Spontaneous, non-sponsored, interventional, controlled, randomized, parallel-arm clinical study.
Primary objective To assess the impact of specific dietary approaches (ketogenic diet, Mediterranean diet, or Mediterranean diet supplemented with GABA-producing probiotics, e.g., Bifidobacterium adolescentis PRL2019) on fibromyalgia (FM) severity-particularly pain, sleep quality, anxiety, and depression-using validated questionnaires in female patients with FM and overweight/class I obesity.
Secondary objectives
* Evaluate effects on anthropometric measures, metabolic profile, and body composition. * Assess changes in gut microbiota composition and metabolomic analysis. * Measure neurosteroids with positive allosteric activity on GABA-A or NMDA receptors in saliva and/or plasma. * Exploratory pilot sub-study to quantify brain GABA and glutamate levels through magnetic resonance spectroscopy (MRS) in a subset of patients.
Methods Participants will be recruited from the Rheumatology Unit outpatient clinics of IRCCS Policlinico San Martino Hospital (Genoa). Eligible subjects will be adult women with FM and overweight/obesity, selected through protocol-defined criteria. Enrollment requires written informed consent.
At enrollment (baseline), participants will complete validated questionnaires assessing FM severity (pain, sleep quality, depression, anxiety, bowel function). Data collection will include sociodemographic information, Mediterranean diet adherence through PREDIMED questionnaire, basal metabolic rate, medical and dietary history, smoking status, blood pressure, and recent laboratory results. Stool, blood, and saliva samples will be collected for routine tests, metabolomics, and ELISA-based measurement of neuroactive steroids like cortisol, progesterone, DHEA.
Within 7 days T1, results will be reviewed and eligible participants randomized to one of three groups: hypocaloric ketogenic diet, Mediterranean diet, or Mediterranean diet plus probiotics. Individualized dietary plans will be provided with written and verbal instructions.
Anthropometric measurements (weight, height, BMI, waist circumference, waist-hip ratio) and body composition via bioelectrical impedance analysis BIA will be recorded at T0, T4, T8, and T12, together with biological sample collection.
Pilot MRS sub-study A subset of participants will undergo brain GABA and glutamate assessment through MRI spectroscopy performed on a 3T Siemens - Prisma magnet at the baseline, before dietary treatment and after 4 weeks. Results will be compared with spectra from control subjects screened through medical history to exclude relevant diseases.
Adult female patients with fibromyalgia, aged ≤ 65 years, who are overweight or obese (BMI 24.9 < ≤34.9 kg/m2);
Patients able to independently provide their written informed consent to participate in the study;
Patients motivated to participate in the project and able to independently manage the dietary plans provided for in the study.
Lack of signature on informed consent form
Age < 18 and > 65 years
Male gender
Patients with food allergies or celiac disease, type 1 diabetes mellitus and autoimmune forms of diabetes mellitus or with severe pancreatic beta cell dysfunction, undergoing treatment with SGLT2 inhibitors, with recent cardiovascular or cerebrovascular events, liver failure, moderate or severe renal failure, respiratory failure, episodes of gout, kidney stones, electrolyte disturbances, NYHA class III-IV heart failure, unstable angina, cardiac arrhythmias or myocardial infarction within the last 12 months, severe depression or any other psychiatric illness, drug, narcotic or alcohol abuse, frail patients, pregnancy and/or breastfeeding, patients about to undergo surgery or invasive procedures, rare diseases (porphyria, carnitine deficiency, carnitine palmitoyltransferase, carnitine acylcarnitine translocase and pyruvate carboxylase, mitochondrial beta oxidation disorders), treatment with diuretics.
Parallel
Very Low-Calorie Ketogenic Diet
BehavioralThe very low calorie ketogenic diet (VLCKD) is a diet characterized by a very low carbohydrate content and reduced calorie intake, while maintaining an adequate amount of protein. In this study, subjects will receive food kits and supplements prepared by SDM, a company belonging to the Pronokal group. The VLCKD involves three different phases of intervention: the 4-week attack phase (phase l), the transition phase (phase Il), and the maintenance phase (phase III). Phase I is characterized by an 800 kcal diet with 1.2 g/kg/ideal weight of protein, 10-15 g of lipids, and 45-70 g of carbohydrates. Phase Il (four weeks) aims to gradually reintroduce carbohydrates, increase calorie intake and reduce consumption of Pronokal products. Phase Ill involves maintenance through a low-calorie Mediterranean-style diet in line with the other arms interventions, of 1400 kcal/day for another 4 weeks.
Mediterranean diet
BehavioralA standardized low-calorie diet of 1400 kcal/day will be drawn up. The macronutrient breakdown will follow the Reference Intake Levels for Nutrients and Enerav (LARN V edition), providing for: 0.9 g/day/kg of ideal body weight of protein, 48% carbohydrates, and 30-35% lipids. The daily calorie breakdown will be: 15% of calories for breakfast, 35-40% for lunch, 30-35% for dinner, and 10% of the remaining calories to be divided into two snacks. Each patient must follow the Mediterranean Diet for the entire duration of the treatment, i.e., 12 weeks, during which any necessary changes will be made to ensure full compliance with the diet plan.
Mediterranean diet enriched by GABA-producing probiotic
BehavioralStandardized low-calorie diet of 1400 kcal/day characterized by: 0.9 g/day/kg of ideal body weight of protein, 48% carbohydrates, and 30-35% lipids. The daily calorie breakdown will be: 15% of calories for breakfast, 35-40% for lunch, 30-35% for dinner, and 10% of the remaining calories to be divided into two snacks. This diet will also be enriched with GABA-producing probiotics such as Bifidobacterium adolescentis PRL2019 (20 CFU/day) present in Gabapral produced by Pharmextracta S.p.A.
Assessing the impact of dietary approach on the severity of fibromyalgia, particularly on pain through the Widespread Pain Index (WPI)
Widespread Pain Index (WPI): this corresponds to the sum of the areas of pain present (ranging from 0 to 19).
Assessing the impact of dietary approach on the severity of fibromyalgia, particularly on pain through the Symptom Severity Scale (SSS).
Symptom Severity Scale (SSS): this corresponds to the sum of the severity levels of three symptoms (fatigue, non-restorative sleep, cognitive problems), measured on a 4-point ordinal scale, and the presence or absence of three other symptoms (migraine, abdominal pain/cramps, depression). The maximum possible score is 12.
Assessing the impact of dietary approach on the severity of fibromyalgia, particularly on pain through the Fibromyalgia Impact Questionnaire (FIQR).
The FIQR comprises 21 questions, structured on numerical rating scales ranging from 0 to 10. The questions are divided into three distinct domains: physical function (9 questions), relating to difficulty in performing common activities of daily living; general health status (2 questions), which investigates the impact of the condition on work performance; and self-assessment of the intensity/severity of condition-related symptoms (10 questions).
Assessing the impact of dietary approach on the severity of fibromyalgia, particularly on pain through the PainDETECT (PD-Q).
The PainDETECT (PD-Q) consists of a series of questions designed to identify the type, location (including any radiating pain) and intensity of the pain. It also includes an image of a figure shown from the front and back, on which the patient must indicate the area affected by the pain.The score ranges from 0 to 35 and is directly proportional to the likelihood of the pain being neuropathic. More specifically, a final score of less than 12 indicates that neuropathic pain is unlikely, whilst a score of more than 19 indicates that the pain is very likely to be neuropathic.
Assess adherence to the Mediterranean diet and the impact of the dietary approach on anthropometric measurements.
Anthropometric measurements will be taken weight (kg), height (m), Body Mass Index (BMI), waist circumference (cm) and waist-to-hip ratio. BMI is calculated by dividing body weight (in kg) by the square of height (in metres): kg/m2. A value between 18.5 and 24.9 indicates a normal weight, whilst values above 25 indicate being overweight and those above 30 indicate obesity.
Evaluate the impact of dietary intervention on the composition of the gut microbiota through metabolomic analysis.
Metabolites will be extracted from the blood sample for untargeted metabolomic analysis with methanol and MTBE, and the MSK-QC-KIT will be added before injection into the UHPLC system. C18 and HILIC chromatographic conditions will be used for separation. MS data will be acquired with a Q-Exactive Plus quadrupole-orbitrap hybrid mass spectrometer in full scan mode in both positive and negative ionisation. The data will be processed for deconvolution, peak collection, alignment and compound identification. A procedural blank sample will be used for background subtraction and noise removal during the pre-processing stage. MS-FINDER ver.3.26 will be used for compound annotations, and the data will then be bioinformatically analysed for metabolite and pathway enrichment.
Assessment of neurosteroids with positive allosteric action on GABA-A receptors or NMDA receptors in saliva and/or plasma.
Participants will also be asked to provide saliva samples, which will be analyzed using ELISA to measure levels of neuroactive steroids such as cortisol, progesterone, and DHEA.
Exploratory pilot sub-study to measure brain levels of GABA and glutamate using magnetic resonance imaging (MRI) in a small sample of patients (18 patients + 6 controls).
For the pilot sub-study, GABA and glutamate levels will be assessed inappropriate brain regions using magnetic resonance spectroscopy (MRS). To this end, a subgroup of 18 patients selected at a rate of 6 per arm will sign a specific informed consent form for this analysis. The procedure will be performed once in phase T1 (depending on equipmen availability), i.e. before the start of the diet, and a second time after 4 weeks (T4). The results o the spectroscopy analysis, aimed at analysing the patients GABA and glutamate levels, will be compared with the spectrum analysis performed on 6 control subjects, defined by remote anc recent pathological history, which allows the potential presence of specific pathologies in all organs to be ruled out at the time of the history taken by the neuroradiologist. The change in concentrations between TO and T4 (at 4 weeks) will be calculated relative to the initial value. The second value at T4 will be compared with the mean value of the controls.
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Universita degli Studi di Genova
Lead sponsor
Ospedale Policlinico San Martino
Collaborator
Istituto Giannina Gaslini
Collaborator
