Human measurement models 2.0: for health research on disease and prevention

The goal of this public private partnership is the development and validation of a human in vivo system to measure continuous gut microbial fermentation. This system will allow measurement of real-time kinetics of fermentation after intake of fermentable substrates. It will provide the unique opportunity to measure real-time microbial fermentation combined with host substrate energy metabolism. This will be the first study on real-time, non-invasive gut microbial fermentation in humans and is funded by the NWO.

Personalized Nutrition

• The PERSON study (https://www.person-studie.nl) is one of the first randomized clinical trials in the field of precision nutrition to test effects of a more personalized dietary intervention based on tissue-specific insulin resistance phenotype on blood glucose control. The PERSON study is a multi-center study executed at Maastricht and Wageningen University. The Study is funded by TIFN, Food and Nutrition, a public private partnership between academia and Food industry, TKI-agrifood and NWO and is part of the larger project ‘The Biology behind perceivable benefits’
• The PersonalizedFiber study focuses on the role of gut microbial substrates to prevent type 2 diabetes. In this project, we aim to study the therapeutic potential of a personalized fibre mixture, selected based on the individuals’ initial gut microbiome, to improve insulin resistance in individuals at high risk of developing T2DM. The project is funded by the Dutch Diabetes Research Foundation (https://www.diabetesfonds.nl/wat-we-doen/alle-onderzoeken/voedingsvezels-en-darmbacterien)

Artificial Sweeteners

The SWEET-project (https://sweetproject.eu) is an European Commission Horizon 2020 funded project, of 29 pan-European research, consumer and industry partners, who will develop and review evidence on long term benefits and potential risks involved in switching over to sweeteners and sweetness enhancers (S&SEs) in the context of public health and safety, obesity, and sustainability. Within this European project, we are involved in a multicenter dietary intervention study with four centers participating (Maastricht, Copenhagen, Harokopio and Navarra). The primary objective of this study is to investigate the efficacy and safety of combined and prolonged use of S&SEs - as part of a healthy diet - in a population of overweight/obese adults and children (https://sweet-maastricht.nl)

Tissue oxygen partial pressure and metabolic health

• The HYPEX project aims to investigate the effects of mild intermittent hypoxia exposure (15% O2 versus 21% Os) for 7 consecutive days on insulin sensitivity, substrate metabolism and inflammation in humans. Within this project, adipose tissue and skeletal muscle oxygen partial pressure (pO2) are measured using a microdialysis-based optochemical measurements system to provide the proof-of-concept that hypoxia exposure induces a hypoxic stimulus in key metabolic organs. Moreover, we combine state-of-the-art in vivo methodology with analyses in tissue biopsies and mechanistic cell culture exoperiments. This project is funded by the Dutch Diabetes Research Foundation (https://www.diabetesfonds.nl/wat-we-doen/onderzoek/wat-doet-zuurstof-met-de-stofwisseling) and an Rising Star Fellowship from the European Foundation for the Study of Diabetes.
• The HYTRIM project Remarkably, individuals residing at high altitude are less prone to develop type 2 diabetes mellitus as compared to individuals living at sea-level. Furthermore, there is evidence to suggest that normobaric hypoxia exposure may improve glucose homeostasis and insulin sensitivity in both rodents and humans. It is well established that performing physical activity improves glucose uptake in the short term, and glycemic control in the long term. Recent studies have demonstrated that an acute bout of exercise under hypoxic conditions may lead to a more pronounced improvement in glucose homeostasis as compared to normoxic exercise. In the present randomized, placebo-controlled, single-blind, cross-over study, the effects of exercise under mild normobaric hypoxic conditions on postprandial substrate metabolism and 24h-glucose levels in people with overweight/obesity will be studied.
• Body fat distribution, mitochondrial function and adipose tissue oxygen. Accumulation of adipose tissue (AT) in the upper body (abdominal obesity) is associated with an increased risk of developing cardiovascular diseases and type 2 diabetes. Conversely, lower-body obesity shows opposite associations with metabolic and cardiovascular risk factors when adjusted for overall adiposity. Despite the numerous studies demonstrating a link between body fat distribution and disease risk, functional differences between upper and lower-body AT have not been investigated much. Moreover, the inciting events causing the metabolic and endocrine derangements in different AT depots in human obesity remain elusive. The aim of this project is to examine whether the metabolic rate of upper as compared to lower-body adipose tissue is related to the adipose tissue inflammatory phenotype and systemic low-grade inflammation in lean and obese individuals, and to determine the effects of prolonged exposure to physiological oxygen levels on the inflammatory signature of abdominal and femoral human adipocytes. This project is funded by the European Foundation for the Study of Diabetes and a joint fellowship from Maastricht University (NL) and the University of Birmingham (UK), and performed in collaboration with the University of Birmingham.

Dietary fibers/proteins, gut microbiota and metabolic health

• The Akkermansia study focuses on the role of specific gut microbial substrates on weight stability and metabolic health. In this project, we aim to study the therapeutic potential of pasteurised Akkermansia muciphilia, a postbiotic supplement, on weight stability after weight loss, as well as the influence on specific metabolic parameters. The proposed study may provide information for new strategies in nutritional prevention of weight re-gain following weight loss  and  related chronic metabolic diseases. 
• The PersonalizedFiber study focuses on the role of gut microbial substrates to prevent type 2 diabetes. In this project, we aim to study the therapeutic potential of a personalized fibre mixture, selected based on the individuals’ initial gut microbiome, to improve insulin resistance in individuals at high risk of developing T2DM. The project is funded by the Dutch Diabetes Research Foundation (https://www.diabetesfonds.nl/wat-we-doen/alle-onderzoeken/voedingsvezels-en-darmbacterien)

• Butyrate/hexanoate in metabolic health study. In this public-private partnership project, we aim to identify a well consumable butyrate/hexanoate-enriched oil that increases circulating short-chain fatty acid concentrations and improves postprandial substrate metabolism, which could be further used for a long-term study. This study is funded by AAK the Netherland.
• The butyrate-enriched triglyceride project. In this public-private partnership project, we aim to test in a proof-of-concept manner whether a chronic increase of the short-chain fatty acid butyrate in the systemic circulation improves peripheral insulin sensitivity and parameters of gut and metabolic health. To study this we execute an in vivo double-blind, randomised, placebo-controlled, parallel-designed trial of 24 weeks (six months) in which individuals with overweight or obesity and at high risk of developing type 2 diabetes will consume a novel oil containing butyrate-enriched triglycerides compared to an isocaloric oil without butyrate. Funding: ‘The collaborative project is co-financed with PPP allowance made available by Health-Holland, Top Sector Life Sciences & Health to stimulate public-private partnerships.

• Carbokinetics. The project ‘Acetate as metabolic target in the prevention of overweight-related chronic metabolic disorders’ is a project within the public private partnership NWO-Carbohydrate Competence Center. The project focuses on identifying fibres yielding a high distal colonic acetate concentration in the in vitro TIM-2 model. The most promising combination of fibres is tested in vivo during fasting and postprandial conditions in lean healthy and overweight prediabetic individuals. The project is a collaboration between Maastricht University, Human biology and campus Venlo) and Wageningen University (Microbiology lab)

• The WholeFiberhealth project. The objective of this proposal is to test in a proof-of-concept manner, whether a crude dietary fiber mixture (WholeFiberTM) yields an optimal gut and circulating SCFA concentration to reverse insulin resistance. Our approach is to use state-of-the art methodology for detailed human physiological and cellular/molecular phenotyping, microbiota composition and activity profiling. The proposed study may provide information for new strategies in nutritional prevention of insulin resistance and chronic metabolic diseases. This study is funded by TKI-Health Holland and is a collaboration between Wageningen University (microbiology lab), Leiden University (Dept of Medicine, div Endocrinology) and Maastricht University.

• The DISTAL study. This project intends to study the therapeutic potential of an innovative dietary fibre mixture targeting the whole colon, especially altering the gut microbial substrate utilization in the distal colon thereby increasing short chain fatty acid (SCFA) production from dietary fiber fermentation and decreasing branched SCFA production from protein fermentation, to prevent the progression of insulin resistance in various organs. This is a project within the Carbohydrate competence center, a public private partnership of Academia and Food industry funded by the NWO Science IPP Fund. The aim of the project is to define carbohydrate formulations to steer gut microbiota and colonic fermentation processes to support metabolic, immune and mental health’. The most optimal carbohydrate formulation is currently tested at our department against the background of a high protein diet in a 12-week dietary intervention study in individuals with overweight/obesity that have a disturbed glucose homeostasis. The main study outcome will be insulin sensitivity and other outcomes will include inflammatory profile, substrate metabolism, food reward-related brain activity, gut microbiota composition and functionality, gut permeability, and tissue-specific metabolism. This project is a collaboration between Maastricht University (Human Biology and campus Venlo), Wageningen University and UMCG.

• Dietary fibers and microbial resilience after antibiotic treatment. The project ‘Carbohydrate-induced resilience of the gut microbiome after antibiotics use’ is a project within the public private partnership NWO-Carbohydrate Competence Center. The project focuses on identifying fibres that may be effective in stimulating antibiotic recovery after antibiotic use thereby improving metabolic health. These fibres are tested in a 9 week intervention study at Maastricht University (the CARMA study). This project is a collaboration between Maastricht University and Wageningen University (microbiology lab)

Liver fat, hepatokines and insulin/anabolic resistance 

Adipose tissue and skeletal muscle are well-recognized endocrine organs, and many studies have identified or characterized functions of a variety of secreted proteins that play a role in regulating whole-body metabolism. The liver is a relatively unexplored organ in this respect. There is a clear link between conditions characterized by hepatic steatosis (obesity, T2D, aging, NAFLD) and the development of muscle insulin resistance and muscle atrophy, but mechanisms are not well investigated. One of my previous studies was innovative, as it was the first one to show that hepatokine secretion is different in livers with hepatic steatosis compared to healthy livers. In addition, we found that secretion products from the fatty liver play a major role in the development of muscle insulin resistance (Meex & Watt, Cell Metabolism, 2015). Our current studies aim investigate the liver secretion profile of humans with hepatic steatosis or NASH and the separate effects of hepatic steatosis and inflammation on muscle insulin resistance and muscle atrophy.

Adipose tissue autophagy 

The main function of the adipose tissue is to store energy in the form of fat. However, the breakdown of these stored fats (lipolysis) in the subcutaneous abdominal fat is greatly reduced in people that are at an increased risk of developing type 2 diabetes (T2D). Due to this reduced lipolytic capacity, fat will be stored in other insulin sensitive tissues (e.g. skeletal muscle, liver). This contributes significantly to the development of T2D. For the past 30-40 years, the breakdown of stored fat has been seen as a process that only takes place on the surface of intracellular cytosolic lipid droplets. However, we have recently shown that this idea is too simplistic, and that the natural waste processing system in the cell (autophagy) might contribute significantly to the breakdown of intracellular stored fat. How this alternative mechanism contributes to the breakdown of stored fat remains to be explored in detail. Therefore, the aim of this research project funded by the Dutch Diabetes Fonds (DFN) is to investigate, for the first time since the 1960s, how the natural waste processing system (autophagy) is involved in the breakdown and combustion of stored fat in human adipocytes and to further investigate potential tissue crosstalk in vitro. The results of this research will provide important insight into how a disturbed storage and release of fat from the adipose tissue contributes to the development of T2D. This will provide more insight into how treatment and prevention of diabetes can be improved with pharmacological and nutritional intervantions that target lipid breakdown in the adipose tissue.

Link: https://www.diabetesfonds.nl/wat-we-doen/onderzoek/vetten-afbreken-en-verbranden