Gut microbial substrate switch to improve metabolic health

In the last 15 years, the connection between the gut microbiota and
obesity-related cardiometabolic disorders is increasingly recognized. Our gut
microbiota affect the cardiometabolic phenotype by fermenting indigestible
dietary components, such as dietary fibers, which are coupled to production of
short-chain fatty acids (SCFA). These SCFA can affect adipose tissue function
and ectopic fat storage thereby modulating host insulin resistance. Our recent
findings, using a unique design to administer SCFA in the proximal and distal
colon, show that distal colonic SCFA administration, in amounts achieved by a
high fiber diet, has pronounced effects on lipolysis, fat oxidation and
inflammatory profile in healthy overweight volunteers. Based on this, we
hypothesize that slowly fermentable fibers with a high degree of polymerization
that increase SCFA specifically in the distal colon are expected to have higher
potential for influencing host metabolism and metabolic health by improving
adipose tissue function, preventing lipid overflow and skeletal muscle fat
accumulation thereby improving insulin sensitivity.

The objective of this proposal is to test in a proof-of-concept manner, whether
the dietary fiber product WholeFiberTM yields an optimal gut and circulating
SCFA concentration to reverse insulin resistance.

Double blind, placebo-controlled, randomized, parallel design.

In this study there will be two different intervention groups:
1. WholeFiberTM product (First two weeks: 2x 7.5g per day, last ten weeks: 2x
15g per day)
2. Placebo: Puffed Millet (First two weeks 2 x 3.9g per day, last ten weeks: 2x
7.8g per day), isocaloric
The intervention period will be at least 12 weeks (84 days) with a maximum of
90 days intervention due to practical reasons.
The type of treatment will be blinded for both the volunteers and the
researchers.

All participants will be screened before participation and thereby receive
information about their health status. In the future there can be general
health benefits for the public, but the volunteers receiving placebo will not
have a personal benefits by participating in the study. Participants receiving
the dietary fibers may have personal health benefits if intervention effects
are according to expectations. The general interest of this study is to
investigate how manipulating the gut microbiota, increasing SCFA production and
shifting colonic SCFA ratios by the intake of dietary fiber mixtures will
influence human peripheral insulin sensitivity and substrate and energy
metabolism.
Burdens that volunteers can experience, such as the time spent with the
study and the dietary and healthy regimen they have to follow. Also the
collection of faecal samples can be experienced as a burden, because they have
to handle them themselves and have to store them at home. Also the 12-week
intake of the dietary fiber can be seen as a burden for the participants.
During the CIDs, blood will be collected via a venous catheter.
Venepunctures can occasionally cause a local hematoma or bruise to occur. Some
participants report pain during venepuncture. During CID 1 and 2 the total
amount of blood sampled is 205ml per CID, totaling 445ml (35ml screening)
during the whole test period. During CID 1 and 2, adipose tissue and skeletal
muscle biopsies will be taken. The adipose tissue biopsy might cause local
hematoma as well. After the muscle biopsy, some participants report pain, which
is experienced as muscle pain. More often the muscle feels stiff for a couple
of days after the biopsy. To minimize the risk for a hematoma, the biopsy place
will be compressed for approximately 5 minutes after biopsy. The place of
incision will leave a small scar (* 3 mm for adipose tissue biopsy and * 8 mm
for skeletal muscle biopsy). To promote good wound healing, the incision will
be sealed with sterile steristrips and a waterproof band-aid. The site of the
muscle biopsy will, in addition, be sealed with a compression bandage. During
the hyperinsulinaemic-euglycemic clamp there is a small risk of hypo- or
hyperglycemia. However, from our own extensive experience, these conditions do
not occur very often and can be reversed immediately. A medical doctor is
always available during the clamp. Concerning the other study procedures (oral
glucose tolerance test (OGTT) (screening), and indirect calorimetry), there are
no known risks (in literature and own extensive experience), and these
measurements are routinely applied in human biology research. SOPs for each
measurement are available in the Human Biology Department*s database.