FATLOSE 2 study *Single versus multiple fecal transplants harvested from lean volunteers on lipid and glucose metabolism in subjects with metabolic syndrome; the FATLOSE 2 trial (Fecal Administration To LOSE insulin resistance)*

The Metabolic Syndrome (MS) is characterised by a constellation of
cardiovascular risk factors, which include elevated triglyceride (TG) levels,
reduced high-density lipoprotein cholesterol (HDL-C) and increased fasting
glucose levels. According to the National Cholesterol Education Program*s
(NCEP*s) Adult Treatment Panel (ATP III) definition, MetS is identified by
having three or more metabolic abnormalities in terms of elevated
triglycerides, decreased HDL-Cholesterol and increased fasting blood glucose
levels, abdominal obesity and elevated blood pressure (1). A most disturbing
consequence of the steady increase in MetS prevalence (2, 3) is the concomitant
rise in the incidence of both diabetes and cardiovascular disease in these
subjects (4, 5). In an effort to limit these detrimental sequelae, therapeutic
strategies are focussing at a comprehensive lowering, or even *normalizing*
these risk factors. In summary, these risk factors as mentioned above catalyze
the process of atherosclerosis and cardiovascular disease in type 2 diabetes
mellitus.
Recent research shows that obesity is associated with changed bowel flora
composition with a relative abundance of the two dominant bacterial divisions,
the Bacteroidetes and the Firmicutes (6). Interestingly, this specific bacteria
associated condition is transmissible: colonization of obese mice with an
*leanmicrobiota* results in a significantly greater decrease in total body fat
(-30%) than colonization with a *obese microbiota* (+5%). In addition,
Bacteroidetes species are decreased and Firmicutes increased in feces of obese
people compared to lean people (7). We recently finished the FATLOSE trial, in
which we studied the therapeutic effect of donor feces infusion from screened
volunteers, after 6 weeks, on insulin resistance (hyperisulinemic clamp with
stable isotopes) in male patients with metabolic syndrome (MEC 07/114, see 8).
We found a 50% reduction in both periferal and hepatic insulin resistance
implicating substantial effects of whole body glucose metabolism. Moreover, we
found significant reductions in fasting lipidprofiles after allogenic fecal
therapy, which are in line with previously published data suggesting a direct
effect between duodenal lipid uptake and glucose production orchestrated by
gutmicrobiota driven brain-gut axis (9). The efficacy of fecal therapy is
explained by enhanced production of specific short chain free fatty acid
butyrate produced by the infused lean donor feces, which probably restores
normal fecal physiology by implantation of missing lean-figure flora components
(10,11). In collaboration with dr Zoetendal and prof de Vos (WUR), we
confirmed by HITCHIP that the butyrate producing bacterial phylum Bacteroidetes
is specifically increased after allogenous feces transplantation (12).

In this follow-up study we would like to compare the effect of single versus
multiple (2x) duodenenal tube infused allogenic versus autologous feces (as
controls) on insulin resistance, cholesterol and (shortchain) free fatty acid
metabolism in obese male subjects with metabolic syndrome.

Objectives

To investigate the pathophysiological role of changes in fecal flora
composition on insulin resistance in patients with metabolic syndrome

I Changes in caloric intake (diet lists and weight) in relation to fecal flora
composition and
shortchain fatty acid metabolism in fecal samples at baseline and
after 3,6, 10, 13, 16 and 20 weeks in a group of uncomplicated male MS patients
receiving either single or twice allogenic or autologic feces transplantation
after total bowel lavage (n=10 per group).

II Longterm changes in fecal flora and insulin resistance (hyperinsulinemic,
normoinsulinemic clamp and glucose disappearance rate Rd) and
lipidmetabolism (mixed
meal test) before and 10 and 20 weeks after intervention with fecal
infusion

III Investigate the interaction between longterm changes in gutmicrobiota and
inflammation
and plasma markers of metabolic control (plasma GLP-1, adiponectin and
leptin levels)

This is a double blind randomized controlled single center trial.

Patients will be treated with infusion of allogenic or autologous feces by
duodenal tube after bowel lavage

Patients will be randomized by sealed envelopes to the following 6 treatment
arms:
1. single (at baseline) allogenic lean donor feces
2. single (at baseline) allogenic obese donor feces
3. multiple (at baseline and 10 weeks) allogenic lean donor feces
4. multiple (at baseline and 10 weeks) allogenic obese donor feces
5. single autologous (own) feces
6. multiple (at baseline and 10 weeks) autologous (own) feces

Subjects are submitted to a hyperinsulinemic normoglycemic clamp. To compensate
for the insulin infusion, glucose 20% is infused to maintain blood sugar levels
between 5 and 5.5 mmol/l, The rate of glucose infusion is determined by
checking the blood sugar level every 5 minutes.
Because strict conditions are there for donors, the risk of spreading potential
pathogens during faecal transplantation seems nil.