Effect of Fecal microbiotA Transplantation combined with MEditerranean Diet on insulin sensitivity in subjects with metabolic syndrome

The prevalence of obesity and type 2 diabetes mellitus (DM) is rising at an
alarming pace. Although many factors have been identified as partakers in the
development of these diseases, the complete pathophysiological pathway is still
not completely understood and moreover, effective therapeutic options seem even
harder to establish.
Mounting evidence links altered fecal intestinal microbiota composition to the
development of obesity, insulin resistance/type 2 diabetes mellitus and even
cardiovascular disease. Previous research has shown that faecal microbiota
transplantation of lean healthy donors improves insulin sensitivity. Moreover,
we recently published that engraftment of these beneficial bacterial strains
from lean donor feces is not equally efficient in all metabolic syndrome
subjects, and that this is related to the level of improvement in insulin
sensitivity upon allogenic fecal transplantation (LI-Nieuwdorp, Science
2016). It seems that especially the recipient microbiota composition
determines whether engraftment of the benificial donor bacteria takes place.
We know that diet is of pivotal importance in gutmicrobiota composition and
changes is diet can rapidly alter gut micriobiota composition. In particular
the mediterranean diet has shown many benificial effect on health in previous
research.
Based on these data, we hypothesize that prescription of a beneficial
(Mediterranean) diet will enhance engraftment of beneficial donor intestinal
bacteria upon lean donor FMT and will thus have a synergistic beneficial effect
on (peripheral) insulin sensitivity and intestinal microbiota composition in
subjects with metabolic syndrome. Furthermore, this therapeutic intervention
study will help us in understanding host-microbiota interactions in human
(glucose) metabolism and will hopefully help to dissect progression from
benign to malign (insulin resistant) obesity and eventually type 2 diabetes
mellitus.

To study the effect of a Mediterranean diet (MD) followed by lean donor fecal
microbiota transplantation (FMT) versus the prescription of Mediterranean diet
(MD) followed by autologous (own) FMT in male subjects with metabolic syndrome
on peripheral insulin sensitivity and (small) intestinal microbiota composition

This is a double blind randomized single centre trial in which we will
randomize 24 male metabolic syndrome patients in 2 treatment arms:
- Mediterranean diet followed by allogenic lean donor FMT (n = 12)
- Mediterranean diet followed by autologous FMT (n = 12)

12 healthy lean male donors will be uses for the allogenic donor FMT

All patient will adhere to the mediterranean for the total duration of the
study with guidance of a dietitian and/or investigator.

Patients will be treated with infusion of either allogenic (lean healthy donor)
or autologous (their own) feces transplantation:

1. Morning stool sample (150-250 gram) is collected by recipient & donor and
brought to AMC for processing
2. Randomization met syndrom subject for either allogenic or autologous
feces transplantation
2. Gastro-duodenoscopy will be perfomed for positioning of duodenal tube;
during the procedure mucosal biopsies from small intestine will be taken.
Correct position of the tube is checked with an abdominal X-ray.
3. Thereafter, bowel lavage with 2-3 liters of Clean Prep through the duodenal
tube (according to standard protocols) will be performed to ensure complete
bowel lavage (duration 2-3 hours)
4. Finally, feces mixed in ~ 500 cc saline (filtered, < 6 hours after
processing) will be infused in the duodenum through positioned duodenal
tube.

Total duration of study will be 14 weeks, during which patients will visit AMC
7 times (total 35 hours and 390 ml blood will be drawn) Moreover, subjects
with metabolic syndrome will be asked to follow mediterranean diet for 8 weeks.

- Fecal transplantation: No side effects of faecal transplantation have been
reported in our previous trials. Because a strict screening protocol is applied
to faeces donors at the AMC, the risk of spreading potential pathogens during
faecal transplantation seems negligible and no long term effects have been
reported at our clinic since 2007 (>500 faecal transplantations performed).
- Gastroduodenoscopy: The risk of bleeding or perforation of the biopsy site
during gastroscopy is regarded as small. The placing of the duodenal tube can
be an unpleasant experience for the subjects, but there are no risks involved.
- Hyperinsulinemic clamp: This is regarded as a save test.The placing of the
intravenous cannula in our study can be an unpleasant experience for the
subjects and it can cause a minor hematoma, which will resolve spontanously.
- Discomfort: the participants could experience minor discomfort from placind
of the intravenous cannula, blood withdrawal, injection with lidocaine during
subcutaneous adipose tissue biopsies or placement of duodenal tube during
gastroduodenoscopy.