Bariatric surgery and fructose handling in obese subjects

The global rising prevalence of obesity is a rapidly growing health problem,
likely driven by a diet rich in fats and sugars; which is commonly seen in the
Western diet. In this regard, the monosaccharide fructose is of particular
interest. he metabolism of fructose bypasses major regulatory steps of
glycolysis which allows an excess in energy balance. This excess is implied to
be a possible causative agent in the development of obesity and associated
diseases of the metabolic syndrome; like type 2 diabetes (T2D) and the spectrum
of non-alcoholic fatty liver disease (NAFLD). A step in the mechanism of these
detrimental effects in this regard might be through the bacteria in the
microbial ecosystem in the gut. Certain characteristics of the microbiota, such
as low diversity and the presence of specific gram negative strains
(Desulfovibrio and Klebsiella) correlate with the progression of metabolic
dysregulation and production of endogenous ethanol in the gut. Dietary intake
of fructose indeed seems to alter this composition of the gut microbiota,
diminishing microbial diversity. This in turn could play a further role in the
development and progression of cardiometabolic diseases. So far, these
mechanisms have only been partially elucidated and are not fully understood.
The driving role of the gut in fructose metabolism has long been
underestimated. Recent proof has come forward that most dietary fructose is
metabolized by the (small) intestine High dietary doses of fructose (>1 g/kg
bodyweight) were found to saturate the small-intestinal catabolic capacity,
leading to fructose overflow in the colon where specific gut microbial strains
mediate fructose catabolism into toxic plasma metabolites like uric acid,
ethanol and glycerolphosphate. Also, we recently showed that aberrant gut
microbiota composition is involved in endogenous ethanol production from
dietary sugars including fructose in obese subjects with fatty liver disease
(8). Thus, the amount of daily fructose intake can affect its location of
catabolism in the gut. Indeed, high dietary fructose dosages are linked to more
diabetes and NAFLD. We thus hypothesize that the amount of dietary fructose
affects (hepatic and systemic) metabolic (glucose) regulation via aberrant gut
microbial processing and production of specific metabolites , and when this
fructose dosage is continued after surgery could adversely affect weight loss
upon surgery. By collecting (during surgery) liver, adipose and jejunum tissue
biopsies for histology (e.g. degree of liver steatosis and GLUT5 staining) and
RNA seq determined gene-expression. Of note, biopsies are taken during
bariatric surgery (similar to the ongoing BARIA study (METC 2015_357) in which
currently about 500 patients are included and biopsies were taken without
adverse events), we aim to gain better insight into the different amounts of
dietary fructose intake affect these organs. Choosing the population from
patients scheduled for bariatric surgery will allow us to acquire the biopsies
with minimal burden to the study participants.
Thus altering the amount of fructose intake before surgery will give insight
into the role of microbiota dietary fructose degradation on (liver and small
intestine driven) metabolic and weight effects, driven by fructose in severely
obese subjects undergoing bariatric surgery. At Spaarne Gasthuis approximately
1000 patients per year undergo bariatric surgery. We thus feel that this study
can be executed in a relatively small timeframe.

Also, our new RCT study allows us to investigate long-term weight loss and
metabolic effects in relation to dietary priming before bariatric surgery,
which could help design future studies in larger populations and longer
follow-ups. Furthermore, this approach generates unique and novel data on the
interaction of a low fructose diet on gut microbiota composition as related to
liver/small intestinal gene expression and metabolic parameters.

To investigate whether changes in fructose dietary intake can help to improve
dietary fructose-induced insulin resistance and post bariatric weight loss in
obese subjects of Caucasian descent

Randomized controlled single-centre trial

Subjects will be put on either their normal regular diet (>100 gram fructose
/ day) versus a low fructose diet (<30 gram fructose intake per day
isocaloric correction of glucose load) 4 weeks before bariatric surgery. For
both groups, an oral fructose challenge will be performed at baseline as well
as 4 weeks after start of the diet (in the week of the surgery).

The total duration of the study is one year. Participants will additionally
visit the Spaarne Gasthuis three times. All participants
are required to fill out food diaries for one week, 4 times in total. Prior to
surgery participants have weekly contact with the dietician. Subjects are
required to collect 24h urine and feces at baseline and week 4 of the study.
Furthermore, subjects will undergo multiple blood sampling after a
Fructose Challenge Test (FCT). The proposed diet is safe and no immediate harm
is likely to occur. However, glycaemic control of
T2D can theoretically worsen. In total subjects will spend 15 hours for study
time in the Spaarne Gasthuis :2x 7 h for the FCT plus REE/BIA at baseline and
4 weeks, as well as 30 minutes during screening. We will collect 170ml blood
(at baseline and week 4). Venous blood will be drawn through a peripherally
placed cannula (therefore only 1 puncture is needed per test day).


Laparoscopic Roux-Y gastric bypass surgery will be performed following
institutional procedure protocols and in accordance with Dutch legislations
(Wet op de Geneeskundige Behandelings Overeenkomst). This means subjects will
be informed about the procedure, alternatives, possible complications, and
follow-up care, prior to the operation. It has to be stated that the operative
procedure itself is not part of the protocol, but regular indicated patient
care.
Biopsies

Pain after the biopsies taken during the surgery is not expected. Bleeding from
the biopsy site might occur, but this risk is minimized by excluding subjects
with coagulation disorders (see exclusion criteria) and by checking local
hemostasis by the surgeon twice.