Rectal Short Chain Fatty Acids Combinations and Substrate and Energy Metabolism
Condition: Obesity; Type 2 Diabetes
Study type: Interventional

Summary: 
      Gut microbiota is being increasingly recognized as an important factor in fat distribution,
      insulin sensitivity and glucose and lipid metabolism. Accordingly, the intestinal microbiota
      could play an important role in the development of obesity and type 2 diabetes mellitus. The
      role of gut-derived short-chain fatty acids (SCFA), the formation of which is enhanced by
      microbial fermentation of fiber, is still controversial. One study found that an increase in
      the formation of SCFA stimulated energy extraction from diet, with subsequent weight gain. In
      contrast, supplementation of non-fermentable carbohydrates, which lead to an increase in SCFA
      formation, had beneficial effects on body weight control and insulin sensitivity. Of note, a
      study showed that butyrate supplementation in mice prevented diet-induced obesity and insulin
      resistance. At the present time, our understanding of the effects of SCFA on human metabolism
      (in gut or systemically) is still limited. Yet, in light of the health claims of certain
      dietary fibers (prebiotics), a detailed picture of the physiology of human SCFA metabolism
      and its interaction with the microbiome is of pivotal importance. We hypothesize that the
      differential availability of SCFA impacts human metabolism differently. To determine whether
      rectal administration of SCFA is a good model for studying the metabolic effects of SCFA we
      first have performed a pilot study (METC 11-3-079). In this pilot study we have determined if
      rectal administration of sodium acetate has the same effects on substrate and energy
      metabolism compared to proximal administration. Our results indicate that the primary outcome
      parameter fat oxidation was significantly changed during post-absorptive conditions, when
      sodium acetate in a concentration of 180mM was administered in the distal part of the colon.
      In contrast, no effect on energy expenditure or substrate oxidation was seen when sodium
      acetate was administered in the proximal colon. Consequently, the distal part of the colon
      seems to be a good model to determine effects of gut-derived SCFA on the human substrate and
      energy metabolism. Therefore, we will administer in this study the SCFA rectally by using
      enemas. We will administer different combinations of SCFA to healthy, overweight male
      volunteers and examine effects on metabolism. This study is an important part of a
      Gastrointestinal Health TIFN project (GH003 WP 1.2), which will provide more insight in how
      increased availability of a beneficial SCFA mixture might serve as a basis for rational
      nutritional strategies in the prevention and treatment of obesity and type 2 diabetes
      mellitus. To obtain rational nutritional strategies, a next step in this TIFN project will be
      focusing on dietary ingredients modulating intestinal microbiota and subsequent SCFA
      production.
    


Intervention name(s): Three different mixture of acetate, butyrate and propionate and palcebo
Intervention type(s): Drug
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Diagnostic