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Dietary flavanols restore hippocampal-dependent memory in older adults with lower diet quality and lower habitual flavanol consumption.
Brickman, AM, Yeung, LK, Alschuler, DM, Ottaviani, JI, Kuhnle, GGC, Sloan, RP, Luttmann-Gibson, H, Copeland, T, Schroeter, H, Sesso, HD, et al
Proceedings of the National Academy of Sciences of the United States of America. 2023;120(23):e2216932120
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“Cognitive aging” is a term used to describe how some of our cognitive abilities decline during the aging process, independent of late-life cognitive diseases. Because cognitive aging is meaningfully disruptive to our lives, it is biomedically justified to identify its etiologic factors. The current study was ancillary to COSMOS and termed COSMOS-Web. COSMOS was designed to examine the effects of cocoa extract and multivitamin supplementation on total cardiovascular disease and total invasive cancer. For this study, the focus is on the cocoa extract intervention only. Participants were randomly assigned to a 3-year intervention of cocoa extract or a placebo. Results showed that a flavanol intervention-based restoration of memory was observed in the lower tertile of habitual diet quality and in the subset of participants with lower habitual flavanol consumption. The improvement in memory was apparent after 12 months of intervention and appeared to be sustained over the 3 years of follow-up. Additionally, diet quality is a key lifestyle factor linked to the hippocampal and not to the prefrontal component of cognitive aging. Authors concluded that habitual flavanol consumption and diet quality at baseline are positively and selectively correlated with hippocampal-dependent memory. Improvements in the flavanol biomarker over the trial were associated with improving memory.
Abstract
Dietary flavanols are food constituents found in certain fruits and vegetables that have been linked to cognitive aging. Previous studies suggested that consumption of dietary flavanols might specifically be associated with the hippocampal-dependent memory component of cognitive aging and that memory benefits of a flavanol intervention might depend on habitual diet quality. Here, we tested these hypotheses in the context of a large-scale study of 3,562 older adults, who were randomly assigned to a 3-y intervention of cocoa extract (500 mg of cocoa flavanols per day) or a placebo [(COcoa Supplement and Multivitamin Outcomes Study) COSMOS-Web, NCT04582617]. Using the alternative Healthy Eating Index in all participants and a urine-based biomarker of flavanol intake in a subset of participants [n = 1,361], we show that habitual flavanol consumption and diet quality at baseline are positively and selectively correlated with hippocampal-dependent memory. While the prespecified primary end point testing for an intervention-related improvement in memory in all participants after 1 y was not statistically significant, the flavanol intervention restored memory among participants in lower tertiles of habitual diet quality or habitual flavanol consumption. Increases in the flavanol biomarker over the course of the trial were associated with improving memory. Collectively, our results allow dietary flavanols to be considered in the context of a depletion-repletion paradigm and suggest that low flavanol consumption can act as a driver of the hippocampal-dependent component of cognitive aging.
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Host-diet-gut microbiome interactions influence human energy balance: a randomized clinical trial.
Corbin, KD, Carnero, EA, Dirks, B, Igudesman, D, Yi, F, Marcus, A, Davis, TL, Pratley, RE, Rittmann, BE, Krajmalnik-Brown, R, et al
Nature communications. 2023;14(1):3161
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Composition of the human gut microbiome has been shown to be associated with chronic diseases such as obesity, however whether they have a causal effect in disease development or whether microbiota composition is a direct result of the disease is unclear. This randomised control trial of 17 individuals aimed to determine the effects of a diet designed to modulate the gut microbiome (MBD) on human energy balance compared to a typical Western style diet (WD). The MBD diet maximised fibre, resistant starch, and limited processed foods and resulted in a significant decrease in the amount of energy produced by individuals compared to the WD. It was also shown that the MBD increased the microbial composition and decreased nutrient breakdown. It was concluded that the MBD increased the amount of gut bacteria and altered the amount of energy produced by individuals on this diet. This study could be used by healthcare practitioners to understand that composition of the gut microbiome can affect the amount of energy gained from food. Diets high in fibre, starch and low in processed foods, which promote microbial diversity may help individuals to lose weight.
Abstract
The gut microbiome is emerging as a key modulator of human energy balance. Prior studies in humans lacked the environmental and dietary controls and precision required to quantitatively evaluate the contributions of the gut microbiome. Using a Microbiome Enhancer Diet (MBD) designed to deliver more dietary substrates to the colon and therefore modulate the gut microbiome, we quantified microbial and host contributions to human energy balance in a controlled feeding study with a randomized crossover design in young, healthy, weight stable males and females (NCT02939703). In a metabolic ward where the environment was strictly controlled, we measured energy intake, energy expenditure, and energy output (fecal and urinary). The primary endpoint was the within-participant difference in host metabolizable energy between experimental conditions [Control, Western Diet (WD) vs. MBD]. The secondary endpoints were enteroendocrine hormones, hunger/satiety, and food intake. Here we show that, compared to the WD, the MBD leads to an additional 116 ± 56 kcals (P < 0.0001) lost in feces daily and thus, lower metabolizable energy for the host (89.5 ± 0.73%; range 84.2-96.1% on the MBD vs. 95.4 ± 0.21%; range 94.1-97.0% on the WD; P < 0.0001) without changes in energy expenditure, hunger/satiety or food intake (P > 0.05). Microbial 16S rRNA gene copy number (a surrogate of biomass) increases (P < 0.0001), beta-diversity changes (whole genome shotgun sequencing; P = 0.02), and fermentation products increase (P < 0.01) on an MBD as compared to a WD along with significant changes in the host enteroendocrine system (P < 0.0001). The substantial interindividual variability in metabolizable energy on the MBD is explained in part by fecal SCFAs and biomass. Our results reveal the complex host-diet-microbiome interplay that modulates energy balance.
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Metabolomic Profiles Associated With Blood Pressure Reduction in Response to the DASH and DASH-Sodium Dietary Interventions.
Kim, H, Appel, LJ, Lichtenstein, AH, Wong, KE, Chatterjee, N, Rhee, EP, Rebholz, CM
Hypertension (Dallas, Tex. : 1979). 2023;80(7):1494-1506
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DASH (Dietary Approaches to Stop Hypertension) diet is recommended for reducing blood pressure (BP) and the risk of cardiovascular disease (CVD). The DASH diet emphasises the intake of fruits, vegetables, and low-fat dairy, includes a variety of protein sources and it is low in red and processed meats and sugar-sweetened beverages. The aim of this study was to identify metabolites associated with differences in systolic blood pressure (SBP) or diastolic blood pressure (DBP) in response to the diet interventions. This study used data from 2 randomised controlled feeding trials (DASH trial and DASH-Sodium trial). Results show the identification of 42 unique metabolites (9 serum and 33 urine) which were significantly associated with changes in SBP or DBP DASH diet versus control diet interventions. Furthermore, pathway overrepresentation analysis revealed metabolite pathways that were relevant for the association between DASH diet and BP. Authors conclude that their findings provide insights on formulating intervention strategies to reduce BP.
Abstract
BACKGROUND The DASH (Dietary Approaches to Stop Hypertension) diets reduced blood pressure (BP) in the DASH and DASH-Sodium trials, but the underlying mechanisms are unclear. We identified metabolites associated with systolic BP or diastolic BP (DBP) changes induced by dietary interventions (DASH versus control arms) in 2 randomized controlled feeding studies-the DASH and DASH-Sodium trials. METHODS Metabolomic profiling was conducted in serum and urine samples collected at the end of diet interventions: DASH (n=219) and DASH-Sodium (n=395). Using multivariable linear regression models, associations were examined between metabolites and change in systolic BP and DBP. Tested for interactions between diet interventions and metabolites were the following comparisons: (1) DASH versus control diets in the DASH trial (serum), (2) DASH high-sodium versus control high-sodium diets in the DASH-Sodium trial (urine), and (3) DASH low-sodium versus control high-sodium diets in the DASH-Sodium trial (urine). RESULTS Sixty-five significant interactions were identified (DASH trial [serum], 12; DASH high sodium [urine], 35; DASH low sodium [urine], 18) between metabolites and systolic BP or DBP. In the DASH trial, serum tryptophan betaine was associated with reductions in DBP in participants consuming the DASH diets but not control diets (P interaction, 0.023). In the DASH-Sodium trial, urine levels of N-methylglutamate and proline derivatives (eg, stachydrine, 3-hydroxystachydrine, N-methylproline, and N-methylhydroxyproline) were associated with reductions in systolic BP or DBP in participants consuming the DASH diets but not control diets (P interaction, <0.05 for all tests). CONCLUSIONS We identified metabolites that were associated with BP lowering in response to dietary interventions. REGISTRATION URL: https://www. CLINICALTRIALS gov/ct2/show/NCT03403166; Unique identifier: NCT03403166 (DASH trial). URL: https://www. CLINICALTRIALS gov/ct2/show/NCT00000608; Unique identifier: NCT00000608 (DASH-Sodium trial).
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Vitamin D for the Immune System in Cystic Fibrosis (DISC): a double-blind, multicenter, randomized, placebo-controlled clinical trial.
Tangpricha, V, Lukemire, J, Chen, Y, Binongo, JNG, Judd, SE, Michalski, ES, Lee, MJ, Walker, S, Ziegler, TR, Tirouvanziam, R, et al
The American journal of clinical nutrition. 2019;109(3):544-553
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Patients with cystic fibrosis (CF) have a mutation in a particular gene which results in derangements in chloride transport across epithelial surfaces, leading to abnormally thickened mucus on the surfaces of the lung, pancreas, intestines, and other organs. The aim of this study was to investigate the impact of high-dose vitamin D3 administered to adults with CF during and after an acute pulmonary exacerbation. The study is a double-blind, randomised, placebo-controlled clinical trial. Subjects were randomly assigned and stratified to one of the two groups: vitamin D (5 capsules of vitamin D3 containing 50,000 IU) or placebo (5 capsules that were identical in size, shape, and colour to the vitamin D3 capsule). Results demonstrated that high-dose vitamin D3 administration to adults with CF initiated at the time of a pulmonary exacerbation did not improve time to next pulmonary exacerbation or 1 year survival. Authors conclude that a high-dose vitamin D3 bolus, combined with maintenance therapy given to adults with CF during acute pulmonary exacerbation of CF did not improve 1 year survival or recovery of lung function.
Abstract
BACKGROUND Patients with cystic fibrosis (CF) have increased risk of vitamin D deficiency owing to fat malabsorption and other factors. Vitamin D deficiency has been associated with increased risk of pulmonary exacerbations of CF. OBJECTIVES The primary objective of this study was to examine the impact of a single high-dose bolus of vitamin D3 followed by maintenance treatment given to adults with CF during an acute pulmonary exacerbation on future recurrence of pulmonary exacerbations. METHODS This was a multicenter, double-blind, placebo-controlled, intent-to-treat clinical trial. Subjects with CF were randomly assigned to oral vitamin D3 given as a single dose of 250,000 International Units (IU) or to placebo within 72 h of hospital admission for an acute pulmonary exacerbation, followed by 50,000 IU of vitamin D3 or an identically matched placebo pill taken orally every other week starting at 3 mo after random assignment. The primary outcome was the composite endpoint of the time to next pulmonary exacerbation or death within 1 y. The secondary outcomes included circulating concentrations of the antimicrobial peptide cathelicidin and recovery of lung function as assessed by the percentage of predicted forced expiratory volume in 1 s (FEV1%). RESULTS A total of 91 subjects were enrolled in the study. There were no differences between the vitamin D3 and placebo groups in time to next pulmonary exacerbation or death at 1 y. In addition, there were no differences in serial recovery of lung function after pulmonary exacerbation by FEV1% or in serial concentrations of plasma cathelicidin. CONCLUSIONS Vitamin D3 initially given at the time of pulmonary exacerbation of CF did not alter the time to the next pulmonary exacerbation, 12-mo mortality, serial lung function, or serial plasma cathelicidin concentrations. This trial was registered at clinicaltrials.gov as NCT01426256.
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Broccoli consumption affects the human gastrointestinal microbiota.
Kaczmarek, JL, Liu, X, Charron, CS, Novotny, JA, Jeffery, EH, Seifried, HE, Ross, SA, Miller, MJ, Swanson, KS, Holscher, HD
The Journal of nutritional biochemistry. 2019;63:27-34
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Diet affects metabolic and gastrointestinal diseases, with the microbiome considered to be a mediating factor. Broccoli is a good source of fibre and phytochemicals including glucosinolates. The aim of this investigator-blinded, controlled feeding, randomised, crossover study was to evaluate the effects of broccoli on the composition and function of the microbiome. 18 healthy adults received 200 g cooked broccoli and 20 g raw daikon radish per day for 18 days in addition to a controlled, brassica-free diet or the same diet without the broccoli and daikon radish, with a 24-day washout period. A statistically significant increase in the ratio of Bacteroidetes to Firmicutes was observed following the broccoli intervention. When stratified by BMI above or below 25, this increase was only seen in those with a lower BMI whilst those with a higher BMI displayed a decrease in the ratio, although the latter was not statistically significant. In those with the lower BMI, there was also a correlation between the changes in the microbiota composition and glucosinolate metabolites. It was predicted that the involved changes would affect the functions of the endocrine system, transport and catabolism and energy metabolism. The authors concluded that eating broccoli may affect both the composition and the function of the microbiome.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Broccoli consumption at dosages of 200g per day were shown to change the composition of gastrointestinal microbiota, increasing Bacteroidetes and decreasing Firmicutes, and impact their function
- The observed results were strongest in those with a BMI of less than 26
- While interesting, the study only included 18 participants and therefore the results should be further confirmed.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
There is growing evidence linking dysbiosis of the gastrointestinal microbiota and diet-induced gastrointestinal and metabolic diseases. Both long-term and acute dietary changes, fasting, eating frequency, and consumption of specific fibres and food phytochemicals play a role in shaping the composition and function of the microbiota, although evidence is lacking for specific foods. This study aimed to determine the impact of broccoli intake on the number of bacterial strains and their functional capacity.
Methods
This was a single-blind, randomised, crossover, complete feeding intervention. Study participants were healthy adults (n=18, females =10). Participants were requested to not eat Brassica vegetables for 3 weeks before the start of the study.
Subjects participated in two 18-day diet periods separated by a 24-hour washout, during which breakfast and dinner were consumed on site to observe compliance. The control diet was prepared using traditional American foods, excluding all Brassica vegetables. During the broccoli intervention period, participants consumed the same base diet with the addition of 200g of broccoli.
Faecal samples were collected on day 1, and day 16. Quantitative polymerase chain reaction was performed on bacterial strains. On day 17, time series plasma sampling and 24-hour urine collection was done.
Results
There was no difference in alpha diversity (a measure of microbiome diversity within a sample) between the two treatment periods. This indicates that no bacterial species were extinguished by broccoli treatment. Beta diversity analysis (a measure of the (dis)similarity between samples) indicated that bacterial communities were impacted by treatment (P=0.03).
After broccoli consumption, Bacteroidetes increased by 10% (P =0.03), while Firmicutes decreased by 8% (P=0.05). Overall the ratio of Bacteroidetes to Firmicutes increased by 37% (P=0.01) versus a 5% decrease in the control period. The Bacteroides genus increased by 6% (P=0.02) versus a 2% decrease in the control period.
Interestingly, the effects were most strong in those with a lower BMI (< 26 kg/m2) who had an increase in metabolites after broccoli consumption. Algorithms to predict the function of the microbiota showed that broccoli increased endocrine (P=0.05), energy metabolism (P=0.01), transport and catabolism (P=0.04) pathways.
Conclusion
Broccoli intake, at 200g daily, changes the composition and potentially impacts the function of the gut microbiota.
Clinical practice applications:
- Studies like this allow practitioners to focus on specific foods in specific quantities to positively alter the microbiota and their function
- Cruciferous vegetables, like broccoli, kale, cauliflower, cabbage, Brussel sprouts, are an important group as they contain fibre and phytonutrients such as glucosinolates. These compounds can be metabolised by the microbiota into active compounds with health benefits. This study has shown the bidirectional benefit of broccoli consumption in that it can positively impact the function and composition of the microbiota
- Interestingly, the results in this small study were driven by participants with a BMI of less than 26. Sub-group analysis found no statistically significant relationships in participants with BMI >26
- It is worth noting that it is possible that the addition of 5g of fibre from the broccoli is also contributing to the changes observed.
Considerations for future research:
- Larger, controlled feeding studies that isolate specific foods to identify their effects on the microbiota are needed
- Genetic sequencing for only a few bacterial myrosinases has been completed and therefore future studies should aim to assess the metabolic capabilities in faecal samples such as myrosinase activity
- While this study and others have shown changes in the types of bacteria after cruciferous vegetable consumption the consistency of results has been mixed potentially due to differing study designs and treatment dosages. Further studies to clarify and confirm these results would be beneficial
- To assess the function of the microbiota a predictive algorithm was used. This requires experimental confirmation by such methods as metabolite profiling and whole genome shotgun sequencing.
Abstract
The human gastrointestinal microbiota is increasingly linked to health outcomes; however, our understanding of how specific foods alter the microbiota is limited. Cruciferous vegetables such as broccoli are a good source of dietary fiber and phytonutrients, including glucosinolates, which can be metabolized by gastrointestinal microbes. This study aimed to determine the impact of broccoli consumption on the gastrointestinal microbiota of healthy adults. A controlled feeding, randomized, crossover study consisting of two 18-day treatment periods separated by a 24-day washout was conducted in healthy adults (n=18). Participants were fed at weight maintenance with the intervention period diet including 200 g of cooked broccoli and 20 g of raw daikon radish per day. Fecal samples were collected at baseline and at the end of each treatment period for microbial analysis. Beta diversity analysis indicated that bacterial communities were impacted by treatment (P=.03). Broccoli consumption decreased the relative abundance of Firmicutes by 9% compared to control (P=.05), increased the relative abundance of Bacteroidetes by 10% compared to control (P=.03) and increased Bacteroides by 8% relative to control (P=.02). Furthermore, the effects were strongest among participants with body mass index <26 kg/m2, and within this group, there were associations between bacterial relative abundance and glucosinolate metabolites. Functional prediction revealed that broccoli consumption increased the pathways involved in the functions of the endocrine system (P=.05), transport and catabolism (P=.04), and energy metabolism (P=.01). These results reveal that broccoli consumption affects the composition and function of the human gastrointestinal microbiota.
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A whole-grain diet reduces peripheral insulin resistance and improves glucose kinetics in obese adults: A randomized-controlled trial.
Malin, SK, Kullman, EL, Scelsi, AR, Haus, JM, Filion, J, Pagadala, MR, Godin, JP, Kochhar, S, Ross, AB, Kirwan, JP
Metabolism: clinical and experimental. 2018;82:111-117
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Literature shows that dietary whole-grain intake is associated with a lower incidence of type 2 diabetes. The aim of the study was to investigate the association between a whole-grain diet and insulin resistance and glucose use in individuals at risk for type 2 diabetes. The study was a randomized, double-blind, controlled crossover trial involving fourteen middle-aged, obese adults at risk for diabetes. Randomisation was carried out prior to metabolic testing. Results indicate that whole-grain intake as part of a mixed-meal diet significantly improved post-prandial (after a meal) glucose metabolism in middle-aged obese adults. Furthermore, both whole-grain and refined-grain interventions induced about 3–6% weight and fat loss. Authors conclude that whole-grain intake effectively promotes glycaemic control by improving insulin action.
Abstract
BACKGROUND Whole-grain intake is associated with lower risk of type 2 diabetes but the mechanisms are unclear. PURPOSE We tested the hypothesis that a WG diet reduces insulin resistance and improves glucose use in individuals at risk for type 2 diabetes compared with an isocaloric-matched refined-grain diet. METHODS A double-blind, randomized, controlled, crossover trial of 14 moderately obese adults (Age, 38 ± 2 y; BMI, 34.0 ± 1.1 kg/m2). Insulin resistance and glucose metabolism was assessed using an oral glucose tolerance test combined with isotopic tracers of [6,6-2H2]-glucose and [U-13C]-glucose, and indirect calorimetry. Peripheral and hepatic insulin resistance was assessed as 1/(rate of disposal/insulin), and endogenous glucose rates of appearance (Ra) iAUC60-240 × insulin iAUC60-240, respectively. Both diets met ADA nutritional guidelines and contained either whole-grain (50 g per 1000 kcal) or equivalent refined-grain. All food was provided for 8 wk. with an 8-10 wk. washout period between diets. RESULTS Post-prandial glucose tolerance, peripheral insulin sensitivity, and metabolic flexibility (insulin-stimulated - fasting carbohydrate oxidation) improvements were greater after whole-grain compared to the refined-grain diet (P < 0.05). Compared to baseline, body fat (~2 kg) and hepatic Ra insulin resistance was reduced by both diets, while fasting glucose and exogenous glucose-meal were unchanged after both interventions. Changes in peripheral insulin resistance and metabolic flexibility correlated with improved glucose tolerance (P < 0.05). CONCLUSION Whole-grains reduced diabetes risk and the mechanisms appear to work through reduced post-prandial blood glucose and peripheral insulin resistance that were statistically linked to enhanced metabolic flexibility.
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A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function.
Vazquez-Roque, MI, Camilleri, M, Smyrk, T, Murray, JA, Marietta, E, O'Neill, J, Carlson, P, Lamsam, J, Janzow, D, Eckert, D, et al
Gastroenterology. 2013;144(5):903-911.e3
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The relationship between gluten exposure and diarrhoea-predominant irritable bowel syndrome (IBS-D) is not well understood. Non-celiac IBS-D patients who are positive for HLA-DQ2/8 genes associated with CD can show symptom improvement on a gluten-free diet (GFD). The aim of this 4-week parallel randomized controlled clinical trial in HLA-DQ2/8 positive and negative patients with IBS-D was to assess the effects of a gluten-containing diet (GCD) compared to a GFD on bowel function, gut transit, small bowel (SB) and colonic barrier functions as measured by two-sugar excretion permeability test and mRNA expression of TJ proteins in mucosa of the small bowel (SB) and rectosigmoid (RS) derived by biopsy. Immune response to diets was also measured as cytokine production from peripheral blood mononuclear cells (PBMCs). Patient were recruited from the Mayo clinic’s database of IBS suffers, and invited to participate. Patients with diagnosed CD were excluded. Genotype analysis was performed for HLA-DQ2 and HLA-DQ8. 22 patients were placed on the GCD (11 HLA-DQ2/8–negative and 11 HLA-DQ2/8–positive) and 23 on the GFD (12 HLA-DQ2/8−negative and 11 HLA-DQ2/8–positive. All meals and snacks were ingested or prepared in the Mayo Clinic. Patients were advised to eat only the foods provided by the study dieticians. Gluten-free and gluten-containing meals were prepared using the same macronutrient content (20% protein, 30% fat, 50% carb). Compliance to the diet was assessed by direct questioning by the dietitians and reported to be excellent. All patients were ingesting gluten in their diet prior to starting the study. At 4-weeks, a statistically significant decrease in stool frequency of subjects on GFD compared to subjects on GCD (p=0.04) was seen. This effect was more pronounced in subjects who were HLA-DQ2 or 8 positive (p=0.019) There was no significant diet effect (GFD vs. GCD) on, daily stool form, ease of passage or gastric emptying. The GCD was associated with higher small bowel (SB) permeability (based on 0–2 hr levels of mannitol (p=0.028) and lactulose:mannitol ratio (P=0.0012)). SB permeability was greater in HLA-DQ2/8–positive than −negative patients (P=.018). No significant differences in colonic permeability were observed. Significant diet-associated changes in occludin expression in SB mucosa in the HLA-DQ2 or 8 positive group were seen (p=0.017). Expressions of tight junction proteins (zonulin (ZO-1), occludin, and claudin-1 mRNA) in colonic mucosa were significantly lower in GCD relative to GFD in the overall groups, particularly in subjects with HLA-DQ2 or 8 positive status. Cytokine response was higher (interleukin-10) in response to GCD than GFD (unrelated to HLA genotype). A limitation in the quantification of TJ protein expression is that it was solely based on PCR (mRNA expression). In future, other methods should be included to directly identify these proteins and their distribution. The inability to document alterations in colonic permeability using the 2-sugar excretion profile from 8 to 24 hours is a limitation. This may be due to lack of sensitivity of the lactulose and mannitol excretion test, for example, due to the metabolism of both sugars by colonic bacteria. Another limitation is that the mechanism for improvement in stool frequency on a GFD in the absence of changes in colonic transit was not elucidated by our studies. This study does not specifically address the effects of gluten protein per se, and it is possible that other proteins in wheat flour may be responsible for the changes observed. The author concludes that this study provide mechanistic explanations for the observation that gluten withdrawal may improve patient symptoms in IBS. The data also partially explains that the biological effects of gluten were associated with HLA-DQ2 or 8 genotype. The relationship of dietary factors, innate and adaptive immune responses and mucosal interactions in IBS-D deserve further study. Further clinical studies evaluating the effects of gluten withdrawal in patients with IBS-D are needed.
Abstract
BACKGROUND & AIMS Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD). METHODS We performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive) and 23 patients were placed on the GFD (12 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive). We measured bowel function daily, small-bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells after exposure to gluten and rice. We collected rectosigmoid biopsy specimens from 28 patients, analyzed levels of messenger RNAs encoding tight junction proteins, and performed H&E staining and immunohistochemical analyses. Analysis of covariance models was used to compare data from the GCD and GFD groups. RESULTS Subjects on the GCD had more bowel movements per day (P = .04); the GCD had a greater effect on bowel movements per day of HLA-DQ2/8-positive than HLA-DQ2/8-negative patients (P = .019). The GCD was associated with higher SB permeability (based on 0-2 h levels of mannitol and the lactulose:mannitol ratio); SB permeability was greater in HLA-DQ2/8-positive than HLA-DQ2/8-negative patients (P = .018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of zonula occludens 1 in SB mucosa and significant decreases in expression of zonula occludens 1, claudin-1, and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8-positive patients. The GCD vs the GFD had no significant effects on transit or histology. Peripheral blood mononuclear cells produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-α in response to gluten than rice (unrelated to HLA genotype). CONCLUSIONS Gluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8-positive patients. These findings reveal a reversible mechanism for the disorder. Clinical trials.govNCT01094041.
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Effects of dietary composition on energy expenditure during weight-loss maintenance.
Ebbeling, CB, Swain, JF, Feldman, HA, Wong, WW, Hachey, DL, Garcia-Lago, E, Ludwig, DS
JAMA. 2012;307(24):2627-34
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Many diets can produce weight loss over the short term, but most people struggle to maintain this loss over the long term. One explanation is that weight loss results in biological effects, such as a decline in energy expenditure and an increase in hunger, that promote weight regain. The aim of the study was to examine the effects of three different diets on energy expenditure, hormones (including leptin, insulin, cortisol and thyroid hormones) and metabolic indicators following a 10-15% weight loss. The three diets differed widely in macronutrient composition and were: low-fat/high glycaemic load (60% energy from carbohydrates, 20%, 20% protein) LF; low glycaemic index (40%-40%-20%) LGI; and very low carbohydrate/low glycaemic load (10%-60%-30%) VLC. Participants were assigned to one of the three diets for four weeks. Participants on the VLC diet had a resting energy expenditure (REE) of 67kcal/day greater than the LF diet, as well as a total energy expenditure (TEE) of 300kcal/day greater. The physiological basis for these differences is unclear. Although the VLC diet produced the greatest improvements in most metabolic syndrome markers, it also resulted in increased cortisol and inflammation markers. These could be deleterious to health in the long term.
Abstract
CONTEXT Reduced energy expenditure following weight loss is thought to contribute to weight gain. However, the effect of dietary composition on energy expenditure during weight-loss maintenance has not been studied. OBJECTIVE To examine the effects of 3 diets differing widely in macronutrient composition and glycemic load on energy expenditure following weight loss. DESIGN, SETTING, AND PARTICIPANTS A controlled 3-way crossover design involving 21 overweight and obese young adults conducted at Children's Hospital Boston and Brigham and Women's Hospital, Boston, Massachusetts, between June 16, 2006, and June 21, 2010, with recruitment by newspaper advertisements and postings. INTERVENTION After achieving 10% to 15% weight loss while consuming a run-in diet, participants consumed an isocaloric low-fat diet (60% of energy from carbohydrate, 20% from fat, 20% from protein; high glycemic load), low-glycemic index diet (40% from carbohydrate, 40% from fat, and 20% from protein; moderate glycemic load), and very low-carbohydrate diet (10% from carbohydrate, 60% from fat, and 30% from protein; low glycemic load) in random order, each for 4 weeks. MAIN OUTCOME MEASURES Primary outcome was resting energy expenditure (REE), with secondary outcomes of total energy expenditure (TEE), hormone levels, and metabolic syndrome components. RESULTS Compared with the pre-weight-loss baseline, the decrease in REE was greatest with the low-fat diet (mean [95% CI], -205 [-265 to -144] kcal/d), intermediate with the low-glycemic index diet (-166 [-227 to -106] kcal/d), and least with the very low-carbohydrate diet (-138 [-198 to -77] kcal/d; overall P = .03; P for trend by glycemic load = .009). The decrease in TEE showed a similar pattern (mean [95% CI], -423 [-606 to -239] kcal/d; -297 [-479 to -115] kcal/d; and -97 [-281 to 86] kcal/d, respectively; overall P = .003; P for trend by glycemic load < .001). Hormone levels and metabolic syndrome components also varied during weight maintenance by diet (leptin, P < .001; 24-hour urinary cortisol, P = .005; indexes of peripheral [P = .02] and hepatic [P = .03] insulin sensitivity; high-density lipoprotein [HDL] cholesterol, P < .001; non-HDL cholesterol, P < .001; triglycerides, P < .001; plasminogen activator inhibitor 1, P for trend = .04; and C-reactive protein, P for trend = .05), but no consistent favorable pattern emerged. CONCLUSION Among overweight and obese young adults compared with pre-weight-loss energy expenditure, isocaloric feeding following 10% to 15% weight loss resulted in decreases in REE and TEE that were greatest with the low-fat diet, intermediate with the low-glycemic index diet, and least with the very low-carbohydrate diet. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00315354.
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9.
A nutrient-wide association study on blood pressure.
Tzoulaki, I, Patel, CJ, Okamura, T, Chan, Q, Brown, IJ, Miura, K, Ueshima, H, Zhao, L, Van Horn, L, Daviglus, ML, et al
Circulation. 2012;126(21):2456-64
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Elevated blood pressure (BP) is a major risk factor for coronary heart disease and stroke. This study aims to examine the association between a wide range of nutrients and BP using a systematic nutrient-wide association study (NWAS) approach. Data obtained from the cross-sectional International Study of Macro/Micro-nutrients and Blood Pressure (INTERMAP) were analysed. All foods and drinks, including supplements, from 24-hours dietary recalls as well as analytes from urine collection were recorded. Statistical analyses were then performed for the associations of 82 nutrients from food only, 73 nutrients from foods plus supplements, as well as 3 urinary electrolytes/electrolyte ratios with systolic and diastolic BP. The study found: direct associations between alcohol and urinary sodium/potassium ratio with systolic BP; inverse associations between dietary phosphorus, magnesium, non-heme iron, thiamin, folacin, and riboflavin with systolic BP; inverse associations between dietary folacin and riboflavin with diastolic BP; and inclusion of nutrients from supplements intake decreased the associations of folacin, thiamin and riboflavin intake with BP. Authors emphasised the importance of NWAS approach to identify the complex array of nutritional correlates of systolic and diastolic BP. Findings have a potential to represent causative relations that need to be further examined in observational and interventional studies.
Abstract
BACKGROUND A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner. METHODS AND RESULTS Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005-2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1-SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP. CONCLUSIONS We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations.
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The fall in leptin concentration is a major determinant of the metabolic adaptation induced by caloric restriction independently of the changes in leptin circadian rhythms.
Lecoultre, V, Ravussin, E, Redman, LM
The Journal of clinical endocrinology and metabolism. 2011;96(9):E1512-6
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Weight loss induced by caloric restriction (CR) is associated with a drop in energy expenditure (EE) beyond that expected for the changes in body composition, often blunting weight loss and predisposing individuals to weight regain. Recent evidence has identified leptin to be associated with this exaggerated decrease in EE. The aim of this trial was to explore the changes in leptin over a 24-hour period in response to caloric restriction, and explore its association with metabolic adaptation. Forty-eight participants were assigned to one of four groups for six months: control, CR, CR with exercise and a low calorie diet. This study indicates that the decline in 24-hour leptin in response to CR is a significant determinant of metabolic adaptation. Based on this study, the authors conclude that this decrease in leptin may underlie the additional reduction in EE observed in individuals following diet-induced weight loss.
Abstract
CONTEXT Leptin is involved in the hormonal regulation of the reproductive, somatotropic, thyroid, and autonomic axes and ultimately in the regulation of energy balance. In parallel to the metabolic adaptation observed in response to caloric restriction (CR), plasma leptin concentrations are substantially decreased, suggesting a role for this hormone in the drop in energy expenditure beyond that predicted by the changes in body composition (metabolic adaptation). AIM: The aim of the study was to explore the changes in 24-h leptin circadian rhythm in response to CR and to investigate the relationship between these changes and metabolic adaptation. DESIGN In a randomized, controlled trial (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy), 48 subjects were assigned to a control group or one of three CR groups for 6 months. Leptin concentration was assessed every 30 min for 24 h, and leptin circadian variations were fitted by Cosinor analysis. Sedentary energy expenditure and urinary catecholamine excretion were measured for 24 h in a metabolic chamber. RESULTS Six months of CR decreased body weight by -11.4 ± 0.6% (mean ± sem; P < 0.001). Mean 24-h circulating leptin concentration decreased by -44 ± 3% (P < 0.001), whereas leptin diurnal amplitude slightly increased over the 6 months of CR. CR caused a metabolic adaptation of -126 ± 25 kcal/d (P <0.001) and a significant decrease in urinary norepinephrine (-13 ± 3%) and T(3) concentrations (10 ± 2%). The metabolic adaptation was significantly and independently related to the changes in 24-h leptin (r(2) = 0 .22, P < 0.01) but not to the changes in leptin amplitude. CONCLUSION Our results confirm an important role for leptin as an independent determinant of the metabolic adaptation in response to CR.