| 1. |
- Bouter, K. E. C., et al.
(author)
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Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects article
- 2018
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In: Clinical and Translational Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 2155-384X. ; 9:5
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Journal article (peer-reviewed)abstract
- Background: Gut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism. Methods: Healthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment. Results: Oral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 μmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1). Conclusions: Oral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus. © 2018 The Author(s).
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| 2. |
- Allin, K. H., et al.
(author)
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Aberrant intestinal microbiota in individuals with prediabetes
- 2018
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 61:4, s. 810-820
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Journal article (peer-reviewed)abstract
- Aims/hypothesis Individuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1-7.0 mmol/l or HbA(1c) of 42-48 mmol/mol [6.0-6.5%]) and a range of clinical biomarkers of poor metabolic health. Methods In the present case-control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age-and sex-matched individuals with normal glucose regulation. Results We found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of Clostridium was decreased (mean log(2) fold change -0.64 (SEM 0.23), p(adj) = 0.0497), whereas the abundances of Dorea, [ Ruminococcus], Sutterella and Streptococcus were increased (mean log(2) fold change 0.51 (SEM 0.12), p(adj) = 5 x 10(-4); 0.51 (SEM 0.11), p(adj) = 1 x 10-4; 0.60 (SEM 0.21), p(adj) = 0.0497; and 0.92 (SEM0.21), padj = 4 x 10(-4), respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and Akkermansia muciniphila, which both displayed lower abundance among individuals with prediabetes (mean log(2) fold change -1.74 (SEM0.41), p(adj) = 2 x 10(-3) and -1.65 (SEM0.34), p(adj) = 4 x 10(-4), respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice. Conclusions/interpretation Collectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus Clostridium and the mucin-degrading bacterium A. muciniphila. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.
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| 3. |
- Belda, E., et al.
(author)
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Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism
- 2022
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In: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 71:12
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Journal article (peer-reviewed)abstract
- Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity.
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| 4. |
- Djekic, Demir, 1989-, et al.
(author)
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VEgetaRian Diet in patients with Ischemic heart disease (VERDI) : an open-label, randomized, prospective, cross-over study
- 2019
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In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 40:Suppl. 1, s. 3819-3819
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Journal article (other academic/artistic)abstract
- Background: A vegetarian diet (VD) in patients diagnosed with ischemic heart disease (IHD) may reduce future cardiovascular risk.Purpose: The study hypothesis was that patients diagnosed with IHD can benefit from a VD assessed by multiple risk markers for this type of disease.Methods: In a crossover study patients diagnosed with IHD, treated by percutaneous coronary intervention and on optimal medical therapy were randomly allocated to a 4-week intervention with ready-made (lunch and dinner) isocaloric VD or meat diet (MD). The primary outcome was change in oxidized low-density lipoprotein cholesterol (LDL-C) levels. Secondary outcomes were difference in changes of blood lipids, weight, body mass index (BMI), blood pressure, heart rate, glycated haemoglobin (HbA1c), number of participants reaching guideline target values, quality of life, gut microbiota, and trimethylamine N-oxide between the two interventions.Results: 31 participants were recruited (median age: 67 years, male sex: 93.5%). Significant between-intervention differences (VD vs MD) were found in oxidized LDL-C (-2.73 U/L; p=.015), total cholesterol (TC) (-0.13 mmol/L, p=.01), LDL-C (-0.10 mmol/L; p=.02), weight (-0.67 kg, p=.008) and BMI (-0.21 kg/m2, p=.009). After VD, numerically more subjects reached guideline LDL-C target values (87% vs 77%) but this did not reach statistical significance (p=.07). During VD intervention the diet led to a significant reduction in oxidized LDL-C, TC, LDL-C, HDL-C, ApoB, and ApoB/ApoA1 ratio.Conclusions: Our results suggest that in patients with IHD a VD compared to a MD, lowers oxidative stress, improves lipid profile and lowers BMI.
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| 5. |
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| 6. |
- Haghikia, A., et al.
(author)
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Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism
- 2022
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 43:6, s. 518-533
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Journal article (peer-reviewed)abstract
- Aims Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. Methods and results Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe(-/-)) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe(-/-) mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. Conclusion Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.
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| 7. |
- Kalin, Kenny, et al.
(author)
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The effect of saccharin consumption on microbiota composition and insulin sensitivity : a clinical, experimental open label pilot study
- 2020
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In: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 63:SUPPL 1, s. S223-S224
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Journal article (other academic/artistic)abstract
- Background and aims: In a previous study it was suggested that consumption of saccharin, a non-caloric artificial sweetener (NAS), often consumed by individuals with type 2 diabetes mellitus, increases the risk of developing glucose intolerance in rodents and humans through microbiota alterations. However, the study was small and did not use insulin clamp, the gold standard for measuring insulin sensitivity in humans. Thus, our aim was to further investigate whether NAS affect insulin sensitivity and gut microbiota in humans.Materials and methods: We recruited 14 participants (8 women and 6 men) who were non-diabetic, 60.0 (IQR 56.8-64.0) years of age with a body mass index of 27.9 (IQR 27.1-28.5). The study was an open label study where participants acted as their own control. Their insulin sensitivity was measured before and after exposure of 240 mg saccharin/day for three months. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp and the ‘M value’ was calculated by dividing the glucose infusion rate during the last 60 minutes of the clamp by body weight (mg/kg/min). Stool samples were collected before and after saccharin consumption. Microbiota was analyzed by sequencing of the 16S rRNA gene.Results: Thirteen of the 14 participants completed the study. There was no change in insulin resistance after exposure to saccharin (mean M value difference (ΔM) 0.0 (SD 1.6). ΔM was not related to age or sex . Individual M values from the first and second insulin clamp are shown in Figure 1 and indicate some individual responses. During the study 6 participants reduced their HbA1c ≥ 3 mmol/mol. Overall, there was no change in composition or richness of the gut microbiota as a result of saccharin consumption. Furthermore, there was no change in microbiota at end of follow-up for participants with a HbA1c reduction compared to participants without a HbA1c reduction of 3 mmol/mol or more. However, there were small differences in gut microbiota between HbA1c reducers and non-reducers at baseline, with lower gut microbiota diversity in reducers. The reducer group was mainly men who tended to lose more weight than non-reducers; the weight loss was, however, not statistically significant. Statistical analyses of study data were performed by using Student’s t-test.Conclusion: In contrast to prior studies we did not find an effect of NAS on insulin sensitivity. Furthermore, NAS consumption did not alter microbiota composition in these overweight, middle aged adults without type 2 diabetes.
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| 8. |
- Lappa, Dimitra, 1988, et al.
(author)
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Self-organized metabotyping of obese individuals identifies clusters responding differently to bariatric surgery
- 2023
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 18:3, s. e0279335-
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Journal article (peer-reviewed)abstract
- Weight loss through bariatric surgery is efficient for treatment or prevention of obesity related diseases such as type 2 diabetes and cardiovascular disease. Long term weight loss response does, however, vary among patients undergoing surgery. Thus, it is difficult to identify predictive markers while most obese individuals have one or more comorbidities. To overcome such challenges, an in-depth multiple omics analyses including fasting peripheral plasma metabolome, fecal metagenome as well as liver, jejunum, and adipose tissue transcriptome were performed for 106 individuals undergoing bariatric surgery. Machine leaning was applied to explore the metabolic differences in individuals and evaluate if metabolism-based patients' stratification is related to their weight loss responses to bariatric surgery. Using Self-Organizing Maps (SOMs) to analyze the plasma metabolome, we identified five distinct metabotypes, which were differentially enriched for KEGG pathways related to immune functions, fatty acid metabolism, protein-signaling, and obesity pathogenesis. The gut metagenome of the most heavily medicated metabotypes, treated simultaneously for multiple cardiometabolic comorbidities, was significantly enriched in Prevotella and Lactobacillus species. This unbiased stratification into SOM-defined metabotypes identified signatures for each metabolic phenotype and we found that the different metabotypes respond differently to bariatric surgery in terms of weight loss after 12 months. An integrative framework that utilizes SOMs and omics integration was developed for stratifying a heterogeneous bariatric surgery cohort. The multiple omics datasets described in this study reveal that the metabotypes are characterized by a concrete metabolic status and different responses in weight loss and adipose tissue reduction over time. Our study thus opens a path to enable patient stratification and hereby allow for improved clinical treatments.
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| 9. |
- Meijnikman, A. S., et al.
(author)
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A systems biology approach to study non-alcoholic fatty liver (NAFL) in women with obesity
- 2022
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In: iScience. - : Elsevier BV. - 2589-0042. ; 25:8
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Journal article (peer-reviewed)abstract
- Non-alcoholic fatty liver disease (NAFLD) is now the most frequent global chronic liver disease. Individuals with NAFLD exhibited an increased risk of all-cause mortality driven by extrahepatic cancers and liver and cardiovascular disease. Once the disease is established, women have a higher risk of disease progression and worse outcome. It is therefore critical to deepen the current knowledge on the pathophysiology of NAFLD in women. Here, we used a systems biology approach to investigate the contribution of different organs to this disease. We analyzed transcriptomics profiles of liver and adipose tissues, fecal metagenomes, and plasma metabolomes of 55 women with and without NAFLD. We observed differences in metabolites, expression of human genes, and gut microbial features between the groups and revealed that there is substantial crosstalk between these different omics sets. Multi-omics analysis of individuals with NAFLD may provide novel strategies to study the pathophysiology of NAFLD in humans.
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| 10. |
- Meijnikman, A. S., et al.
(author)
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Distinct differences in gut microbial composition and functional potential from lean to morbidly obese subjects.
- 2020
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 288:6, s. 699-710
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Journal article (peer-reviewed)abstract
- Introduction The gut microbiome may contribute to the development of obesity. So far, the extent of microbiome variation in people with obesity has not been determined in large cohorts and for a wide range of body mass index (BMI). Here, we aimed to investigate whether the faecal microbial metagenome can explain the variance in several clinical phenotypes associated with morbid obesity. Methods Caucasian subjects were recruited at our hospital. Blood pressure and anthropometric measurements were taken. Dietary intake was determined using questionnaires. Shotgun metagenomic sequencing was performed on faecal samples from 177 subjects. Results Subjects without obesity (n = 82, BMI 24.7 +/- 2.9 kg m(-2)) and subjects with obesity (n = 95, BMI 38.6 +/- 5.1 kg m(-2)) could be clearly distinguished based on microbial composition and microbial metabolic pathways. A total number of 52 bacterial species differed significantly in people with and without obesity. Independent of dietary intake, we found that microbial pathways involved in biosynthesis of amino acids were enriched in subjects with obesity, whereas pathways involved in the degradation of amino acids were depleted. Machine learning models showed that more than half of the variance in body fat composition followed by BMI could be explained by the gut microbiome composition and microbial metabolic pathways, compared to 6% of variation explained in triglycerides and 9% in HDL. Conclusion Based on the faecal microbiota composition, we were able to separate subjects with and without obesity. In addition, we found strong associations between gut microbial amino acid metabolism and specific microbial species in relation to clinical features of obesity.
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