Effect of oral Eubacterium Hallii on postprandial glucose metabolism in males with type 2 diabetes treated with metformin

The development of culture-independent approaches, using high-throughput
metagenomic sequencing via 16S rRNA3, has drastically increased the knowledge
of the gut microbiome, now linking any disturbances in it, both in human and
animal models, to the pathophysiology of metabolic diseases such as obesity and
type 2 diabetes mellitus (T2DM). Transplantation of lean healthy microbiota in
subjects with insulin resistance showed an significantly increased insulin
sensitivity and an increased abundance of butyrate-producing bacteria in the
gut. In this pilot study we identified a specific increase in the
butyrate-producer Eubacterium hallii in small intestinal biopsies of human
obese and insulin resistant subjects upon lean donor fecal transplantation.We
recently published an animal study in which we studied the effect of E. hallii
treatment on metabolism in mice. We found that increasing dosage of daily E.
hallii treatment was safe and did not induce adverse effects. Moreover we
observed a dose dependent effect of E. hallii on improved insulin sensitivity
in correspondence with fecal E. hallii levels.In the recently finished DIME
study (METC 2014_285) we studied safety and optimal dose of daily ingested oral
E. hallii L2-7 strain for 4 weeks on insulin resistance/lipid metabolism in 27
male subjects with metabolic syndrome. No side effects were seen on either
dosage during the treatment.
In this regard, it is interesting to note that DM2 subjects on metformin
treatment have increased levels of lactate in their feces. Since E hallii uses
intestinally produced lactate to produce butyrate that is thought to be the
beneficial compound driving the effects on insulin sentivity, we hypothesize
that adding E hallii to metformin treatment in subjects with DM2 may improve
their glycemic control. This as the produced lactate by metformin treatment
potentially could be converted by E hallii bacterial strains into the more
metabolically beneficial SCFA butyrate. Thus, in the current study we propose
to test the effect of daily oral E. hallii treatment in 10e9/ml dose (duration
14 days) in males with type 2 diabetes treated with stable dosages of metformin
(3dd 500mg once daily). In order to test the efficacy of 2 weeks oral E. hallii
treatment on (postprandial) glucose excursions subjects are asked to wear a
subcutaneous continuous glucose monitor (CGM), which measures interstitial
fluid glucose on certain time points, during seven days.

to investigate the effect of 14 days once daily oral Eubacterium hallii (E.
hallii) treatment on postprandial glucose levels in relation to SCFA levels in
feces in patients with type 2 diabetes treated with metformin.

randomized, double-blind, placebo-controlled single center study

Subjects will be given oral 10 ml E. hallii suspension with a total
concentration of 10e9 cells/ml in 10% glycerol (vial A) or 10ml 10 % glycerol
only (Vial D) once daily during 14 days.

The total duration of this study is 4 weeks and participants will visit the AMC
four (screening, run in, randomization and end of study visit) times. All
participants are required to fill out food diaries three days per week and are
required to collect 24h urine and feces at baseline, week 2 and week 4 of the
study. Furthermore, subjects will undergo a mixed meal test (MMT) before and
after the intervention with blood sampling during 2 hours from a placed
venflon. Afterwards, subjects are provided with a disposable continuous glucose
sensor (FreeStyle Libre)1, which will be worn for 14 days before and 14 days
after the intervention to monitor (postprandial) glucose excursions both short
term and long term, with this Free Style glucose sensor no additional blood
glucose measurements with finger pricks need to be done. Also, subjects receive
an blood pressure monitor to ambulatory measure their blood pressure during 24
hours before and after treatment. In total subjects will spent 6 hours in the
AMC (screening visit, 2x 2 hours for the MMT plus CGM at baseline,
randomization and after intervention) and we will collect 240 ml blood (at
baseline, week 2 and week 4) in total.