Effect of fecal transplantation on satiety and energy metabolism in female patients with anorexIa nervosa;

Anorexia nervosa (AN) is a psychiatric disease resulting in severely reduced
food intake partly due to altered appetite/satiety balance resulting in very
low BMI and the highest mortality rate of all mental illnesses1. Several forms
of psychological therapies, with or without medication, have been tried, but
have not been very successful. The pathophysiology of AN is incompletely
understood. It is unclear whether cognitive deficits and an abnormal balance in
factors involved in sensing appetite or satiety are the cause or consequence of
starvation in AN. In the current study, we want to focus on compensatory
changes in satiety and energy metabolism that possibly contribute to the
pathophysiology 2. Preliminary evidence has shown that the gut microbiota might
be involved in these compensatory mechanisms, including weight regulation,
energy metabolism3, anxiety and depression4. These gut microbiota promote
colonic serotonin (5-HT) production through stimulatory activities of short
chain fatty acids (SCFA) on enterochromaffin (EC) cells 5. Serotonin pathways
are known to contribute to the modulation of a range of behaviours, such as
anxiety and is a key regulator of gastrointestinal motility and satiety for
food6 7 8 9 5.One hypothesis is, that an imbalance of the gut microbiota, so
called dysbiosis, might cause a dysregulation of serotonin (5-HT) in patients
with AN, resulting in anxiety in AN. Indeed, upon examining the composition and
diversity of the gut microbiota in patients with AN, significant differences
(more gramnegative pathogens) were seen in feces of patients with AN versus
healthy controls10. The main question however thus remains if the imbalance of
the gut microbiota composition in AN is a cause or a consequence of the
disease. Fecal microbiota transplantation (FMT) can dissect causality from
association with respect to gut microbiota and metabolism11, and perhaps offer
an alternative therapeutic approach.

Primary objective: To investigate the effect of fecal transplantation (harvest
from donors with a normal BMI, 22-25 kg/m2) in patients with anorexia nervosa
between baseline and after 6 and 12 weeks. Our primary endpoint is the change
in the composition of fecal microbiota in relation to appetite. Satiety will be
measured by response to food cues in the CNS using functional magnetic
resonance imaging (fMRI)12 as well as by visual analog scale (VAS), Satiety
Labeled Intensity Magnitude (SLIM) scale and plasma markers for satiety
(tryptophan, ghrelin, leptin, neuropeptide Y and orexin levels)13 upon
nutrient drink test.

Secondary objectives: The effect of fecal transplantation between baseline and
after 6 and 12 weeks in: 1. Energy metabolism (as measured by resting energy
expenditure (REE), physical activity energy expenditure (PAEE) 2. Serotonin
levels, measured by platelet/serum serotonin and 24 hour collected urine
(5-HIAA). 3. Dietary intake (https://mijn.voedingscentrum.nl/nl/eetmeter) in
relation to weight body composition (Body Impedance Analysis, BIA). 4.
Psychological response: Score on the Yale-Brown-Corneel Eating Disorder Scale
(YBC-EDS) and obsessive compulsive symptoms and/or compulsivity about feeding
will be measured with the Yale Brown Obsessive Compulsive Scale (YBOCS). 5.
Quality of life (Eating Disorders Quality of Life, EDQOL) and assessment of
eating behaviour with the Eating Disorder Inventory (EDI-II), the Eating
Disorder Examination Questionnaire (EDEQ).

Pilot study (uncontrolled open-label)

Patients will be treated with infusion allogenic (feces from femal donor with a
BMI 22-25 kg/m2) microbial transplantation by duodenal tube after bowel lavage.
Bowel lavage is performed by infusion of 3-4 l KleanPrep through the duodenal
tube. De duodenal tube is placed using the Cortraksystem and abdominal X is
performed afterward to check position of the tube in the duodenum. Meanwhile,
donor feces mixed in 500 cc saline (filtered, <2 hours after processing) and
will be infused in the duodenum through positioned duodenal tube.

Total study duration is 12 weeks, during which subjects will visit the AMC 4
times (4-5 hours) extra (total duration 18 hours) and in total 200 (20ml
screening and 60 ml blood at 0,6 and 12 weeks). At -1 day, 6 and 12 weeks, a
REE and BIA will be performed. Furthermore during these days a functional MRI
and nutrient drink test will be performed. At baselinge (T=0) faecaltransfusion
will be performed. In the last 5 years we have performed over 300 fecal
transplantations at the AMC in several patientgroeps without seeing any short
or long term complications (FANFARE MEC 2013_278, FATLOSE-1 MEC, 07/114;
FATLOSE-2 MEC 11/023; FEBALIGO MEC 2013_090). Although in theory there is
always the risk of transferring (unknown) infectious diseases (just like with
bloodtransfusions), however using a thorough donor screening protocol can
minimize this risk. The total dose equivalent of the participating patients
will be 0.7mSv for the abdominal X-ray during coretrack (which is less than the
currently allowed 10.0 mSv WHO category IIb). Since we feel that this
intervention can help us to improve metabolic dysregulation in patients with
metastasized or locally advanced oesophageal and/or gastric cancer, we believe
that the burden of this study is in line with the potential therapeutic insight
that will be gained.