Primary objective is to evaluate the clinical effect of high intensity exercise on NAFLD genes by altering the gut microbiome. Secondary objective is to analyse gut microbiota composition and identify novel biomarkers of high intensity exercise…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- NAFL disease progression compared between baseline and after 12 weeks
intervention, evaluated by liver biopsy and MRI/MRS scan. This is based on
analysis between baseline and endpoint.
- Hepatic, muscle and adipose tissue histology and gene expression (evaluated
by RNA-sequencing) that is affected by exercise intervention. This is based on
liver, muscle and adipose tissue biopsy at baseline and endpoint.
Secondary outcome
- Fecal microbial composition variation, evaluated by metagenomic sequencing.
This is based on fecal sample at baseline, midway, and endpoint.
- Metabolite quantification of plasma and urine samples. This is based on urine
samples at baseline and endpoint, and blood samples at baseline, midway and
endpoint.
Background summary
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of liver
dysfunction with a global prevalence of 25 % which is accompanied by increasing
obesity and obesity related metabolic diseases. NAFLD is defined as at least 5
% of fat in hepatocytes in absence of other hepatopathies. It covers a spectrum
of different disease stages varying from non-alcoholic fatty liver disease
(NAFL) to an advanced stage of the disease called non-alcoholic steatohepatitis
(NASH). NASH is defined as steatosis with hepatocyte injury, inflammation and
fibrosis while in NAFL only lipid accumulation is detected. Hepatocellular
carcinoma (HCC) can develop at the fibrotic stage before any sign of symptoms
of liver dysfunction. The end stage of the disease is cirrhosis which is an
increasing cause of liver transplantations in the western world. There are
currently no pharmacological treatment options to treat NAFLD or to prevent its
progression to NASH, NAFL-related fibrosis or cirrhosis. Internationally
recommended therapies include lifestyle intervention modifications targeting
weight loss. Nevertheless, lifestyle interventions require a lot of resources.
Additionally, weight loss as a clinical intervention is rather unsustainable.
Exercise has been demonstrated to reduce hepatic lipid content in NAFLD
patients without overall weight loss. However, the mechanism behind the effect
of exercise independently of body weight change is unclear. There is a strong
link between gut microbiota and the development of NAFLD. Additionally,
exercise modulates gut microbiota. Thus, it can be suggested that the effects
of exercise on NAFLD may not only be mediated through a physiological response
to the liver, but through the gut microbiota and related metabolites. This
study aims to investigate the clinical effect of exercise on NAFLD and explore
whether these effects are related to changes in the gut microbiome and its
composition. In addition to this we will study whether potential changes in the
gut microbiota can be used to monitor exercise progression and predict the
prognosis of NAFLD. Finally, potential biomarkers will also be searched for by
transcriptomic analyses of liver, muscle and adipose tissue, and metabolomic
analyses of blood, feces and urine.
Study objective
Primary objective is to evaluate the clinical effect of high intensity exercise
on NAFLD genes by altering the gut microbiome. Secondary objective is to
analyse gut microbiota composition and identify novel biomarkers of high
intensity exercise effect on NAFLD.
Study design
This study is designed as a high-intensity exercise intervention study.
Intervention
The participants will follow the 12-week exercise intervention with specified
instructions according to the study group. HIIT group will receive structions
for high-intensity aerobic interval training.
Study burden and risks
Participant may benefit in the short term from the exercise since it may
improve their physical fitness and motivation to actively perform exercise.
Additionally, patients are helping to futher unravel the relation between
exercise induced changes in gutmicrobiota in relation to metabolic control in
liver, muscle and adipose tissue which may lead to novel diagnostic and
therapeutic leads
The placing of the intravenous cannula in our study can be an unpleasant
experience for the subjects and may result in (self-limiting) bruising.
An experienced interventional radiologist will perform ultrasound-guided liver
biopsy. Ultrasound-guided percutaneous liver biopsy is a safe method with very
low the risk of complications (< 0.1 %) comprising mostly bleeding from the
biopsy site. Moreover, local hemostasis after the procedure can be observed.
Liver biopsy will be performed under local anaesthesia.
Adipose tissue biopsy will be taken from the fat of the abdomen. The abdominal
skin will be anesthetized at the site of the biopsy so it will be painless for
the participants. However, it is unpleasant but not harmful since anaesthetic
is a small prick and may feel uncomfortable. In few hours after the biopsy, the
area of biopsy may feel a bit sore and a bruise may develop.
Muscle biopsy will be taken from the muscle of leg under aesthetic conditions.
Following a muscle biopsy the leg may stay sensitive for a few days. It is a
minor intervention, usually without any events but like any procedure there is
a minor risk of bleeding or infection.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
- Diagnosis of steatosis on transient elastography, conventional ultrasound,
magnetic resonance imaging, computed tomography , or by liver biopsy, or
identified as steatotic subject by fatty liver index (FLI) algorithm which is
based on waist circumference, body mass index, and levels of triglyceride and γ-
glutamyltransferase.
- 18-70 years of age
- BMI < 40 kg/m2
Exclusion criteria
- Acute illness or current evidence of acute or chronic inflammatory or
infective diseases
- Abusive alcohol use (> 21 IU/week for men, > 14 IU/week for women)
- Diagnosed liver cirrhosis and/or hepatocellular carcinoma
- Diagnosed cardiorespiratory, neurological or musculoskeletal disease
- Diagnosed insulin or GLP-1 agonist treated type 2 diabetes or type 1 diabetes
- Hepatitis B and/or C or auto-immune hepatitis
- Wilsons disease/ alpha-1-antitripsine deficiency
- Hemochromatosis
- Untreated hypothyroidism
- Lipoatrophy
- Bleeding disorder or anti-coagulant use which cannot be temporarily
discontinued
- Not able or willing to undergo MRI (for example claustrophobia, ICD,
pacemaker)
- Diagnosed depression or any mental illness rendering the patients unable to
understand the nature, scope and possible sequences of the study
- Any participation in regular exercise and/or diet program more than 2 times
per week in the 3 months prior to recruitment
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL69349.018.19 |