 30-70 years) at increased cardiometabolic risk. Interaction was determined after habitual diet at recruitment, at baseline after a 4-week high-SFA (HS) diet, and after a 24-week reference (HS), high-MUFA (HM), or low-fat (LF) diet. At recruitment, there were no significant associations between genotype and plasma lipids; however, P:S × genotype interaction influenced plasma total cholesterol (TC) (P = 0.02), LDL-cholesterol (LDL-C) (P = 0.002), and triglyceride (TG) (P = 0.02) concentrations. At P:S ratio ≤ 0.33, mean TC and LDL-C concentrations in Ala12 allele carriers were significantly higher than in noncarriers (respectively, P = 0.003; P = 0.0001). Significant trends in reduction of plasma TC (P = 0.02) and TG (P = 0.002) concentrations occurred with increasing P:S (respectively, ≤0.33 to >0.65; 0.34 to >0.65) in Ala12 allele carriers. There were no significant differences between carriers and noncarriers after the 4-week HS diet or 24-week interventions. Plasma TC and TG concentrations in PPARG Ala12 allele carriers decrease as P:S increases, but they are not dependent on a reduction in SFA intake.

Small dense LDL particles--a predictor of coronary artery disease evaluated by invasive and CT-based techniques: a case-control study.

BACKGROUND: Coronary angiography is the current standard method to evaluate coronary atherosclerosis in patients with suspected angina pectoris, but non-invasive CT scanning of the coronaries are increasingly used for the same purpose. Low-density lipoprotein (LDL) cholesterol and other lipid and lipoprotein variables are major risk factors for coronary artery disease. Small dense LDL particles may be of particular importance, but clinical studies evaluating their predictive value for coronary atherosclerosis are few. METHODS: We performed a study of 194 consecutive patients with chest pain, a priori considered of low to intermediate risk for significant coronary stenosis (>50% lumen obstruction) who were referred for elective coronary angiography. Plasma lipids and lipoproteins were measured including the subtype pattern of LDL particles, and all patients were examined by coronary CT scanning before coronary angiography. RESULTS: The proportion of small dense LDL was a strong univariate predictor of significant coronary artery stenosis evaluated by both methods. After adjustment for age, gender, smoking, and waist circumference only results obtained by traditional coronary angiography remained statistically significant. CONCLUSION: Small dense LDL particles may add to risk stratification of patients with suspected angina pectoris.