Publications by authors named "Ben Van Ommen"

112 Publications

An altered microbiota pattern precedes Type 2 diabetes mellitus development: From the CORDIOPREV study.

J Adv Res 2022 01 13;35:99-108. Epub 2021 May 13.

Lipids and Atherosclerosis Unit, Internal Medicine Unit, Reina Sofia University Hospital, Córdoba 14004, Spain.

Introduction: A distinctive gut microbiome have been linked to type 2 diabetes mellitus (T2DM).

Objectives: We aimed to evaluate whether gut microbiota composition, in addition to clinical biomarkers, could improve the prediction of new incident cases of diabetes in patients with coronary heart disease.

Methods: All the patients from the CORDIOPREV (Clinical Trials.gov.Identifier: NCT00924937) study without T2DM at baseline were included (n = 462). Overall, 107 patients developed it after a median of 60 months. The gut microbiota composition was determined by 16S rRNA gene sequencing and predictive models were created using hold-out method.

Results: A gut microbiota profile associated with T2DM development was determined through a microbiome-based predictive model. The addition of microbiome data to clinical parameters (variables included in FINDRISC risk score and the diabetes risk score of the American Diabetes Association, HDL, triglycerides and HbA1c) improved the prediction increasing the area under the curve from 0.632 to 0.946. Furthermore, a microbiome-based risk score including the ten most discriminant genera, was associated with the probability of develop T2DM.

Conclusion: These results suggest that a microbiota profile is associated to the T2DM development. An integrate predictive model of microbiome and clinical data that can improve the prediction of T2DM is also proposed, if is validated in independent populations to prevent this disease.
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http://dx.doi.org/10.1016/j.jare.2021.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721255PMC
January 2022

The Effect of a Lifestyle Intervention on Type 2 Diabetes Pathophysiology and Remission: The Stevenshof Pilot Study.

Nutrients 2021 Jun 25;13(7). Epub 2021 Jun 25.

Research Group Microbiology & Systems Biology, TNO, Netherlands Organization for Applied Scientific Research, 3700 AJ Zeist, The Netherlands.

Although lifestyle interventions can lead to diabetes remission, it is unclear to what extent type 2 diabetes (T2D) remission alters or improves the underlying pathophysiology of the disease. Here, we assess the effects of a lifestyle intervention on T2D reversal or remission and the effects on the underlying pathology. In a Dutch primary care setting, 15 adults with an average T2D duration of 13.4 years who were (pharmacologically) treated for T2D received a diabetes subtyping ("diabetyping") lifestyle intervention (DLI) for six months, aiming for T2D remission. T2D subtype was determined based on an OGTT. Insulin and sulphonylurea (SU) derivative treatment could be terminated for all participants. Body weight, waist/hip ratio, triglyceride levels, HbA1c, fasting, and 2h glucose were significantly improved after three and six months of intervention. Remission and reversal were achieved in two and three participants, respectively. Indices of insulin resistance and beta cell capacity improved, but never reached healthy values, resulting in unchanged T2D subtypes. Our study implies that achieving diabetes remission in individuals with a longer T2D duration is possible, but underlying pathology is only minimally affected, possibly due to an impaired beta cell function. Thus, even when T2D remission is achieved, patients need to continue adhering to lifestyle therapy.
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http://dx.doi.org/10.3390/nu13072193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308398PMC
June 2021

Current and Future Nutritional Strategies to Modulate Inflammatory Dynamics in Metabolic Disorders.

Front Nutr 2019 26;6:129. Epub 2019 Aug 26.

Department of Microbiology and Systems Biology, Netherlands Organisation for Applied Scientific Research (TNO), Zeist, Netherlands.

Obesity, type 2 diabetes, and other metabolic disorders have a large impact on global health, especially in Western countries. An important hallmark of metabolic disorders is chronic low-grade inflammation. A key player in chronic low-grade inflammation is dysmetabolism, which is defined as the inability to keep homeostasis resulting in loss of lipid control, oxidative stress, inflammation, and insulin resistance. Although often not yet detectable in the circulation, chronic low-grade inflammation can be present in one or multiple organs. The response to a metabolic challenge containing lipids may magnify dysfunctionalities at the tissue level, causing an overflow of inflammatory markers into the circulation and hence allow detection of early low-grade inflammation. Here, we summarize the evidence of successful application of metabolic challenge tests in type 2 diabetes, metabolic syndrome, obesity, and unhealthy aging. We also review how metabolic challenge tests have been successfully applied to evaluate nutritional intervention effects, including an "anti-inflammatory" mixture, dark chocolate, whole grain wheat and overfeeding. Additionally, we elaborate on future strategies to (re)gain inflammatory flexibility. Through epigenetic and metabolic regulation, the inflammatory response may be trained by regular mild and metabolic triggers, which can be understood from the perspective of trained immunity, hormesis and pro-resolution. New strategies to optimize dynamics of inflammation may become available.
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http://dx.doi.org/10.3389/fnut.2019.00129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718105PMC
August 2019

A plasma circulating miRNAs profile predicts type 2 diabetes mellitus and prediabetes: from the CORDIOPREV study.

Exp Mol Med 2018 12 26;50(12):1-12. Epub 2018 Dec 26.

Lipids and Atherosclerosis Unit, Reina Sofıa University Hospital, Córdoba, Spain.

We aimed to explore whether changes in circulating levels of miRNAs according to type 2 diabetes mellitus (T2DM) or prediabetes status could be used as biomarkers to evaluate the risk of developing the disease. The study included 462 patients without T2DM at baseline from the CORDIOPREV trial. After a median follow-up of 60 months, 107 of the subjects developed T2DM, 30 developed prediabetes, 223 maintained prediabetes and 78 remained disease-free. Plasma levels of four miRNAs related to insulin signaling and beta-cell function were measured by RT-PCR. We analyzed the relationship between miRNAs levels and insulin signaling and release indexes at baseline and after the follow-up period. The risk of developing disease based on tertiles (T1-T2-T3) of baseline miRNAs levels was evaluated by COX analysis. Thus, we observed higher miR-150 and miR-30a-5p and lower miR-15a and miR-375 baseline levels in subjects with T2DM than in disease-free subjects. Patients with high miR-150 and miR-30a-5p baseline levels had lower disposition index (p = 0.047 and p = 0.007, respectively). The higher risk of disease was associated with high levels (T3) of miR-150 and miR-30a-5p (HR = 4.218 and HR = 2.527, respectively) and low levels (T1) of miR-15a and miR-375 (HR = 3.269 and HR = 1.604, respectively). In conclusion, our study showed that deregulated plasma levels of miR-150, miR-30a-5p, miR-15a, and miR-375 were observed years before the onset of T2DM and pre-DM and could be used to evaluate the risk of developing the disease, which may improve prediction and prevention among individuals at high risk for T2DM.
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http://dx.doi.org/10.1038/s12276-018-0194-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312530PMC
December 2018

Environmental Forces that Shape Early Development: What We Know and Still Need to Know.

Curr Dev Nutr 2018 Aug 22;2(8):nzx002. Epub 2017 Nov 22.

Department of Human Nutrition, Ohio State University, Columbus, OH.

Understanding health requires more than knowledge of the genome. Environmental factors regulate gene function through epigenetics. Collectively, environmental exposures have been called the "exposome." Caregivers are instrumental in shaping exposures in a child's initial years. Maternal dietary patterns, physical activity, degree of weight gain, and body composition while pregnant will influence not only fetal growth, but also the infant's metabolic response to nutrients and energy. Maternal over- or underweight, excess caloric intake, nutrient imbalances, glucose dysregulation, and presence of chronic inflammatory states have been shown to establish risk for many later chronic diseases. During the period from birth to age 3 y, when the infant's metabolic rate is high and synaptogenesis and myelination of the brain are occurring extremely rapidly, the infant is especially prone to damaging effects from nutrient imbalances. During this period, the infant changes from a purely milk-based diet to one including a wide variety of foods. The process, timing, quality, and ultimate dietary pattern acquired are a direct outcome of the caregiver-infant feeding relationship, with potentially lifelong consequences. More research on how meal time interactions shape food acceptance is needed to avoid eating patterns that augment existing disease risk. Traditional clinical trials in nutrition, meant to isolate single factors for study, are inadequate to study the highly interconnected realm of environment-gene interactions in early life. Novel technologies are being used to gather broad exposure data on disparate populations, employing pioneering statistical approaches and correlations applied specifically to the individual, based on their genetic make-up and unique environmental experiences.
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http://dx.doi.org/10.3945/cdn.117.001826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111237PMC
August 2018

Plasma metabolome analysis identifies distinct human metabotypes in the postprandial state with different susceptibility to weight loss-mediated metabolic improvements.

FASEB J 2018 10 2;32(10):5447-5458. Epub 2018 May 2.

Department of Food and Nutrition, Technische Universität München, Freising-Weihenstephan, Germany.

Health has been defined as the capability of the organism to adapt to challenges. In this study, we tested to what extent comprehensively phenotyped individuals reveal differences in metabolic responses to a standardized mixed meal tolerance test (MMTT) and how these responses change when individuals experience moderate weight loss. Metabolome analysis was used in 70 healthy individuals. with profiling of ∼300 plasma metabolites during an MMTT over 8 h. Multivariate analysis of plasma markers of fatty acid catabolism identified 2 distinct metabotype clusters (A and B). Individuals from metabotype B showed slower glucose clearance, had increased intra-abdominal adipose tissue mass and higher hepatic lipid levels when compared with individuals from metabotype A. An NMR-based urine analysis revealed that these individuals also to have a less healthy dietary pattern. After a weight loss of ∼5.6 kg over 12 wk, only the subjects from metabotype B showed positive changes in the glycemic response during the MMTT and in markers of metabolic diseases. Our study in healthy individuals demonstrates that more comprehensive phenotyping can reveal discrete metabotypes with different outcomes in a dietary intervention and that markers of lipid catabolism in plasma could allow early detection of the metabolic syndrome.-Fiamoncini, J., Rundle, M., Gibbons, H., Thomas, E. L., Geillinger-Kästle, K., Bunzel, D., Trezzi, J.-P., Kiselova-Kaneva, Y., Wopereis, S., Wahrheit, J., Kulling, S. E., Hiller, K., Sonntag, D., Ivanova, D., van Ommen, B., Frost, G., Brennan, L., Bell, J. Daniel, H. Plasma metabolome analysis identifies distinct human metabotypes in the postprandial state with different susceptibility to weight loss-mediated metabolic improvements.
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http://dx.doi.org/10.1096/fj.201800330RDOI Listing
October 2018

Postprandial endotoxemia may influence the development of type 2 diabetes mellitus: From the CORDIOPREV study.

Clin Nutr 2019 04 11;38(2):529-538. Epub 2018 Apr 11.

Lipids and Atherosclerosis Unit, GC9 Nutrigenomics, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Cordoba, Spain. Electronic address:

Background & Aims: Insulin resistance (IR) and impaired beta-cell function are key determinants of type 2 diabetes mellitus (T2DM). Intestinal absorption of bacterial components activates the toll-like receptors inducing inflammation, and this in turn IR. We evaluated the role of endotoxemia in promoting inflammation-induced insulin resistance (IR) in the development of T2DM, and its usefulness as predictive biomarker.

Methods: We included in this study 462 patients from the CORDIOPREV study without T2DM at baseline. Of these, 107 patients developed T2DM according to the American Diabetes Association (ADA) diagnosis criteria after a median follow-up of 60 months (Incident-DIAB group), whereas 355 patients did not developed it during this period of time (Non-DIAB group).

Results: We observed a postprandial increase in lipopolysaccharides (LPS) levels in the Incident-DIAB at baseline (P < 0.001), whereas LPS levels were not modified in the Non-DIAB. Disease-free survival curves based on the LPS postprandial fold change improved T2DM Risk Assessment as compared with the previously described FINDRISC score (hazard ratio of 2.076, 95% CI 1.149-3.750 vs. 1.384, 95% CI 0.740-2.589). Moreover, disease-free survival curves combining the LPS postprandial fold change and FINDRISC score together showed a hazard ratio of 3.835 (95% CI 1.323-11.114), linked to high values of both parameters.

Conclusion: Our results suggest that a high postprandial endotoxemia precedes the development of T2DM. Our results also showed the potential use of LPS plasma levels as a biomarker predictor of T2DM development. CLINICAL TRIALS.GOV.

Identifier: NCT00924937.
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http://dx.doi.org/10.1016/j.clnu.2018.03.016DOI Listing
April 2019

From Diabetes Care to Diabetes Cure-The Integration of Systems Biology, eHealth, and Behavioral Change.

Front Endocrinol (Lausanne) 2017 22;8:381. Epub 2018 Jan 22.

Leiden University Medical Center (LUMC), Department of Internal Medicine, Leiden, Netherlands.

From a biological view, most of the processes involved in insulin resistance, which drives the pathobiology of type 2 diabetes, are reversible. This theoretically makes the disease reversible and curable by changing dietary habits and physical activity, particularly when adopted early in the disease process. Yet, this is not fully implemented and exploited in health care due to numerous obstacles. This article reviews the state of the art in all areas involved in a diabetes cure-focused therapy and discusses the scientific and technological advancements that need to be integrated into a systems approach sustainable lifestyle-based healthcare system and economy. The implementation of lifestyle as cure necessitates personalized and sustained lifestyle adaptations, which can only be established by a systems approach, including all relevant aspects (personalized diagnosis and diet, physical activity and stress management, self-empowerment, motivation, participation and health literacy, all facilitated by blended care and ehealth). Introduction of such a systems approach in type 2 diabetes therapy not only requires a concerted action of many stakeholders but also a change in healthcare economy, with new winners and losers. A "call for action" is put forward to actually initiate this transition. The solution provided for type 2 diabetes is translatable to other lifestyle-related disorders.
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http://dx.doi.org/10.3389/fendo.2017.00381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786854PMC
January 2018

Proposed guidelines to evaluate scientific validity and evidence for genotype-based dietary advice.

Genes Nutr 2017 15;12:35. Epub 2017 Dec 15.

Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre + (MUMC+), Maastricht, The Netherlands.

Nutrigenetic research examines the effects of inter-individual differences in genotype on responses to nutrients and other food components, in the context of health and of nutrient requirements. A practical application of nutrigenetics is the use of personal genetic information to guide recommendations for dietary choices that are more efficacious at the individual or genetic subgroup level relative to generic dietary advice. Nutrigenetics is unregulated, with no defined standards, beyond some commercially adopted codes of practice. Only a few official nutrition-related professional bodies have embraced the subject, and, consequently, there is a lack of educational resources or guidance for implementation of the outcomes of nutrigenetic research. To avoid misuse and to protect the public, personalised nutrigenetic advice and information should be based on clear evidence of validity grounded in a careful and defensible interpretation of outcomes from nutrigenetic research studies. Evidence requirements are clearly stated and assessed within the context of state-of-the-art 'evidence-based nutrition'. We have developed and present here a draft framework that can be used to assess the strength of the evidence for scientific validity of nutrigenetic knowledge and whether 'actionable'. In addition, we propose that this framework be used as the basis for developing transparent and scientifically sound advice to the public based on nutrigenetic tests. We feel that although this area is still in its infancy, minimal guidelines are required. Though these guidelines are based on semi-quantitative data, they should stimulate debate on their utility. This framework will be revised biennially, as knowledge on the subject increases.
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http://dx.doi.org/10.1186/s12263-017-0584-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732517PMC
December 2017

Mediterranean Diet Adherence and Genetic Background Roles within a Web-Based Nutritional Intervention: The Food4Me Study.

Nutrients 2017 Oct 11;9(10). Epub 2017 Oct 11.

Department of Nutrition, and Food Science Physiology, Centre for Nutrition Research, University of Navarra, 31008 Pamplona, Spain.

Mediterranean Diet (MedDiet) adherence has been proven to produce numerous health benefits. In addition, nutrigenetic studies have explained some individual variations in the response to specific dietary patterns. The present research aimed to explore associations and potential interactions between MedDiet adherence and genetic background throughout the Food4Me web-based nutritional intervention. Dietary, anthropometrical and biochemical data from volunteers of the Food4Me study were collected at baseline and after 6 months. Several genetic variants related to metabolic risk features were also analysed. A Genetic Risk Score (GRS) was derived from risk alleles and a Mediterranean Diet Score (MDS), based on validated food intake data, was estimated. At baseline, there were no interactions between GRS and MDS categories for metabolic traits. Linear mixed model repeated measures analyses showed a significantly greater decrease in total cholesterol in participants with a low GRS after a 6-month period, compared to those with a high GRS. Meanwhile, a high baseline MDS was associated with greater decreases in Body Mass Index (BMI), waist circumference and glucose. There also was a significant interaction between GRS and the MedDiet after the follow-up period. Among subjects with a high GRS, those with a high MDS evidenced a highly significant reduction in total carotenoids, while among those with a low GRS, there was no difference associated with MDS levels. These results suggest that a higher MedDiet adherence induces beneficial effects on metabolic outcomes, which can be affected by the genetic background in some specific markers.
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http://dx.doi.org/10.3390/nu9101107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691723PMC
October 2017

HDL cholesterol efflux normalised to apoA-I is associated with future development of type 2 diabetes: from the CORDIOPREV trial.

Sci Rep 2017 10 2;7(1):12499. Epub 2017 Oct 2.

Lipids and Atherosclerosis Unit, UGC Internal Medicine, Reina Sofia University Hospital, Cordoba, Spain.

This prospective study evaluated whether baseline cholesterol efflux is associated with future development of type 2 diabetes (T2DM) in cardiovascular patients. We measured cholesterol efflux in all CORDIOPREV study (NCT00924937) participants free of T2DM at baseline (n = 462) and assessed its relationship with T2DM incidence during a 4.5 years of follow-up. Cholesterol efflux was quantified by incubation of cholesterol-loaded THP-1 cells with the participants' apoB-depleted plasma. Disposition index was estimated as beta-cell function indicator. During follow-up 106 individuals progressed to T2DM. The cholesterol efflux/apoA-1 ratio was inversely associated with T2DM development independently of traditional risk factors (model-1, OR: 0.647, 95%CI: 0.495-0.846), and after additional adjustment for glycaemic parameters (model-2, OR: 0.670, 95%CI: 0.511-0.878). When cumulative incidence of diabetes was analysed by quartiles of cholesterol efflux/apoA-I, incidence of T2DM was reduced by 54% in subjects who were in the higher cholesterol efflux/apoA-I quartile compared to subjects in the lowest quartile (p = 0.018 and p = 0.042 for model-1 and 2). Moreover, participants who were in the higher cholesterol efflux/apoA-I presented significantly higher disposition index (β = 0.056, SE = 0.026; p = 0.035). In conclusion, HDL-cholesterol efflux normalised to apoA-I was inversely associated with T2DM development in cardiovascular patients. This association was independent of several T2DM risk factors, and may be related to a preserved beta-cell function.
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http://dx.doi.org/10.1038/s41598-017-12678-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624929PMC
October 2017

Systems biology of personalized nutrition.

Nutr Rev 2017 Aug;75(8):579-599

TNO (The Netherlands Organization for Applied Scientific Research), Zeist, the Netherlands.

Personalized nutrition is fast becoming a reality due to a number of technological, scientific, and societal developments that complement and extend current public health nutrition recommendations. Personalized nutrition tailors dietary recommendations to specific biological requirements on the basis of a person's health status and goals. The biology underpinning these recommendations is complex, and thus any recommendations must account for multiple biological processes and subprocesses occurring in various tissues and must be formed with an appreciation for how these processes interact with dietary nutrients and environmental factors. Therefore, a systems biology-based approach that considers the most relevant interacting biological mechanisms is necessary to formulate the best recommendations to help people meet their wellness goals. Here, the concept of "systems flexibility" is introduced to personalized nutrition biology. Systems flexibility allows the real-time evaluation of metabolism and other processes that maintain homeostasis following an environmental challenge, thereby enabling the formulation of personalized recommendations. Examples in the area of macro- and micronutrients are reviewed. Genetic variations and performance goals are integrated into this systems approach to provide a strategy for a balanced evaluation and an introduction to personalized nutrition. Finally, modeling approaches that combine personalized diagnosis and nutritional intervention into practice are reviewed.
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http://dx.doi.org/10.1093/nutrit/nux029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914356PMC
August 2017

Multi-parameter comparison of a standardized mixed meal tolerance test in healthy and type 2 diabetic subjects: the PhenFlex challenge.

Genes Nutr 2017 29;12:21. Epub 2017 Aug 29.

TNO, Netherlands Institute for Applied Scientific Research, Zeist, The Netherlands.

Background: A key feature of metabolic health is the ability to adapt upon dietary perturbations. Recently, it was shown that metabolic challenge tests in combination with the new generation biomarkers allow the simultaneous quantification of major metabolic health processes. Currently, applied challenge tests are largely non-standardized. A systematic review defined an optimal nutritional challenge test, the "PhenFlex test" (PFT). This study aimed to prove that PFT modulates all relevant processes governing metabolic health thereby allowing to distinguish subjects with different metabolic health status. Therefore, 20 healthy and 20 type 2 diabetic (T2D) male subjects were challenged both by PFT and oral glucose tolerance test (OGTT). During the 8-h response time course, 132 parameters were quantified that report on 26 metabolic processes distributed over 7 organs (gut, liver, adipose, pancreas, vasculature, muscle, kidney) and systemic stress.

Results: In healthy subjects, 110 of the 132 parameters showed a time course response. Patients with T2D showed 18 parameters to be significantly different after overnight fasting compared to healthy subjects, while 58 parameters were different in the post-challenge time course after the PFT. This demonstrates the added value of PFT in distinguishing subjects with different health status. The OGTT and PFT response was highly comparable for glucose metabolism as identical amounts of glucose were present in both challenge tests. Yet the PFT reports on additional processes, including vasculature, systemic stress, and metabolic flexibility.

Conclusion: The PFT enables the quantification of all relevant metabolic processes involved in maintaining or regaining homeostasis of metabolic health. Studying both healthy subjects and subjects with impaired metabolic health showed that the PFT revealed new processes laying underneath health. This study provides the first evidence towards adopting the PFT as gold standard in nutrition research.
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http://dx.doi.org/10.1186/s12263-017-0570-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576306PMC
August 2017

Determinants of postprandial plasma bile acid kinetics in human volunteers.

Am J Physiol Gastrointest Liver Physiol 2017 Oct 29;313(4):G300-G312. Epub 2017 Jun 29.

Nutrition and Food Sciences, Technische Universität München, Freising-Weihenstephan, Germany.

Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual variability. Healthy men and women ( = 72, 62 ± 8 yr, mean ± SE) were enrolled into a 12-wk weight loss intervention. All subjects underwent an oral glucose tolerance test and a mixed-meal tolerance test before and after the intervention. BA were quantified in plasma by liquid chromatography-tandem mass spectrometry combined with whole genome exome sequencing and fecal microbiota profiling. Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma BA profiles. Fasting and postprandial BA profiles revealed high interindividual variability, and three main patterns in postprandial BA response were identified using multivariate analysis. Although the women enrolled were postmenopausal, effects of sex difference in BA response were evident. Exome data revealed the contribution of preselected genes to the observed interindividual variability. In particular, a variant in the gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases. Fecal microbiota analysis did not reveal evidence for a significant influence of bacterial diversity and/or composition on plasma BA profiles. The analysis of plasma BA profiles in response to two different dietary challenges revealed a high interindividual variability, which was mainly determined by genetics and sex difference of host with minimal effects of the microbiota. Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma bile acid (BA) profiles. Despite high interindividual variability, three main patterns in postprandial BA response were identified using multivariate analysis. A variant in the gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases in response to both the oral glucose tolerance test and the mixed-meal tolerance test.
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http://dx.doi.org/10.1152/ajpgi.00157.2017DOI Listing
October 2017

Lifestyle recommendations for the prevention and management of metabolic syndrome: an international panel recommendation.

Nutr Rev 2017 05;75(5):307-326

P. Pérez-Martínez, J. Delgado-Lista, A. García-Ríos, F. Pérez-Jiménez, and J. López-Miranda are with the Lipid and Atherosclerosis Unit, IMIBIC/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain. P. Pérez-Martínez, M. Bullo, M.I. Covas, J. Delgado-Lista, A. Díaz-López, R. Estruch, M. Fitó, A. García-Ríos, G. Mena-Sánchez, A. Muñoz-Garach, F. Pérez-Jiménez, J. Salas-Salvadó, F.J. Tinahones, R. de la Torre, E. Ros, and J. López-Miranda are with the CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. D.P. Mikhailidis is with the Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London, London, United Kingdom. V.G. Athyros and N. Katsiki are with the Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece. M. Bullo, A. Díaz-López, G. Mena-Sánchez, and J. Salas-Salvadó are with the Human Nutrition Unit, Biochemistry Biotechnology Department, Faculty of Medicine and Health Sciences, Hospital Universitari de Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Reus, Spain. P. Couture and B. Lamarche are with the Institute on Nutrition and Functional Foods, Laval University, Quebec, Canada. M.I. Covas, M. Fitó, and H. Schröder are with the Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Research Institute, Barcelona, Spain. M.I. Covas is with the NUPROAS (Nutritional Project Assessment) Handesbolag, Nacka?, Sweden. L. de Koning is with the the Department of Pathology and Department of Laboratory Medicine, Pediatrics, and Community Health Sciences, University of Calgary, Alberta, Canada. C.A. Drevon is with the Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway. R. Estruch is with the Department of Internal Medicine, Hospital Clínic, Institut d'Investigacions Biomédiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. K. Esposito, D. Giugliano, and M. Ida Maiorino are with the Division of Endocrinology and Metabolic Diseases, Second University of Naples Diabetes Unit, Second University of Naples, Naples, Italy. M. Garaulet is with the Chronobiology Laboratory, Department of Physiology, University of Murcia and Research Biomedical Institute of Murcia, Murcia, Spain. G. Kolovou is with the 1st Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece. A. Muñoz-Garach and F.J. Tinahones are with the Servicio de Endocrinologia y Nutricion, Hospital Clinico Virgen de la Victoria, Malaga, Spain. D. Nikolic and M. Rizzo are with the Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy. J.M. Ordovás is with the Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University School of Medicine, Boston, Massachusetts, United States. J.M. Ordovás is with the Department of Epidemiology, National Center of Cardiovascular Investigations, Madrid, Spain; and the Madrid Institute of Advanced Studies-Food, Madrid, Spain. H. Schröder is with the CIBER de Epidemiologia y Salud Pública, Madrid, Spain. R. de la Torre is with the Human Pharmacology and Clinical Neurosciences Research Group, Hospital del Mar Research Institute, Barcelona, Spain. B. van Ommen and S. Wopereis are with the Toegepast Natuurwetenschappelijk Onderzoek, Zeist, The Netherlands. E. Ros is with the Lipid Clinic, Endocrinology and Nutrition Service, Institut d'Investigacions Biomédiques August Pi i Sunyer, Hospital Clínic, Barcelona, Spain.

The importance of metabolic syndrome (MetS) lies in its associated risk of cardiovascular disease and type 2 diabetes, as well as other harmful conditions such as nonalcoholic fatty liver disease. In this report, the available scientific evidence on the associations between lifestyle changes and MetS and its components is reviewed to derive recommendations for MetS prevention and management. Weight loss through an energy-restricted diet together with increased energy expenditure through physical activity contribute to the prevention and treatment of MetS. A Mediterranean-type diet, with or without energy restriction, is an effective treatment component. This dietary pattern should be built upon an increased intake of unsaturated fat, primarily from olive oil, and emphasize the consumption of legumes, cereals (whole grains), fruits, vegetables, nuts, fish, and low-fat dairy products, as well as moderate consumption of alcohol. Other dietary patterns (Dietary Approaches to Stop Hypertension, new Nordic, and vegetarian diets) have also been proposed as alternatives for preventing MetS. Quitting smoking and reducing intake of sugar-sweetened beverages and meat and meat products are mandatory. Nevertheless, there are inconsistencies and gaps in the evidence, and additional research is needed to define the most appropriate therapies for MetS. In conclusion, a healthy lifestyle is critical to prevent or delay the onset of MetS in susceptible individuals and to prevent cardiovascular disease and type 2 diabetes in those with existing MetS. The recommendations provided in this article should help patients and clinicians understand and implement the most effective approaches for lifestyle change to prevent MetS and improve cardiometabolic health.
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http://dx.doi.org/10.1093/nutrit/nux014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914407PMC
May 2017

Associations of vitamin D status with dietary intakes and physical activity levels among adults from seven European countries: the Food4Me study.

Eur J Nutr 2018 Jun 13;57(4):1357-1368. Epub 2017 Mar 13.

ZIEL Research Center of Nutrition and Food Sciences, Biochemistry Unit, Technische Universität München, Munich, Germany.

Purpose: To report the vitamin D status in adults from seven European countries and to identify behavioural correlates.

Methods: In total, 1075 eligible adult men and women from Ireland, Netherlands, Spain, Greece, UK, Poland and Germany, were included in the study.

Results: Vitamin D deficiency and insufficiency, defined as 25-hydroxy vitamin D (25-OHD) concentration of <30 and 30-49.9 nmol/L, respectively, were observed in 3.3 and 30.6% of the participants. The highest prevalence of vitamin D deficiency was found in the UK and the lowest in the Netherlands (8.2 vs. 1.1%, P < 0.05). In addition, the prevalence of vitamin D insufficiency was higher in females compared with males (36.6 vs. 22.6%, P < 0.001), in winter compared with summer months (39.3 vs. 25.0%, P < 0.05) and in younger compared with older participants (36.0 vs. 24.4%, P < 0.05). Positive dose-response associations were also observed between 25-OHD concentrations and dietary vitamin D intake from foods and supplements, as well as with physical activity (PA) levels. Vitamin D intakes of ≥5 μg/day from foods and ≥5 μg/day from supplements, as well as engagement in ≥30 min/day of moderate- and vigorous-intensity PA were associated with higher odds (P < 0.05) for maintaining sufficient (≥50 nmol/L) 25-OHD concentrations.

Conclusions: The prevalence of vitamin D deficiency varied considerably among European adults. Dietary intakes of ≥10 μg/day of vitamin D from foods and/or supplements and at least 30 min/day of moderate- and vigorous-intensity PA were the minimum thresholds associated with vitamin D sufficiency.
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http://dx.doi.org/10.1007/s00394-017-1415-1DOI Listing
June 2018

The impact of micronutrient status on health: correlation network analysis to understand the role of micronutrients in metabolic-inflammatory processes regulating homeostasis and phenotypic flexibility.

Genes Nutr 2017 8;12. Epub 2017 Feb 8.

Netherlands Institute for Applied Science (TNO), Research Group Microbiology & Systems Biology, Zeist, The Netherlands.

Background: Vitamins and carotenoids are key micronutrients facilitating the maintenance of health, as evidenced by the increased risk of disease with low intake. Optimal phenotypic flexibility, i.e., the ability to respond to a physiological challenge, is an essential indicator of health status. Therefore, health can be measured by applying a challenge test and monitoring the response of relevant phenotypic processes. In this study, we assessed the correlation of three fat-soluble vitamins, (i.e., vitamin A or retinol, vitamin D, two homologues of vitamin E) and four carotenoids (i.e., α-carotene, β-carotene, β-cryptoxanthin, and lycopene), with characteristics of metabolic and inflammatory parameters at baseline and in response to a nutritional challenge test (NCT) in a group of 36 overweight and obese male subjects, using proteomics and metabolomics platforms. The phenotypic flexibility concept implies that health can be measured by the ability to adapt to a NCT, which may offer a more sensitive way to assess changes in health status of healthy subjects.

Results: Correlation analyses of results after overnight fasting revealed a rather evenly distributed network in a number of relatively strong correlations per micronutrient, with minor overlap between correlation profiles of each compound. Correlation analyses of challenge response profiles for metabolite and protein parameters with micronutrient status revealed a network that is more skewed towards α-carotene and γ-tocopherol suggesting a more prominent role for these micronutrients in the maintenance of phenotypic flexibility. Comparison of the networks revealed that there is merely overlap of two parameters (inositol and oleic acid (C18:1)) affirming that there is a specific biomarker response profile upon NCT.

Conclusions: Our study shows that applying the challenge test concept is able to reveal previously unidentified correlations between specific micronutrients and health-related processes, with potential relevance for maintenance of health that were not observed by correlating homeostatic measurements. This approach will contribute to insights on the influence of micronutrients on health and help to create efficient micronutrient intervention programs.
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http://dx.doi.org/10.1186/s12263-017-0553-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299688PMC
February 2017

Effect of personalized nutrition on health-related behaviour change: evidence from the Food4Me European randomized controlled trial.

Int J Epidemiol 2017 04;46(2):578-588

Hugh Sinclair Unit of Human Nutrition and Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK.

Background: Optimal nutritional choices are linked with better health, but many current interventions to improve diet have limited effect. We tested the hypothesis that providing personalized nutrition (PN) advice based on information on individual diet and lifestyle, phenotype and/or genotype would promote larger, more appropriate, and sustained changes in dietary behaviour.

Methods: : Adults from seven European countries were recruited to an internet-delivered intervention (Food4Me) and randomized to: (i) conventional dietary advice (control) or to PN advice based on: (ii) individual baseline diet; (iii) individual baseline diet plus phenotype (anthropometry and blood biomarkers); or (iv) individual baseline diet plus phenotype plus genotype (five diet-responsive genetic variants). Outcomes were dietary intake, anthropometry and blood biomarkers measured at baseline and after 3 and 6 months' intervention.

Results: At baseline, mean age of participants was 39.8 years (range 18-79), 59% of participants were female and mean body mass index (BMI) was 25.5 kg/m 2 . From the enrolled participants, 1269 completed the study. Following a 6-month intervention, participants randomized to PN consumed less red meat [-5.48 g, (95% confidence interval:-10.8,-0.09), P  = 0.046], salt [-0.65 g, (-1.1,-0.25), P  = 0.002] and saturated fat [-1.14 % of energy, (-1.6,-0.67), P  < 0.0001], increased folate [29.6 µg, (0.21,59.0), P  = 0.048] intake and had higher Healthy Eating Index scores [1.27, (0.30, 2.25), P  = 0.010) than those randomized to the control arm. There was no evidence that including phenotypic and phenotypic plus genotypic information enhanced the effectiveness of the PN advice.

Conclusions: Among European adults, PN advice via internet-delivered intervention produced larger and more appropriate changes in dietary behaviour than a conventional approach.
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http://dx.doi.org/10.1093/ije/dyw186DOI Listing
April 2017

A dysregulation of glucose metabolism control is associated with carotid atherosclerosis in patients with coronary heart disease (CORDIOPREV-DIAB study).

Atherosclerosis 2016 10 16;253:178-185. Epub 2016 Jul 16.

Lipids and Atherosclerosis Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain; CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain. Electronic address:

Background And Aims: Patients with coexisting coronary heart disease (CHD) and type 2 diabetes mellitus (T2DM) are at high risk of cardiovascular recurrence, however, it is not well established whether they exhibit an increased intima-media thickness of both common carotid arteries (IMT-CC). Furthermore, whether this relationship is inherent to T2DM or depends on glycemic control has not been tested in large cohorts. Our aim was to determine whether clinical categories and/or analytical markers of glucose metabolism control were associated with IMT-CC in CHD patients.

Methods: 1002 patients aged 20-75 years, categorized into normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or T2DM, underwent an oral glucose tolerance test (OGTT) and an IMT-CC measurement.

Results: IMT-CC was higher in T2DM patients with HbA1c > 6.5% compared to T2DM patients with HbA1c < 6.5% (p = 0.001), patients with IFG or IGT (p < 0.001) and NGT (p < 0.001). When age was considered, IMT-CC was influenced by glucose metabolism control only in e patients with age <61 years (p < 0.01). In a multiple linear regression analysis, glucose concentration at 120 min, but not other OGTT time-points appeared as a significant independent contributor of IMT-CC (p < 0.001). Moreover, a multiple logistic regression and the area under curve (AUC) of the ROC curve analysis showed a predictive power of glucose at 120 min to detect those CHD patients at the highest risk, defined as IMT-CC ≥ 0.7 mm (R = 0.221; AUC = 0.761).

Conclusions: Our results highlight the importance of properly controlling glucose metabolism in CHD patients, in younger populations in particular, providing an easy way of categorizing patients with an increased IMT-CC. Moreover, glucose concentration at 120 min could contribute to CVD risk and its determination could be used as a predictive tool to identify those CHD patients at the highest risk.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.07.903DOI Listing
October 2016

Weight loss predictability by plasma metabolic signatures in adults with obesity and morbid obesity of the DiOGenes study.

Obesity (Silver Spring) 2016 Feb;24(2):379-88

Netherlands Metabolomics Centre, Leiden, The Netherlands.

Objective: Aim is to predict successful weight loss by metabolic signatures at baseline and to identify which differences in metabolic status may underlie variations in weight loss success.

Methods: In DiOGenes, a randomized, controlled trial, weight loss was induced using a low-calorie diet (800 kcal) for 8 weeks. Men (N = 236) and women (N = 431) as well as groups with overweight/obesity and morbid obesity were studied separately. The relation between the metabolic status before weight loss and weight loss was assessed by stepwise regression on multiple data sets, including anthropometric parameters, NMR-based plasma metabolites, and LC-MS-based plasma lipid species.

Results: Maximally, 57% of the variation in weight loss success can be predicted by baseline parameters. The most powerful predictive models were obtained in subjects with morbid obesity. In these models, the metabolites most predictive for weight loss were acetoacetate, triacylglycerols, phosphatidylcholines, specific amino acids, and creatine and creatinine. This metabolic profile suggests that high energy metabolism activity results in higher amounts of weight loss.

Conclusions: Possible predictive (pre-diet) markers were found for amount of weight loss for specific subgroups.
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http://dx.doi.org/10.1002/oby.21361DOI Listing
February 2016

Metabolomic biomarkers for personalised glucose lowering drugs treatment in type 2 diabetes.

Metabolomics 2016 6;12:27. Epub 2016 Jan 6.

Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Str. 6.131, PO Box 85500, 3508 GA Utrecht, The Netherlands.

We aimed to identify metabolites to predict patients' response to glucose lowering treatment during the first 5 years after detection of type 2 diabetes. Metabolites were measured by GC-MS in baseline samples from 346 screen-detected type 2 diabetes patients in the ADDITION-NL study. The response to treatment with metformin and/or sulphonylurea (SU) was analysed to identify metabolites predictive of 5 year HbA1c change by multiple regression analysis. Baseline glucose and 1,5 anhydro-glucitol were associated with HbA decrease in all medication groups. In patients on SU no other metabolite was associated with HbA1c decrease. A larger set of metabolites was associated with HbA1c change in the metformin and the combination therapy (metformin + SU) groups. These metabolites included metabolites related to liver metabolism, such as 2-hydroxybutanoic acid, 3-hydroxybutanoic acid, 2-hydroxypiperidine and 4-oxoproline). Metabolites involved in oxidative stress and insulin resistance were higher when the HbA1c decrease was larger in the metformin/sulphonylurea group. The associations between baseline metabolites and responsiveness to medication are in line with its mode of action. If these results could be replicated in other populations, the most promising predictive candidates might be tested to assess whether they could enhance personalised treatment.
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http://dx.doi.org/10.1007/s11306-015-0930-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703625PMC
January 2016

Next-Generation Biomarkers of Health.

Nestle Nutr Inst Workshop Ser 2016 14;84:25-33. Epub 2016 Jan 14.

Current biomarkers used in health care and in nutrition and health research are based on quantifying disease onset and its progress. Yet, both health care and nutrition should focus on maintaining optimal health, where the related biology is essentially differing from biomedical science. Health is characterized by the ability to continuously adapt in varying circumstances where multiple mechanisms of systems flexibility are involved. A new generation of biomarkers is needed that quantifies all aspects of systems flexibility, opening the door to real lifestyle-related health optimization, self-empowerment, and related products and services.
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http://dx.doi.org/10.1159/000436949DOI Listing
October 2016

The insulin resistance phenotype (muscle or liver) interacts with the type of diet to determine changes in disposition index after 2 years of intervention: the CORDIOPREV-DIAB randomised clinical trial.

Diabetologia 2016 Jan 16;59(1):67-76. Epub 2015 Oct 16.

Lipids and Atherosclerosis Research Unit, Reina Sofia University Hospital, Avda Menendez Pidal, s/n, 14004, Cordoba, Spain.

Aims/hypothesis: The aim of the study was to determine whether basal insulin resistance (IR) phenotype (muscle and/or liver) determines the effect of long-term consumption of a Mediterranean diet or a low-fat diet on tissue-specific IR and beta cell function.

Methods: The study was performed in 642 patients included in The effect of an olive oil rich Mediterranean diet on type 2 diabetes mellitus risk and incidence study (CORDIOPREV-DIAB). A total of 327 patients were randomised to a Mediterranean diet (35% fat; 22% from monounsaturated fatty acids) and 315 to a low-fat diet (<28% fat). At baseline, the patients were classified into four phenotypes according to the type of IR: (1) no IR; (2) muscle IR; (3) liver IR; (4) muscle + liver IR. The hepatic insulin resistance index (HIRI), muscular insulin sensitivity index (MISI) and disposition index were analysed at baseline and after 2 years of follow-up.

Results: At baseline, 322 patients presented no IR, 106 presented muscle IR, 109 presented liver IR, and 105 presented muscle + liver IR. With both dietary interventions, HIRI decreased in all patients (p < 0.001) and MISI increased in muscle IR and muscle + liver IR patients (p < 0.01). Long-term intake of the Mediterranean diet increased the disposition index and insulinogenic index in the muscle IR patients (p = 0.042 and p = 0.044, respectively) and the disposition index in the muscle + liver IR patients (p = 0.048), whereas the low-fat diet increased the disposition index in the liver IR patients (p = 0.017).

Conclusions/interpretation: Although both diets improve insulin sensitivity, there are differences based on basal IR phenotypes. Moreover, according to insulinogenic and disposition index data, a low-fat diet might be more beneficial to patients with liver IR, whereas patients with muscle IR and muscle + liver IR might benefit more from a Mediterranean diet. Trial registration ClinicalTrials.gov NCT00924937 FUNDING: The study was supported by the Ministerio de Economia y Competitividad (AGL2012/39615) and by the Ministerio de Ciencia e Innovacion (PIE14/00005 and PI13/00023).
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http://dx.doi.org/10.1007/s00125-015-3776-4DOI Listing
January 2016

Quantifying phenotypic flexibility as the response to a high-fat challenge test in different states of metabolic health.

FASEB J 2015 Nov 21;29(11):4600-13. Epub 2015 Jul 21.

Microbiology Systems and Biology Group, Netherlands Organisation for Applied Scientific Research (TNO), Zeist, The Netherlands

Metabolism maintains homeostasis at chronic hypercaloric conditions, activating postprandial response mechanisms, which come at the cost of adaptation processes such as energy storage, eventually with negative health consequences. This study quantified the metabolic adaptation capacity by studying challenge response curves. After a high-fat challenge, the 8 h response curves of 61 biomarkers related to adipose tissue mass and function, systemic stress, metabolic flexibility, vascular health, and glucose metabolism was compared between 3 metabolic health stages: 10 healthy men, before and after 4 wk of high-fat, high-calorie diet (1300 kcal/d extra), and 9 men with metabolic syndrome (MetS). The MetS subjects had increased fasting concentrations of biomarkers representing the 3 core processes, glucose, TG, and inflammation control, and the challenge response curves of most biomarkers were altered. After the 4 wk hypercaloric dietary intervention, these 3 processes were not changed, as compared with the preintervention state in the healthy subjects, whereas the challenge response curves of almost all endocrine, metabolic, and inflammatory processes regulating these core processes were altered, demonstrating major molecular physiologic efforts to maintain homeostasis. This study thus demonstrates that change in challenge response is a more sensitive biomarker of metabolic resilience than are changes in fasting concentrations.
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http://dx.doi.org/10.1096/fj.14-269852DOI Listing
November 2015

Phenotypic flexibility as a measure of health: the optimal nutritional stress response test.

Genes Nutr 2015 May 21;10(3):13. Epub 2015 Apr 21.

TNO, PO Box 360, 3700 AJ Zeist, The Netherlands.

Nutrition research is struggling to demonstrate beneficial health effects, since nutritional effects are often subtle and long term. Health has been redefined as the ability of our body to cope with daily-life challenges. Physiology acts as a well-orchestrated machinery to adapt to the continuously changing environment. We term this adaptive capacity "phenotypic flexibility." The phenotypic flexibility concept implies that health can be measured by the ability to adapt to conditions of temporary stress, such as physical exercise, infections or mental stress, in a healthy manner. This may offer a more sensitive way to assess changes in health status of healthy subjects. Here, we performed a systematic review of 61 studies applying different nutritional stress tests to quantify health and nutritional health effects, with the objective to define an optimal nutritional stress test that has the potential to be adopted as the golden standard in nutrition research. To acknowledge the multi-target role of nutrition, a relevant subset of 50 processes that govern optimal health, with high relevance to diet, was used to define phenotypic flexibility. Subsequently, we assessed the response of biomarkers related to this subset of processes to the different challenge tests. Based on the obtained insights, we propose a nutritional stress test composed of a high-fat, high-caloric drink, containing 60 g palm olein, 75 g glucose and 20 g dairy protein in a total volume of 400 ml. The use of such a standardized nutritional challenge test in intervention studies is expected to demonstrate subtle improvements of phenotypic flexibility, thereby enabling substantiation of nutritional health effects.
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http://dx.doi.org/10.1007/s12263-015-0459-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404421PMC
May 2015

Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE).

J Nutr 2015 May 1;145(5):1039S-1108S. Epub 2015 Apr 1.

TNO, Zeist, The Netherlands.

An increasing recognition has emerged of the complexities of the global health agenda—specifically, the collision of infections and noncommunicable diseases and the dual burden of over- and undernutrition. Of particular practical concern are both 1) the need for a better understanding of the bidirectional relations between nutritional status and the development and function of the immune and inflammatory response and 2) the specific impact of the inflammatory response on the selection, use, and interpretation of nutrient biomarkers. The goal of the Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) is to provide guidance for those users represented by the global food and nutrition enterprise. These include researchers (bench and clinical), clinicians providing care/treatment, those developing and evaluating programs/interventions at scale, and those responsible for generating evidence-based policy. The INSPIRE process included convening 5 thematic working groups (WGs) charged with developing summary reports around the following issues: 1) basic overview of the interactions between nutrition, immune function, and the inflammatory response; 2) examination of the evidence regarding the impact of nutrition on immune function and inflammation; 3) evaluation of the impact of inflammation and clinical conditions (acute and chronic) on nutrition; 4) examination of existing and potential new approaches to account for the impact of inflammation on biomarker interpretation and use; and 5) the presentation of new approaches to the study of these relations. Each WG was tasked with synthesizing a summary of the evidence for each of these topics and delineating the remaining gaps in our knowledge. This review consists of a summary of the INSPIRE workshop and the WG deliberations.
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http://dx.doi.org/10.3945/jn.114.194571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448820PMC
May 2015

White adipose tissue reference network: a knowledge resource for exploring health-relevant relations.

Genes Nutr 2015 Jan 3;10(1):439. Epub 2014 Dec 3.

Microbiology & Systems Biology, TNO, Zeist, The Netherlands.

Optimal health is maintained by interaction of multiple intrinsic and environmental factors at different levels of complexity-from molecular, to physiological, to social. Understanding and quantification of these interactions will aid design of successful health interventions. We introduce the reference network concept as a platform for multi-level exploration of biological relations relevant for metabolic health, by integration and mining of biological interactions derived from public resources and context-specific experimental data. A White Adipose Tissue Health Reference Network (WATRefNet) was constructed as a resource for discovery and prioritization of mechanism-based biomarkers for white adipose tissue (WAT) health status and the effect of food and drug compounds on WAT health status. The WATRefNet (6,797 nodes and 32,171 edges) is based on (1) experimental data obtained from 10 studies addressing different adiposity states, (2) seven public knowledge bases of molecular interactions, (3) expert's definitions of five physiologically relevant processes key to WAT health, namely WAT expandability, Oxidative capacity, Metabolic state, Oxidative stress and Tissue inflammation, and (4) a collection of relevant biomarkers of these processes identified by BIOCLAIMS ( http://bioclaims.uib.es ). The WATRefNet comprehends multiple layers of biological complexity as it contains various types of nodes and edges that represent different biological levels and interactions. We have validated the reference network by showing overrepresentation with anti-obesity drug targets, pathology-associated genes and differentially expressed genes from an external disease model dataset. The resulting network has been used to extract subnetworks specific to the above-mentioned expert-defined physiological processes. Each of these process-specific signatures represents a mechanistically supported composite biomarker for assessing and quantifying the effect of interventions on a physiological aspect that determines WAT health status. Following this principle, five anti-diabetic drug interventions and one diet intervention were scored for the match of their expression signature to the five biomarker signatures derived from the WATRefNet. This confirmed previous observations of successful intervention by dietary lifestyle and revealed WAT-specific effects of drug interventions. The WATRefNet represents a sustainable knowledge resource for extraction of relevant relationships such as mechanisms of action, nutrient intervention targets and biomarkers and for assessment of health effects for support of health claims made on food products.
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http://dx.doi.org/10.1007/s12263-014-0439-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252261PMC
January 2015

Network signatures link hepatic effects of anti-diabetic interventions with systemic disease parameters.

BMC Syst Biol 2014 Sep 11;8:108. Epub 2014 Sep 11.

TNO, Research Group Microbiology & Systems Biology, Zeist, The Netherlands.

Background: Multifactorial diseases such as type 2 diabetes mellitus (T2DM), are driven by a complex network of interconnected mechanisms that translate to a diverse range of complications at the physiological level. To optimally treat T2DM, pharmacological interventions should, ideally, target key nodes in this network that act as determinants of disease progression.

Results: We set out to discover key nodes in molecular networks based on the hepatic transcriptome dataset from a preclinical study in obese LDLR-/- mice recently published by Radonjic et al. Here, we focus on comparing efficacy of anti-diabetic dietary (DLI) and two drug treatments, namely PPARA agonist fenofibrate and LXR agonist T0901317. By combining knowledge-based and data-driven networks with a random walks based algorithm, we extracted network signatures that link the DLI and two drug interventions to dyslipidemia-related disease parameters.

Conclusions: This study identified specific and prioritized sets of key nodes in hepatic molecular networks underlying T2DM, uncovering pathways that are to be modulated by targeted T2DM drug interventions in order to modulate the complex disease phenotype.
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http://dx.doi.org/10.1186/s12918-014-0108-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363943PMC
September 2014

Predicting individual responses to pravastatin using a physiologically based kinetic model for plasma cholesterol concentrations.

J Pharmacokinet Pharmacodyn 2014 Aug 9;41(4):351-62. Epub 2014 Aug 9.

The Netherlands Organization for Applied Scientific Research (TNO), Utrechtseweg 48, P.O. Box 360, 3700 AJ, Zeist, The Netherlands.

We used a previously developed physiologically based kinetic (PBK) model to analyze the effect of individual variations in metabolism and transport of cholesterol on pravastatin response. The PBK model is based on kinetic expressions for 21 reactions that interconnect eight different body cholesterol pools including plasma HDL and non-HDL cholesterol. A pravastatin pharmacokinetic model was constructed and the simulated hepatic pravastatin concentration was used to modulate the reaction rate constant of hepatic free cholesterol synthesis in the PBK model. The integrated model was then used to predict plasma cholesterol concentrations as a function of pravastatin dose. Predicted versus observed values at 40 mg/d pravastatin were 15 versus 22 % reduction of total plasma cholesterol, and 10 versus 5.6 % increase of HDL cholesterol. A population of 7,609 virtual subjects was generated using a Monte Carlo approach, and the response to a 40 mg/d pravastatin dose was simulated for each subject. Linear regression analysis of the pravastatin response in this virtual population showed that hepatic and peripheral cholesterol synthesis had the largest regression coefficients for the non-HDL-C response. However, the modeling also showed that these processes alone did not suffice to predict non-HDL-C response to pravastatin, contradicting the hypothesis that people with high cholesterol synthesis rates are good statin responders. In conclusion, we have developed a PBK model that is able to accurately describe the effect of pravastatin treatment on plasma cholesterol concentrations and can be used to provide insight in the mechanisms behind individual variation in statin response.
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http://dx.doi.org/10.1007/s10928-014-9369-xDOI Listing
August 2014
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