Effects of a high-fat and a low-fat diet on early biomarkers of metabolic stress in blood and gene expression in the small intestine of healthy subjects

The prevalence of the metabolic syndrome is strongly increasing in developed
countries. The role of the small intestine seems important in the development
of the metabolic syndrome. Although it is known that a high-fat Western-style
of diet has deleterious effects on (post-prandial) lipidemia and glucose
homeostase, effects of such a diet on the small intestine is not known. To
elucidate the role of the small intestine on the early development of the
metabolic syndrome, the effects of a high-fat (HF) and a low-fat (LF) diet will
be examined on gene expression in the small intestine and early biomarkers in
blood of healthy subjects.

The objective of this study is to compare in healthy subjects the effects of a
HF diet (40 En% fat) with those of a LF diet (20 En% fat) on early biomarkers
and parameters of metabolic stress in blood and on expression of genes in the
small intestine. Additional research objectives are:
- To compare the diet-induced changes in transcriptome profile of the small
intestine with more easily accessible peripheral blood mononuclear cells (PBMC)
- To establish effects of HF and LF diet on basal gut permeability and after a
chenodeoxycholic acid (CDCA) load (second hit).

Randomised crossover design. The duration of the experimental periods (HF and
LF diet) will be 28 days, separated by a wash out period of at least 3 weeks.
At day 21 of each intervention period a postprandial test will be performed and
duodenum biopsies will be taken. At day 25 and 28 of each intervention period,
respectively, basal gut permeability and gut permeability after a CDCA load
will be determined with a sugar recovery test.

Subjects will consume in random order a) a HF diet (40 En% fat, 45 En%
carbohydrates and 15 En% proteins) and b) a LF diet (20 En% fat, 65 En%
carbohydrates and 15 En% proteins).

At the screening visit a blood sample (15 mL) will be taken, and blood pressure
and body weight will be measured. During the study six blood samples (300 mL)
and two duodenum biopsies (at day 21 of each experimental period) will be
taken. At the end of each experimental period the subjects will have to collect
urine for 24 hours (day 24) and on two occasions they will have to collect
urine for 5 hours after ingestion of a beverage containing sugar probes, once
for a basal gut permeability test (day 25), and once after a CDCA load (day
28). Three weeks after the diet intervention once again basal gut permeability
will be measured to determine basal gut permeability under standard dietary
conditions. During the study subjects will have to record their daily fat
intake during the intervention periods and two weeks after the last
intervention period in diaries. At each visit body weight will be measured.
Total time investment for the subjects will be 88 hours.
Blood samples might cause bruises or haematoma. Obtaining duodenum biopsies by
standard flexible gastroduodenoscopy induces local discomfort in the pharynx
only during the procedure, which takes about 10 minutes, and causes a
theoretical risk for perforations (1:1000) and an infection risk of
1:1.800.000. A single CDCA load is not known to have major side effects; some
diarrhea might occur.