Chronic Low Back Pain (Non-specific, Uncomplicated), Chronic Low Back Pain (CLBP)
Conditions
Keywords
Epigenetic, DNA methylation, Glucose metabolism, IGF1/GH axis, Chronic low back pain, CLBP
Brief summary
Chronic low back pain (CLBP) is a global health problem. The first step for developing effective treatments is a better understanding of underlying mechanisms, including its comorbidities. Cumulative findings, including breakthrough findings from our own group, point to impaired glucose metabolism as an important CLBP comorbidity. In addition to its metabolic role, the insulin-like growth factor 1 (IGF1)/ growth hormone (GH) axis plays a key role in pain modulation. Therefore, the project aims to examine whether DNA methylation and functional protein levels predicts postprandial glycemic responses to standardized drinks, standardized meals, and real-life meals in patients with CLBP. This will be examined using two (i.e., 1 in CLBP and 1 in healthy controls) double-blind, randomized cross-over experiments (high versus low glycaemic index beverages). After the 14-day experimental phase, all participants will be studied for an additional week to examine whether the experimental findings have ecological validity, i.e., whether they can be confirmed in response to real-life meals in their home environment. Genome-wide changes in DNA methylation will be studied using whole genome bisulfite sequencing and targeted next-generation sequencing. The project allows identification of a biomarker for a potentially very significant CLBP comorbidity, including identifying targetable mechanisms to develop innovative, personalized treatments.
Detailed description
With this collaboration between KU Leuven and Vrije Universiteit Brussel, we aim to investigate the role of epigenetic mechanisms in impaired glucose tolerance in patients with CLBP by assessing DNA methylation patterns in genes related to the IGF1/GH-axis. The main objective is to identify whether DNA methylation in these genes predict postprandial glycaemic response (PPGR) to standardized drinks, standardized meals, and real-life meals in patients with CLBP. Secondary objectives are to investigate whether CLBP patients differ from healthy controls in DNA methylation; whether DNA methylation in these genes is associated with serum levels of their functional proteins, pain sensitivity and quality of life in CLBP patients; and whether dietary factors relate to DNA methylation in these genes and impaired glucose metabolism in CLBP patients. We hypothesize that CLBP patients display significantly higher DNA methylation in IGF1/GH-axis genes, accounting for lower serum levels of their proteins, and contributing to impaired glucose metabolism. Moreover, we expect that these epigenetic changes predict PPGR and relate with pain sensitivity and quality of life in patients with CLBP. We will perform a 2-arm, double-blind, randomized, cross-over experiment on 62 patients with CLBP and 62 healthy controls. During the first lab visit, the participants will fill out questionnaires on demographic and medical data, mental health, quality of life and pain, and autonomic nervous system (ANS) function and pain sensitivity will be assessed. Then the participants are randomized (1:1) to one of the interventions. This beverage is either a glucose solution or an isomaltulose solution (high vs low glycaemic index (GI)). For the third visit, they are crossed over to the other beverage. During the second and third visit, identical assessments will be performed. Preprandial assessments include questionnaires on anxiety and pain, blood collection, and ANS measurement. Then the participants consume the standardized drink within 5 minutes and remain seated for 2 hours, after which a postprandial blood collection is done. During the last week of the study the participants will consume a standardized meal (55g of white bread and 50g of dark chocolate) once daily after an overnight fast. For the full duration of the study, glucose levels, nutrition, sleep and physical activity will be measured continuously.
Interventions
OTHERGlucose beverage
This beverage is made by dissolving 75 g of glucose in 200 ml of water.
OTHERIsomaltulose beverage
The isomaltulose beverage consists of 75 g of isomaltulose dissolved in 200 ml of water.
During week 3 of the study, all partcipants consume a standardized breakfast after an overnight fast for seven days. This breakfast consists of 55g of white bread and 50g of dark chocolate. The participants are asked not to eat or perform strenuous exercise for up to two hours after consuming the breakfast.
Sponsors
Vrije Universiteit Brussel
Universitair Ziekenhuis Brussel
KU Leuven
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 18 and 65 years old * For patient group: participants must comply to the non-specific CLBP criteria which are low back pain every day for three months or pain for at least half the days in the last six months, without leg pain that exceeds 7 out of 10 on a numeric rating scale and without evidence of specific spinal pathologies. * For healthy volunteers: pain-free for the entire duration of the study
Exclusion criteria
* Systemic diseases (e.g., hypertension, cardiovascular disease, chronic gastrointestinal disorder, skin disease, active neuropathic disorder, severe eating disorders, myocardial infarction or cerebrovascular accident in the 6 months prior to the study) * Current pregnancy or pregnancy in the last year * Start-up of new medication or (dietary) treatment in the six weeks before the study * Antibiotic use in the three months prior to the study * History of bariatric surgery * Use of analgesics, alcohol, immunosuppressive drugs or smoking 48 hours prior to study participation * Classified as diabetic according to the American Diabetes criteria: fasting blood glucose ≥ 126 mg/dl, blood HbA1c ≥ 6.5%, or 2-hour PPGR ≥ 200 mg/dl Additionally, study participation will be postponed in case the participant donated blood \< 8 weeks before baseline and participants will be asked not to donate blood for the duration of the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Postprandial glycaemic response (PPGR) | During the first and last week of the study, for PPGR to real-life meals and standardized meals respectively, and during the second and third study visit (day 7 and day 14). | The primary outcome measure is the postprandial glycaemic response (PPGR) following standardized drinks, standardized breakfasts and real-life meals using a continuous glucose monitor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DNA methylation of IGF1/GH-axis genes | PBMCs will be isolated after blood collection on day 7 and day 14. | DNA methylation patterns in specific regions of 4 IGF1/GH-axis genes will be determined by whole genome bisulfite sequencing and targeted next-generation sequencing using Peripheral Blood Mononuclear Cells (PBMCs). |
| Serum levels of IGF1/GH-axis genes | Blood collection will be done on day 7 and day 14. | To assess the effect of differential DNA methylation in the genes of these proteins, we will measure functional protein levels in serum samples using Enzyme-Linked ImmunoSorbent Assays (ELISAs). We expect increased DNA methylation to result in lower serum protein levels. |
| Temperature pain thresholds | During the first study visit (day 1). | Detection and pain thresholds will be determined for both warmth and cold. |
| Pressure pain thresholds | During the first study visit (day 1). | Pain thresholds and temporal summation for pressure will be determined. |
| 36-item Short Form Health Survey (SF-36) | This questionnaire is completed by the participants at baseline (day 1). | Self-reported quality of life will be assessed through the 36-Item Short Form Health Survey (SF-36). Its score varies between 0 and 100, with higher values representing a better quality of life. |
| Brief Pain Inventory (BPI) | The BPI is completed during every study visit (day 1, day 7 and day 14). | The BPI will assess the pain sensitivity in the last 24 hours as reported by the participant. Its score ranges from 0 to 10, with higher scores representing increased pain symptoms. |
| Central Sensitization Inventory (CSI) | The CSI is completed during the baseline visit on day 1. | Signs of central sensitization are assessed using a self-reported questionnaire. Its score varies between 0 and 100 with higher scores indicating increased central sensitization and scores of 40 or higher suggesting central sensitization syndrome. |
| Douleur Neuropathic 4 (DN4) | This assessment will be performed during the baseline visit on day 1. | This assessement consists of 2 self-reported questions and 2 assessments performed by the investigator to test for signs of neuropathic pain. The total score varies between 0 and 10 with higher scores indicating increased neuropathic pain and values of 4 or more suggesting clinically relevant neuropathic pain. |
| Pain Catastrophizing Scale (PCS) | This assessment will be performed during the baseline visit on day 1. | As catastrophizing pain can influence pain perception, this will be assessed using a self-reported questionnaire. Its values range between 0 and 52 with higher scores indicating increased catastrophizing and scores of 30 or higher suggesting clinically relevant catastrophizing. |
| Pain Vigilance and Awareness Questionnaire (PVAQ) | This assessment will be performed during the baseline visit on day 1. | This self-reported questionnaire assesses pain vigilance and awareness. Its scores range between 0 and 80 with higher scores indicating increased pain vigilance and awareness. |
| Widespread Pain Index (WPI) | This assessment will be performed during the baseline visit on day 1. | This self-reported questionnaire assesses the presence and nature of widespread pain. Its scores range between 0 and 19 with higher scores indicating an increased number of painful regions. |
| Calorie intake | During the first week, they will complete a 3-day dietary diary with details on the type of food, the amount consumed and the timing of the meals. During the last week, the same diary is filled out for seven days. | Calorie intake will be measured in a real-life setting using dietary diaries. |
| Macronutrient intake | During the first week, they will complete a 3-day dietary diary with details on the type of food, the amount consumed and the timing of the meals. During the last week, the same diary is filled out for seven days. | Macronutrient intake will be monitored using a dietary diary. |
| Micronutrient intake | During the first week, they will complete a 3-day dietary diary with details on the type of food, the amount consumed and the timing of the meals. During the last week, the same diary is filled out for seven days. | Micronutrient intake will be assessed using a dietary diary. |
| Healthy Eating Index (HEI) | During the first week, they will complete a 3-day dietary diary with details on the type of food, the amount consumed and the timing of the meals. During the last week, the same diary is filled out for seven days. | Using the dietary diaries, the HEI will be determined to assess how healthy the participants' diet are. Its scores range between 0 and 100 with higher scores indicating a healthier diet. |
Countries
Belgium
Contacts
CONTACTJoni Michiels, PhD student
CONTACTJinane Ben Amar, PhD student
PRINCIPAL_INVESTIGATORJo Nijs, Professor
Vrije Universiteit Brussel
Outcome results
None listed