Effect of duodenal infusion of Eubacterium Hallii on gene expression, postprandial metabolites and glucose metabolism in males with metabolic syndrome

Also see page 5, 6, 7, 8 of the protocol.
Due to recently developed high-throughput metagenomic sequencing by 16S rRNA ,
more knowlegde has been acquired on the role of the (small) intestinal
microbiota in the pathofysiologie of metabolic diseases such as obesity and
type 2 diabetes mellitus (T2DM) . Based on our earlier lean donor fecal
transplantation studies (Vrieze Gastroenterology 2012) , we found that E.
hallii bacteria were increased in the small intestine of insulin resistant
subjects which was associated with an improvement in insulin sensitivity (Rd)
as determined by clamp. Eubacterium hallii type stam L2-7 was thus HACCP
produced at NIZO for human use as it is unique in its capacity to produce
butyrate from lactate (which is 10 fold increased in the gut of T2D patients)
In our recent pilot study we studied the effect of different E. hallii doses on
insulin sensitivity in 27 patients with metabolic syndrome (DIME study, METC
2014_285). We found that daily oral treatment during 4 wks with E hallii was
safe and had no side effects. However, the effect on Rd/insulin sensitivity was
differential, and although we saw no overall significant effect in all groups,
we found that subgroups of patiënts upon E. Hallii did show a response (as
defined by insulin sensitivity increase Rd>10%), low dose (10e5/ml E hallii per
day ): 2 out of 9 subjects , middle dose(10e7/ml Ehallii per day): 4 out of 9
subjects and highest dose (10e9/ml Ehallii per day): 5 out of 9 responders. We
thus postulate that in some subjects E. Hallii cannot pass the stomach and thus
cannot engraft in the (small) intestinal microbiota and thus not improve
metabolism. In this study we therefore aim to test the maximal effect of E.
Hallii suspension in males with metabolic syndrome by infusing it at the high
dosage, which was tested to be safe and most effective in humans in the DIME
trial, via a duodenal tube, making sure it passes the stomach unscathed.
Following duodenal infusion of E. Hallii we will obtain duodenal biopsies 6h
later, as previously described . Furthermore, we will test the efficacy of the
E Hallii suspension on short / long term glucose metabolism by subjecting the
subjects to a 2h mixed meal test as well as 7 dgn measurement of glucose levels
(CMG by Free Style Libre)

In this randomised, double-blind, placebo-controlled cross-over single centre
study we propose to study the effect of duodenal infusion of single E. Hallii
treatment of 10 ml 10E9/ml in 10% glycerol or 10ml 10 % glycerol (administered
via duodenal tube) on gene expression, bacterial composition and short/long
term glucose metabolism in subjects with metabolic syndrome.

Subjects will be given duodenal infusion of 10 ml E. Hallii suspension 10E9/ml
in 10% glycerol or 10ml 10 % glycerol . After 6 hours duodenal biopsies will be
taken via gastroduodenoscopy, followed by a mixed meal test (2h) as well as CGM
by free style libre for short/long term monitoring of glucose metaboism/
insulin sensitivity. After 4 weeks the above will be repeated with either E.
Hallii suspension or placebo.

Subjects will be given duodenal infusion of 10 ml E. Hallii 10E9/ml suspension
in glycerol or placebo (10 ml of glycerol alone).

There will be 2 studyvisits. Both will take about 9h. During them a Cortrak
procedure is performed for tube placement and 6h later followed by a
gastroduodenoscopy with duodenal biopsies, followed by a mixed meal test taking
an additional 2h. Then a continuous glucose sensor (Free style libre) will a
fixed on the upper arm of the patient for 7 days measurement.A
gastroduodenoscopy is performed for small intestinal biopsies; this is a very
frequently performed intervention at our department of Gastroenterology clinic
with a very low (<0.1%) complication rate.E. Hallii treatment from the same
Batch has been given in our previous study, the DIME trial. No adverse events
were expected and none did.