Rectal Short Chain Fatty Acids Combinations and Substrate and Energy Metabolism

Study Overview
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Brief Summary
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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.

Official Title
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The Effects of Rectal Administration of SCFA on Human Substrate and Energy Metabolism

Conditions
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Obesity, Type 2 Diabetes

Intervention / Treatment
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* Drug: Three different mixture of acetate, butyrate and propionate and palcebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overweight Obese men Exclusion Criteria: Athletes Diabetes mellitus

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>placebo | Drug: Three different mixture of acetate, butyrate and propionate and palcebo<br> <br> |
| Active Comparator: high acetate ratio<br>high acetate ratio | Drug: Three different mixture of acetate, butyrate and propionate and palcebo<br> <br> |
| Active Comparator: high butyrate ratio<br>high butyrate ratio | Drug: Three different mixture of acetate, butyrate and propionate and palcebo<br> <br> |
| Active Comparator: high propionate ratio<br>high propionate ratio | Drug: Three different mixture of acetate, butyrate and propionate and palcebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| fat oxidation | we will measure fat oxidation and energy expenditure by using the ventilated hood system | 4 hours total (2 hours fasting, 2 hours postprandial) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hormones that influence energy metabolism |  | 4 hours total (2 hours fasting and 2 hours postprandial) | 
| Circulating metabolites |  | 4 hours total (2 hours fasting and 2 hours postprandial) | 
| Hormones that influence energy metabolism - Circulating metabolites - Inflammatory markers - plasma SCFA content; - Indirect markers of insulin sensitivity - Appetite (VAS-scoring). |  | 4 hours total (2 hours fasting and 2 hours postprandial) |