Carbohydrate induced resilience of the gut microbiome after antibiotics use

The gut microbiome is a complex ecosystem with a wide range of functions, and
it is thought that it can influence multiple processes in the human body. In
turn, the composition and activity of the gut microbiome is affected by many
factors as well. Two of these factors are antibiotics and prebiotics, and they
are central in this study.

Antibiotics can be very effective in treating bacterial infections, but they
are also associated with detrimental health effects. Previous studies have
already shown that antibiotics disturb the human gut microbiome composition by
destroying commensal bacteria. As it is well known that the microbiome
influences host metabolism, perturbation of the healthy microbiome (dysbiosis)
is thought to be disease causing.

Prebiotics, on the other hand, are beneficial for the gut microbiome. These
so-called indigestible fibers are naturally present in our foods, but cannot be
metabolised by the human body. Many bacteria in the human gut are able to
ferment these fibers and they subsequently produce beneficial products for the
rest of the body. Besides this, fiber intake stimulates growth of commensal
bacteria in the human gut.

Although it has become increasingly clear that prebiotics have a beneficial
effect on the gut microbiome and general health, it is still unclear to which
extent the beneficial effects of prebiotics supplementation occur after the gut
microbiome is disturbed by antibiotics. We hypothesize that prebiotics
supplementation after antibiotics use will improve restoration of the gut
microbiome to a healthy state compared to placebo.

The objective of this study is to investigate the potential of a dietary fiber,
2'-fucosyllactose (2'-FL), to improve gut microbiome resilience after
antibiotics use.
Furthermore it will also be investigated whether there is a link between
restoration of the gut microbiome and changes in metabolic parameters such as
glucose or fat metabolism, and if this is affected by 2'-FL supplementation.

The proposed study is a double-blind, randomized placebo-controlled study.
Here, 40 healthy adults will first receive the antibiotic vancomycin for 7 days
to disturb the gut microbiome, after which they will receive either 2'-FL
supplementation or placebo (maltodextrin) for 8 weeks.
All study parameters will be assessed in two parallel groups, to which subjects
will be assigned using minimization.

During the first 7 da7s of the study period, all participants will be provided
with the antibiotic vancomycin. Participants will be asked to take two capsules
of 250 mg three times per day for 7 days, leading to a total dose of 1500 mg
per day.

After this period the group will be randomized into two groups using
minimization. One group will receive the 2'-FL supplementation for 8 weeks,
which consists of three portions of 4 g 2'-FL per day, for a total of 12 g
2'-FL daily. The other group will receive a placebo (maltodextrin)
supplementation during this period, which consists of three portions of 2 g
maltodextrin per day for a total of 6 g maltodextrin daily. The two
supplementations are isocaloric.

The total study period, from screening until the last clinical investigation
day, will take approximately 11 weeks. During this period participants will be
asked to visit the university a total of 8 times for both clinical
investigation days and supplementation days. The investigation days will take 4
hours, while the supplementation days will take at the most 30 minutes.
Although 11 weeks is quite a long period of time, the number of hours
participants are asked to be present at university is limited.
Participants will be asked to take the antibiotic vancomycin for 7 days and
subsequently, for a period of 8 weeks, to take either the 2*-FL supplementation
or placebo. During this period participants will be asked to keep to their
habitual diet and physical activity. This will be checked at six timepoints via
food diaries and a physical activity questionnaire. At these timepoints,
participants will also be asked to collect feces and fill in a questionnaire
regarding gastrointestinal symptoms. These actions will take approximately 2
hours per timepoint.

There are no risks associated with 2'-FL or maltodextrin. 2'-FL has been shown
to be safe in the dose used here, with side-effects being limited to
gastrointestinal discomfort.
The main risk for participants in this study is associated with the 7 days of
antibiotics use. Although side-effects of vancomycin are mainly limited to mild
gastrointestinal discomfort, permanent hearing loss and kidney insufficiency
have been reported in some cases. Furthermore, participants might be allergic
to vancomycin without knowing this.

Furthermore, during the clinical investigation days certain measurements will
be performed which may be causing some discomfort for participants. One example
of such a measurement is the placement of a peripheral intravenous cannula,
which will be used to draw blood multiple times during the investigation days.
Besides this, an abdominal subcutaneous adipose tissue biopsy will be taken at
the investigation days. During this, the discomfort may be higher. As
participants can experience these measurements as unpleasant, they will be
performed by well-trained and exprienced professionals. Furthermore the amount
of blood-drawings and biopsies is kept to a minimum, to limit participant
discomfort.

During the screening prior to the start of the study, potential participants
will be screened for health risks. If these are present, invidividuals will be
excluded from participation. All clinical investigation days will take place in
the Metabolic Research Unit Maastricht and the responsible medical doctor will
be aware of all investigation days. Furthermore participants are able to
contact the researchers and an independent expert at all times in case of
complications or questions.

Given the duration of the study period of 11 weeks, the time-investment is
considerable. The amount of time participants have to be present at the
university is limited however. Besides this, possible risks for the
participants with regards to study products and measurements are limited as
much as possible. There are also suffiicient safety measures in place and
sufficient professionals on site to minimize potential risks. Given these
burden and risks, we feel that is justifiable to conduct the study.