The immune system and microbial tone in relation to NAFLD/NASH before and after BARIatric surgery in the morbidly obese in Amsterdam; the BARIA cohort study.

Non alcoholic fatty liver disease (NAFLD) is present in 80 % of all morbidly
obese subjects and is a major risk factor for development of non alcoholic
steatohepatis (NASH), with the latter becoming the major indication for liver
transplantation in the USA. It is increasingly recognized that the immune
system is a major player in obesity related disease and the switch from benign
to malign (insulin resistance and DM2) obesity is associated with changes in
the immune system and development of NAFLD/NASH. In this regard, the intestinal
microbiome is thought to play a major role in driving these immunological
changes (via portal vein metabolites). Moreover, the innate immune system
including the recently discovered innate lymphoid cells (ILC*s) has
increasingly gained attention in metabolic disease. However, at this moment it
is unknown whether and to that extend intestinal microbiota and immunological
tone can predict metabolic response (improvement in NAFLD/NASH) and
improvement in insulin sensitivity upon bariatric surgery. Increased
understanding of the pathophysiological mechanism as well as their relationship
to metabolic disturbances are thought to be of crucial importance to discover
new diagnostic and therapeutical targets in obesity associated NAFLD/NASH and
insulin resistance. Moreover, this study will identify the underlying
pathophysiological mechanisms that drive NAFLD/NASH reduction upon the surgery
(responders) and those that have no beneficial effect on at all
(non-responders) . This might help to predict who will benefit from the
bariatric surgical intervention and in whom this is not effective.

To gain insight in the metabolic, microbiota and immunologic changes after
bariatric surgery that drive NAFLD/NASH and weightless resulting in subsequent
conversion of malign to benign obesity.

Prospective cohort study

Participants will be recruited from the outpatient clinics of Surgery and
internal medicine at Spaarne Gasthuis. After informed consent, they will
collect faeces sample and will undergo mixed meal test within one month prior
to scheduled surgery, preferably during their regular hospital admission. In
addition to length, weight and blood pressure, they will be instrumented with a
non-invasive finger plethysmography (nexfin) for the assessment of central
haemodynamics (cardiac output, systemic vascular resistance) and baroreflex
sensitivity (BRS). During the mixed meal test, an ultrasonography of the
gallbladder will be performed for the detection of gallstones.
During surgery, tissue including liver biopsy and blood will be collected.
During 2 months after surgery, 3 (regularly scheduled) visits will be used for
extra sample collection. In the two years following surgery 2 visits to the AMC
or Spaarne Gasthuis (decided by the participant) will be scheduled for sample
collection and performing one 2h mixed meal tests,. At these visits weight,
blood pressure, central haemodynamics and baroreflex sensitivity will again be
measured. The ultrasonography of the gallbladder will also be performed again
during this follow-up visits. After the first two years after surgery, the
intensity of the study will be drastically decreased. Only at 5 and 10n years
after surgery, the participant will be asked to collect a faeces sample, urine
sample, oral swab and will be asked to fill in a psychological questionnaire. A
final visit will take place 10 years after surgery. This will amount to a total
of 30 hours of study time additional to the normal procedure.
It is known that 8-10% of all bariatric surgery patient need to undergo
revision surgery within the next 1-2 years ( Li et al, Surg Endosc. 2009
Jul;23(7):1640-4). If patients will be scheduled for abdominal surgery
(revision of bypass or cholecystectomy) in the 10 years following the first
surgery. These patients will be asked to give permission to again obtain
samples (liver biopsy and portal blood as well as adipose tissue) during this
abdominal surgery. In addition, subjects with definite NASH or advanced
fibrosis based on liver biopsy obtained during the primary bariatric surgery
will be referred to the NAFLD outpatient clinic. If the clinician finds it
necessary to repeat the liver biopsy based on clinical grounds, a small part of
this sample taken for clinical reasons will be collected if the subjects has
given permission. In addition, in the case of referral to a gastroenterologist
for upper gastro-intestinal complaints, the subjects might undergo an
endoscopy. If the gastroenterologist finds it necessary to perform an
endoscopy, a small part of the intestinal biopsy will be collected if the
subjects has given permission.
The risk of bleeding from the biopsy sites and portal vein sample during the
bariatric surgery procedure is very low because the biopsy sites are completely
visible to the surgeon and local haemostasis will be checked. Moreover,
bleeding disorders are an exclusion criterion. The adipose tissue biopsies
after surgery will be performed under local anaesthesia, there is a chance of a
localized temporary haematoma. The risk associated with blood pressure
measurement and assessment of non-invasive haemodynamics by
fingerphotoplethysmography (Nexfin) is negligible. The burden consists of the
extra time invested in the instrumentation and measurement. The risk associated
with the ultrasonography of the gallbladder is negligible, the time burden
(5min done in parallel with Nexfin) is also negligible since the
ultrasonography is performed during the 2 hour mixed meal test. This study will
identify the subjects that will have great weight gain upon the surgery
(responders) and those that have no beneficial effect on weight at all
(non-responders) and for whom the surgery is not effective. We therefore
believe that the scientific insight of our findings will outweigh the minimal
risks for the participating subjects in this study. Total blood amount taken
is 210 ml (2x mixed meal test at 65 ml per test, 1x baseline+DNA 40ml, 10 ml
for portal vein plasma and 3x 10ml follow up).