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The intestinal microbiome is a co-determinant of the postprandial plasma glucose response.
Søndertoft, NB, Vogt, JK, Arumugam, M, Kristensen, M, Gøbel, RJ, Fan, Y, Lyu, L, Bahl, MI, Eriksen, C, Ängquist, L, et al
PloS one. 2020;(9):e0238648
Abstract
Elevated postprandial plasma glucose is a risk factor for development of type 2 diabetes and cardiovascular disease. We hypothesized that the inter-individual postprandial plasma glucose response varies partly depending on the intestinal microbiome composition and function. We analyzed data from Danish adults (n = 106), who were self-reported healthy and attended the baseline visit of two previously reported randomized controlled cross-over trials within the Gut, Grain and Greens project. Plasma glucose concentrations at five time points were measured before and during three hours after a standardized breakfast. Based on these data, we devised machine learning algorithms integrating bio-clinical, as well as shotgun-sequencing-derived taxa and functional potentials of the intestinal microbiome to predict individual postprandial glucose excursions. In this post hoc study, we found microbial and clinical features, which predicted up to 48% of the inter-individual variance of postprandial plasma glucose responses (Pearson correlation coefficient of measured vs. predicted values, R = 0.69, 95% CI: 0.45 to 0.84, p<0.001). The features were age, fasting serum triglycerides, systolic blood pressure, BMI, fasting total serum cholesterol, abundance of Bifidobacterium genus, richness of metagenomics species and abundance of a metagenomic species annotated to Clostridiales at order level. A model based only on microbial features predicted up to 14% of the variance in postprandial plasma glucose excursions (R = 0.37, 95% CI: 0.02 to 0.64, p = 0.04). Adding fasting glycaemic measures to the model including microbial and bio-clinical features increased the predictive power to R = 0.78 (95% CI: 0.59 to 0.89, p<0.001), explaining more than 60% of the inter-individual variance of postprandial plasma glucose concentrations. The outcome of the study points to a potential role of the taxa and functional potentials of the intestinal microbiome. If validated in larger studies our findings may be included in future algorithms attempting to develop personalized nutrition, especially for prediction of individual blood glucose excursions in dys-glycaemic individuals.
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Effect of vitamin D fortified foods on bone markers and muscle strength in women of Pakistani and Danish origin living in Denmark: a randomised controlled trial.
Grønborg, IM, Tetens, I, Andersen, EW, Kristensen, M, Larsen, REK, Tran, TLL, Andersen, R
Nutrition journal. 2019;(1):82
Abstract
BACKGROUND Deficient and insufficient vitamin D status (defined as serum 25(OH)D < 30 nmol/L and > 50 nmol/L) is prevalent worldwide and associated with decreased muscle strength and poor bone health. We aimed to investigate the effect of vitamin D fortification on bone markers and muscle strength among younger adult women at risk of vitamin D deficiency. METHODS A 12-week randomised double-blinded placebo-controlled winter intervention trial, providing 30 μg vitamin D3/day through fortified yoghurt, cheese, eggs and crisp-bread or similar placebo products. Participants were 143 women of Danish and Pakistani origin 18-50 years of age, living in Denmark, randomised into four groups stratified by ethnicity. Serum 25-hydroxyvitamin D (25(OH)D) by LC-MS/MS and the secondary endpoints: four specific bone markers (osteocalcin (OC), Bone specific Alkaline Phosphatase (BALP), Procollagen type 1 amino-terminal propeptide (P1NP), C-terminal crosslinked telopeptide of type 1 collagen (CTX)) and three muscle strength measures (handgrip, knee extension strength, chair-standing), were assessed using one-way ANOVA, Tukey HSD and subsequent linear ANCOVA models, adjusted for relevant covariates. RESULTS Significantly increased serum 25(OH)D concentration from 53.3 (17) to 77.8 (14) nmol/L and from 44.5 (21) to 54.7 (18) nmol/L among Danish and Pakistani women in the fortified groups, respectively (P < 0.05). The bone turnover markers OC, BALP, P1NP and CTX did not change significantly. Muscle strength by handgrip, knee extension and chair-standing test did not change significantly following the intervention. CONCLUSIONS Consumption of vitamin D fortified foods for 12 weeks did not result in significant changes of the bone turnover markers OC, BALP, P1NP and CTX. Muscle strength measured as hand grip strength, knee extension strength and chair-standing did not change significantly following the intervention.
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Effect of folate supplementation on insulin sensitivity and type 2 diabetes: a meta-analysis of randomized controlled trials.
Lind, MV, Lauritzen, L, Kristensen, M, Ross, AB, Eriksen, JN
The American journal of clinical nutrition. 2019;(1):29-42
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BACKGROUND Various mechanisms link higher total homocysteine to higher insulin resistance (IR) and risk of type 2 diabetes (T2D). Folate supplementation is recognized as a way to lower homocysteine. However, randomized controlled trials (RCTs) show inconsistent results on IR and T2D outcomes. OBJECTIVE The aim of this study was to examine the effect of folate supplementation on IR and T2D outcomes. DESIGN We conducted a systematic literature search in PubMed, Web of Science, and EMBASE and prior systematic reviews and meta-analyses and identified 29 RCTs (22,250 participants) that assessed the effect of placebo-controlled folate supplementation alone or in combination with other B vitamins on fasting glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-IR), glycated hemoglobin (HbA1c), or risk of T2D. The meta-analysis was conducted using both random- and fixed-effects models to calculate weighted mean differences (WMDs) or risk ratios with 95% CIs. Subgroup analyses were conducted based on intervention type (folate alone or in combination with other B vitamins), as well as analysis based on population characteristics, duration, dose, and change in homocysteine. RESULTS When compared with placebo, folate supplementation lowered fasting insulin (WMD: -13.47 pmol/L; 95% CI: -21.41, -5.53 pmol/L; P < 0.001) and HOMA-IR (WMD: -0.57 units; 95% CI: -0.76, -0.37 units; P < 0.0001), but no overall effects were observed for fasting glucose or HbA1c. Heterogeneity was low in all meta-analyses, and subgroup analysis showed no signs of effect modification except for change in homocysteine, with the most pronounced effects in trials with a change of >2.5 µmol/L. Changes in homocysteine after folate supplementation correlated with changes in fasting glucose (β = 0.07; 95% CI: 0.01, 0.14; P = 0.025) and HbA1c (β = 0.46; 95% CI: 0.06, 0.85; P = 0.02). Only 2 studies examined folate supplementation on risk of T2D, and they found no change in RR (pooled RR: 0.91; 95% CI: 0.80, 1.04; P = 0.16). CONCLUSION Folate supplementation might be beneficial for glucose homeostasis and lowering IR, but at present there are insufficient data to conclusively determine the effect on development of T2D. This trial was registered on the Prospero database as CRD42016048254.
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Winter vitamin D3 supplementation does not increase muscle strength, but modulates the IGF-axis in young children.
Mortensen, C, Mølgaard, C, Hauger, H, Kristensen, M, Damsgaard, CT
European journal of nutrition. 2019;(3):1183-1192
Abstract
PURPOSE To explore whether muscle strength, the insulin-like growth factor axis (IGF-axis), height, and body composition were associated with serum 25-hydroxyvitamin D [25(OH)D] and affected by winter vitamin D supplementation in healthy children, and furthermore to explore potential sex differences. METHODS We performed a double-blind, placebo-controlled, dose-response winter trial at 55ºN. A total of 117 children aged 4-8 years were randomly assigned to either placebo, 10, or 20 µg/day of vitamin D3 for 20 weeks. At baseline and endpoint, we measured muscle strength with handgrip dynamometer, fat mass index (FMI), fat free mass index (FFMI), height, plasma IGF-1, IGF-binding protein 3 (IGFBP-3), and serum 25(OH)D. RESULTS At baseline, serum 25(OH)D was positively associated with muscle strength, FFMI, and IGFBP-3 in girls only (all p < 0.01). At endpoint, baseline-adjusted muscle strength, FMI and FFMI did not differ between intervention groups. However, baseline-adjusted IGF-1 and IGFBP-3 were higher after 20 µg/day compared to placebo (p = 0.043 and p = 0.006, respectively) and IGFBP-3 was also higher after 20 µg/day compared to 10 µg/day (p = 0.011). Children tended to be taller after 20 µg/day compared to placebo (p = 0.064). No sex interactions were seen at endpoint. CONCLUSIONS Avoiding the winter-related decline in serum 25(OH)D may influence IGF-1 and IGFBP-3 in children. Larger trials are required to confirm these effects, and the long-term implication for linear growth.
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Reply to RB Yarandi.
Lind, MV, Lauritzen, L, Kristensen, M, Ross, AB, Eriksen, JN
The American journal of clinical nutrition. 2019;(4):1233-1234
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Prevotella Abundance Predicts Weight Loss Success in Healthy, Overweight Adults Consuming a Whole-Grain Diet Ad Libitum: A Post Hoc Analysis of a 6-Wk Randomized Controlled Trial.
Christensen, L, Vuholm, S, Roager, HM, Nielsen, DS, Krych, L, Kristensen, M, Astrup, A, Hjorth, MF
The Journal of nutrition. 2019;(12):2174-2181
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BACKGROUND The key to effective weight loss may be to match diet and gut microbes, since recent studies have found that subjects with high Prevotella abundances in their gut microbiota lose more weight on diets rich in fiber than subjects with low Prevotella abundances. OBJECTIVES We reanalyzed a 6-wk, parallel, randomized trial to investigate difference in body weight changes when participants, stratified by fecal microbiota composition, consumed ad libitum a whole-grain (WG) or a refined-wheat (RW) diet. METHODS We stratified 46 (19 men, 27 women; ages 30-65 y) healthy, overweight adults by baseline Prevotella-to-Bacteroides ratios and Prevotella abundances. Subjects with no Prevotella were analyzed separately (n = 24). Compared with the RW diet (mean = 221 g/d), the WG diet (mean = 228 g/d) had a higher fiber content (33 g/d compared with 23 g/d). Linear mixed models and correlations were applied to link 6-wk changes in body weights and metabolic and microbiota markers, according to Prevotella groups and diets. RESULTS The Prevotella abundances correlated inversely with weight changes (r = -0.34; P = 0.043). Consequently, subjects with high Prevotella abundances (n = 15) spontaneously lost 1.80 kg (95% CI: -3.23, -0.37 kg; P = 0.013) more on the WG diet than on the RW diet, whereas those with low Prevotella abundances (n = 31) were weight stable (-0.22 kg; 95% CI: -1.40, 0.96 kg; P = 0.72). Thus, the mean difference between the Prevotella groups was 2.02 kg (95% CI: -3.87, -0.17 kg; P = 0.032). Subjects with no Prevotella lost 1.59 kg (95% CI: -2.65, -0.52 kg; P = 0.004) more on the WG diet than on the RW diet. No 6-wk changes in appetite sensations, glucose metabolisms, or fecal SCFAs were associated with the Prevotella groups. CONCLUSIONS Healthy, overweight adults with high Prevotella abundances lost more weight than subjects with low Prevotella abundances when consuming a diet rich in WG and fiber ad libitum for 6 wk. This further supports enterotypes as a potential biomarker in personalized nutrition for obesity management. This t rial was registered at clinicaltrials.gov as NCT02358122.
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Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial.
Roager, HM, Vogt, JK, Kristensen, M, Hansen, LBS, Ibrügger, S, Mærkedahl, RB, Bahl, MI, Lind, MV, Nielsen, RL, Frøkiær, H, et al
Gut. 2019;68(1):83-93
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Whole grain consumption has been linked with decreased risk of lifestyle-related diseases. While animal studies have shown the gut microbiome to be a mediator of metabolic health, human studies examining the effect of whole grain intake of the gut remain inconclusive. The aim of this study was to investigate the effects of a whole grain diet on the gut microbiome, gut functionality and biomarkers of metabolic health. In this randomised, controlled, crossover study, 50 participants completed two 8-week dietary intervention periods comprising of a whole grain diet and a refined grain diet with a 6-week washout period. Examinations were done at the beginning and end of each intervention period to assess anthropometry and various plasma and gut markers. This study found that a whole grain diet as compared with a refined grain diet reduced energy intake and body weight as well as circulating markers of inflammation. Contrary to the hypothesis, these benefits were all observed independent of changes in the gut microbiome. Based on these results, the authors conclude higher intake of whole grains should be recommended to those at risk of inflammation-related disease.
Abstract
OBJECTIVE To investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality. DESIGN 60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of ≥6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed. RESULTS 50 participants completed both periods with a whole grain intake of 179±50 g/day and 13±10 g/day in the whole grain and refined grain period, respectively. Compliance was confirmed by a difference in plasma alkylresorcinols (p<0.0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did, however, compared with the refined grain diet, decrease body weight (p<0.0001), serum inflammatory markers, interleukin (IL)-6 (p=0.009) and C-reactive protein (p=0.003). The reduction in body weight was consistent with a reduction in energy intake, and IL-6 reduction was associated with the amount of whole grain consumed, in particular with intake of rye. CONCLUSION Compared with refined grain diet, whole grain diet did not alter insulin sensitivity and gut microbiome but reduced body weight and systemic low-grade inflammation. TRIAL REGISTRATION NUMBER NCT01731366; Results.
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A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults.
Hansen, LBS, Roager, HM, Søndertoft, NB, Gøbel, RJ, Kristensen, M, Vallès-Colomer, M, Vieira-Silva, S, Ibrügger, S, Lind, MV, Mærkedahl, RB, et al
Nature communications. 2018;(1):4630
Abstract
Adherence to a low-gluten diet has become increasingly common in parts of the general population. However, the effects of reducing gluten-rich food items including wheat, barley and rye cereals in healthy adults are unclear. Here, we undertook a randomised, controlled, cross-over trial involving 60 middle-aged Danish adults without known disorders with two 8-week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day). We find that, in comparison with a high-gluten diet, a low-gluten diet induces moderate changes in the intestinal microbiome, reduces fasting and postprandial hydrogen exhalation, and leads to improvements in self-reported bloating. These observations suggest that most of the effects of a low-gluten diet in non-coeliac adults may be driven by qualitative changes in dietary fibres.
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Supplementation with dairy calcium and/or flaxseed fibers in conjunction with orlistat augments fecal fat excretion without altering ratings of gastrointestinal comfort.
Kristensen, M, Juul, SR, Sørensen, KV, Lorenzen, JK, Astrup, A
Nutrition & metabolism. 2017;:13
Abstract
BACKGROUND Orlistat is a lipase inhibitor which reduced absorption of dietary fat by ~30% thereby inducing a weight loss; however, side effects occur as a consequence of increased colonic fat content. To test the hypothesis that most gastrointestinal side events induced by treatment with orlistat could be prevented/ameliorated by concomitant use of natural dietary components, flaxseed fiber (FF) and/or dairy calcium (Ca), binding liquid fats to more solid complexes. METHODS A randomized controlled dietary intervention study. Thirty-eight obese adults completed a 1-week run-in period, where all participants were treated with orlistat (60 mg t.i.d) and were hereafter randomized to 12 weeks dietary supplementation with/without 5 g FF (FF+/FF-) and/or 1200 mg dairy calcium (Ca+/Ca-) in conjunction with orlistat. All feces were collected for 3 days, and diet was recorded for 5 days, during run-in and week 4. The primary end-point, gastrointestinal symptoms, was assessed biweekly. At baseline and after 12 weeks, cardiometabolic risk markers and anthropometrics were evaluated as secondary end-points. RESULTS Both FF and Ca increased fecal fat excretion (P = 0.02 and P = 0.04, respectively). Although fecal fat excretion increased by ~100% in the FF+/Ca + group, and only by ~12% in the FF-/Ca + group, no interaction between FF and Ca was present, suggesting an additive effect. The fecal fat excretion was ~10 g/d higher with FF and Ca (~25 g/d) compared to fecal fat excretion with orlistat alone (~15 g/d). Mean ratings of severity of diarrhea tended to increase with Ca (P = 0.03) but not with FF. No other gastrointestinal symptoms, or a composite score of symptoms, were affected by the dietary supplements. Body weight was reduced in all groups but did not differ between groups, whereas waist circumference was most reduced in the FF+/Ca + group. No effects of dietary supplements on cardiometabolic risk factors were observed, except a slight increase in diastolic blood pressure (P = 0.03) with FF, but not Ca. CONCLUSIONS Our results do not support an improvement in orlistat-induced gastrointestinal side effects by concomitant use of FF and Ca. However, fecal fat excretion was increased with both FF and Ca in the absence of a worsening of symptoms, warranting further studies powered to detect potential additive weight loss effects. TRIAL REGISTRATION Ethical Committee of the Capital Region of Denmark reg. no. H-1-2010-110, 02-11-2010 database no. NCT01320228, 21-03-2011.
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Wholegrain rye, but not wholegrain wheat, lowers body weight and fat mass compared with refined wheat: a 6-week randomized study.
Suhr, J, Vuholm, S, Iversen, KN, Landberg, R, Kristensen, M
European journal of clinical nutrition. 2017;(8):959-967
Abstract
BACKGROUND Observational studies suggest inverse associations between wholegrain intake and body weight gain. Only few controlled intervention studies have supported this association and few compare effects of different grain varieties. OBJECTIVE To investigate how wholegrain wheat (WGW) and rye compared with refined wheat (RW) affect body weight and composition and appetite sensation. DESIGN Seventy overweight/obese adults participated in this 6-week randomized parallel study, in which they replaced their habitual cereal foods with RW, WGW or wholegrain rye (WGR). Further, a 4 h postprandial test meal challenge was completed with meals corresponding to diet allocation in the beginning and after the intervention. Body weight and composition, fasted blood samples, compliance and 4-day dietary intake were obtained before and after the intervention period. Appetite and breath hydrogen excretion was assessed during the postprandial test meal challenge. RESULTS Diet allocation affected body weight significantly (P=0.013) and tended also to affect fat mass (P=0.065). Both body weight and fat mass decreased more in the WGR group (-1.06±1.60 and -0.75±1.29 kg, respectively) compared with the RW group (+0.15±1.28 and -0.04±0.82 kg, respectively; P<0.01 and P<0.05, respectively). Further, the decrease in fat mass in the WGR group tended to exceed that in the WGW group (P=0.07). Overall, no effect of diet on appetite sensation was observed; however, energy intake from study products was ~200 kcal lower in the WGR group when compared with that in the RW group (P<0.05), although total energy intake did not differ between groups. CONCLUSIONS Our results support a role for WGR foods in body weight regulation, when provided ad libitum. The effect may be mediated by satiation reflected in a reduction in energy intake, mainly from the wholegrain products without compensation in other parts of the diets, despite no difference in appetite.