BACKGROUND: The relation between gut microbiota and obesity originates from animal studies, showing that the change of gut microbiota can induce changes in both insulin resistance and body composition. In addition, these studies have shown changes in gut permeability inducing a pro-inflammatory state, changes in adipose tissue function and inflammation, effects on energy harvesting and metabolism, skeletal muscle fatty acid partitioning and fat oxidation. Human data is lacking, although several studies suggested that the composition of the gut microbiota differs between lean and obese, and between diabetic and non-diabetic individuals. OBJECTIVE: To provide insight in the physiological significance and underlying mechanisms involved in the relation between gut microbiota, energy balance and insulin sensitivity in overweight men with impaired glucose homeostasis.
The view on the putative significance of gut microbiota in metabolism emerged from animal studies. Bäcked et al. showed that germ free mice had 40% less body fat compared to conventionally raised mice. Transplantation of a cecum-derived microbial community of conventional mice into germ free mice, resulted in a significant increase of body weight and insulin resistance within 2 weeks. Application of metagenomic techniques in leptin-deficient ob/ob mice showed a different proportion of bacteria belonging when compared to lean, wild-type or heterozygous mice, with a greater representation of Firmicutes and fewer Bacteroidetes. This obese gut microbiome showed an enrichment in genes involved in energy extraction from food, less energy left over in the faeces and higher contents of the short-chain fatty acids (SCFAs) propionate, acetate and butyrate in the cecum. Furthermore, microbiota composition may alter gut permeability, and may play a role in the development of metabolic endotoxemia (inflammation) and related impairments in glucose metabolism. In addition, the gut microbiota may determine AMP-activated protein kinase (AMPK) levels in muscle and liver, thereby affecting fatty acid oxidation (substrate metabolism) and fat storage. However, underlying mechanisms are not completely understood. Therefore, researchers within the Top Institute Food and Nutrition (TIFN) have designed a multidisciplinary project ('Microbiota, energy balance and metabolism'), to fill the unmet gap between gut microbiota and human energy metabolism. The current protocol is designed to clarify the role of the gut microbiota in host energy metabolism and insulin sensitivity, with the main focus on underlying mechanisms.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
TRIPLE
Enrollment
57
Maastricht University
Maastricht, Netherlands
Insulin sensitivity
Before and after the intervention, insulin sensitivity will be measured by using the hyperinsulinemic-euglycemic clamp technique including a glucose tracer to accurately quantify glucose fluxes at the whole body level. Glucose and Insulin levels will be determined.
Time frame: up to two weeks
Fatty Acid Handling in the muscle
Because skeletal muscle is responsible for almost 80% of insulin-stimulated glucose disposal, and comprises up to 40% of total body mass, it can be considered to be a major tissue in the etiology of insulin resistance. Therefore, it is important to study the role of skeletal muscle substrate metabolism (fatty acid handling)in the context of this study. Fatty acids, glycerol, triacylglycerol and labelled palmitate in the chylomicron fraction will be measured.
Time frame: up to two weeks
Markers of inflammation
Low-grade inflammation seems to contribute to insulin resistance in obese insulin resistant subjects. Therefore, muscle and adipose tissue expression/secretion of inflammatory molecules (i.e. TNFα, IL-6) will be measured.
Time frame: up to two weeks
Energy expenditure
Indirect calorimetry measurements will be done to determine energy expenditure (O2 and CO2). While the gut microbiota plays an important role in nutrient metabolism and energy extraction from the diet, the determination of energy expenditure and energy content in faeces will provide important insight into the role of the gut microbiota in body weight regulation.
Time frame: up to two weeks
Microbiota composition and energy content in faecal samples
The composition of bacteria in the gut will be determined before and after intervention to link the composition to the primary and other secondary parameters. The energy content in the faeces will provide insight in the energy extraction capacity of the bacteria present.
Time frame: up to two weeks
Gut wall permeability
A proposed hypothesis is that gut permeability plays an important role in the induction of inflammation in obese insulin resistant subjects. A multi-sugar whole gut permeability assay will be performed.
Time frame: up to two weeks
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