Author:

Abstract:

The human colon harbours a dense and complex bacterial community, referred to as microbiota, which exceeds 10-fold the number of host cells and plays a crucial role in human physiology. In a state of homeostatic interaction with the host, the microbiota fulfil important roles, such as the extraction of energy from undigested nutrients, the development and maintenance of the host immune system and the creation of resilience against disturbances. Dysbiosis, a condition of microbial imbalance, has increasingly been associated to a number of inflammatory or life-style related diseases. It results in dysregulation of the adaptive and innate immune system, thus underlying many intestinal disorders such as inflammatory bowel diseases, malabsorption and gastrointestinal infections. Furthermore, dysbiosis has also been associated with colon discomfort and the occurrence of obesity and related metabolic disorders, such as diabetes, non-alcoholic steatohepatitis or cardiovascular diseases. Fermentation of undigested carbohydrates is an important metabolic function of the microbiota. Carbohydrate fermentation mainly occurs in the proximal colon and results in the production of short chain fatty acids (SCFA; acetate, propionate and butyrate) which are generally believed to beneficially affect the host. Several studies showed that SCFA and in particular butyrate improve the intestinal barrier function and reduce inflammation by inhibition of NFκB activation. Besides their effect on local gut health and maintenance, SCFA may also provide benefits on peripheral glucose and lipid metabolism. Since the identification of SCFA as endogenous ligands of the free fatty acid receptor 2 and 3 (FFAR 2 and 3) that are located on enteroendocrine L-cells, kidney cells, adipocytes, blood vessels, muscle cells and immune cells, SCFA are recognised as signalling molecules that pass information from the luminal microbiota to the host. Activation of the FFAR by SCFA stimulates the release of the satiety hormones peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) from the enteroendocrine L-cells, resulting in a modulation of food intake, improved insulin sensitivity and hepatic lipid metabolism. In view of the different effects of individual SCFA, their relative proportions are likely as relevant as their total levels. This association between dysbiosis and gastrointestinal and metabolic disorders has led to a growing interest in functional foods that improve health through steering the gut microbiome. The best known approaches to modulate the gut microbiome are the administration of probiotics and prebiotics. Probiotics are live microorganisms, often strains from bifidobacteria and lactobacilli that confer a health benefit to the host when administered in adequate amounts. Prebiotics are defined as non-digestible, selectively fermented carbohydrates that allow specific changes in the composition and activity of the intestinal microbiota. More drastic approaches include the application of faecal microbiota transplantations. A novel strategy proposed in this project, is the use of insoluble particles that serve as dietary platforms, which will stimulate cross-feeding thereby modulating the intestinal microbiota. Undigested substrates which enter the colon often cannot be fermented by the action of a single bacterial species but require a collaborative action of many different bacteria, which is called cross-feeding. The best known example of cross-feeding is the production of butyrate from fermentable carbohydrates like inulin-type fructans. Bifidobacteria degrade inulin-type fructans into acetate and lactate, but do not produce butyrate. Acetate and lactate converting bacteria, in turn will then produce butyrate. Besides, cross-feeding is also necessary for the fermentation of plant cell wall material, which is the most abundant undigested substrate entering the colon. Primary degraders such as Ruminococcus or Fibrobacter have the ability to degrade cellulose and make the solubilised products available to other members of the community (e.g. Bacteroides) through cross-feeding. It has indeed been shown that insoluble particles in human stool samples are colonised by specific microbial teams. These microbial teams were enriched in Clostridium clusters IV and XIVa that are crucial for the production of butyrate. We propose to use wheat bran as a dietary platform to stimulate cross-feeding. Wheat bran is an important constituent of whole grain products which display several beneficial effects, such as a lower risk for developing cancer, type II diabetes, cardiovascular disease and obesity. In addition, wheat bran is a plant-based component that is readily available and that can easily be technically modified. The influence of different modified wheat bran fractions on the fermentation of a carbohydrate and on several parameters for systemic health will be determined in healthy and obese volunteers in two human intervention trials.