Plant-based diets have gained increasing recognition for their sustainability and their benefits on cardiometabolic and liver health. However, evidence regarding their effects in patients with metabolic liver disease (MetLD) remains limited. The primary objective of this project is to compare the effects of a traditional Mediterranean diet and a Mediterranean diet exclusively based on plant-derived foods on liver parameters, cardiometabolic health, gut microbiota, and exposure to environmental contaminants in patients with MetLD. This study is a randomized clinical trial with a 1:1 allocation ratio into two groups: a traditional Mediterranean diet, considered the standard diet in our setting and recommended for this condition, and a Mediterranean diet exclusively based on plant-derived foods, both designed by registered dietitians. The intervention will last 12 weeks. Anthropometric, metabolic, hepatic, inflammatory, and quality of life variables will be assessed. Additionally, gut microbiota, genetic variants associated with MetLD, and internal exposure to environmental contaminants will be evaluated using biological samples. A 4-week follow-up after the intervention will also be conducted to assess the integration of lifestyle recommendations among participants. The results will contribute to the development of safe, sustainable, and cost-effective nutritional strategies and may serve as a basis for future clinical guidelines integrating precision nutrition and planetary health in the management of chronic liver diseases. The traditional Mediterranean diet has shown metabolic and hepatic benefits; however, its reformulation toward a predominantly plant-based pattern may enhance these effects by reducing saturated fat intake and increasing the consumption of fiber, bioactive compounds, and fatty acids with a more favorable profile. Moreover, this type of diet limits the intake of animal-based foods associated with the bioaccumulation of environmental contaminants such as PFAS and heavy metals, which are increasingly implicated in the progression of MetLD. This project hypothesizes that a Mediterranean diet based exclusively on plant-derived foods, compared to a traditional Mediterranean diet, will lead to greater improvements in hepatic, metabolic, and inflammatory parameters in patients with MetLD, and will additionally be associated with a lower internal burden of bioaccumulative environmental contaminants. Primary objective To evaluate the effect of a Mediterranean diet based exclusively on plant-derived foods on MetLD, assessed non-invasively through biochemical and elastographic parameters. Secondary objectives To evaluate changes in metabolic parameters, anthropometric measures, and body composition. To examine changes in systemic inflammatory markers, such as C-reactive protein and the neutrophil-to-lymphocyte ratio. To assess exposure to environmental contaminants, specifically heavy metals (lead, cadmium, mercury) and endocrine disruptors such as perfluorinated compounds (PFAS), and their relationship with liver damage. To evaluate whether genetic variants associated with susceptibility to and progression of MetLD modulate hepatic and metabolic responses to dietary patterns. To analyze changes in gut microbiota following the plant-based diet and their association with liver improvement.
Metabolic dysfunction-associated liver disease (MetLD) is currently the most prevalent chronic liver disease worldwide, representing the hepatic manifestation of metabolic syndrome and closely associated with obesity, type 2 diabetes mellitus, dyslipidemia, and hypertension. Its global burden continues to rise in parallel with increasing rates of cardiometabolic disorders, posing a major public health challenge. The natural history of MetLD ranges from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Disease progression is influenced by a complex interplay of metabolic, genetic, environmental, and lifestyle-related factors. Lifestyle modification remains the cornerstone of MetLD management, with dietary intervention being a key therapeutic strategy. Current clinical guidelines recommend the Mediterranean diet as the standard dietary approach, given its demonstrated benefits in reducing hepatic steatosis, improving insulin sensitivity, lowering systemic inflammation, and enhancing overall cardiometabolic health. Notably, these benefits have been observed even in the absence of substantial weight loss. In recent years, plant-based dietary patterns have gained increasing attention due to their potential to further improve metabolic and hepatic outcomes. Diets rich in plant-derived foods are characterized by higher intakes of dietary fiber, polyphenols, antioxidants, and unsaturated fatty acids, alongside lower intakes of saturated fats and cholesterol. These nutritional characteristics may contribute to improved insulin sensitivity, modulation of lipid metabolism, and attenuation of chronic low-grade inflammation. Furthermore, plant-based diets may influence liver health through mechanisms beyond traditional metabolic pathways. Emerging evidence highlights the role of environmental contaminants and endocrine-disrupting chemicals in the pathogenesis and progression of MetLD. Compounds such as per- and polyfluoroalkyl substances (PFAS) and heavy metals (e.g., cadmium, lead, mercury) have been associated with oxidative stress, mitochondrial dysfunction, alterations in glucose and lipid homeostasis, and hepatic injury. These contaminants are known to bioaccumulate predominantly in animal-derived foods, including fish, seafood, red meat, and organ meats. Therefore, dietary patterns that reduce or eliminate animal-based foods may lower internal exposure to these harmful substances. In addition to environmental exposures, genetic susceptibility and gut microbiota composition play critical roles in MetLD development and progression. Genetic variants such as PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13 have been consistently associated with liver fat accumulation, inflammation, and fibrosis. Meanwhile, the gut microbiota acts as a key regulator of host metabolism and immune function through the gut-liver axis, influencing bile acid metabolism, short-chain fatty acid production, and inflammatory signaling pathways. Diet is one of the main determinants of microbiota composition and function, and plant-based diets have been associated with increased microbial diversity and beneficial metabolic profiles. Despite these advances, there is currently a lack of randomized clinical trials specifically evaluating the effects of a Mediterranean diet exclusively based on plant-derived foods in patients with MetLD, particularly considering the integrated assessment of hepatic outcomes, cardiometabolic risk factors, gut microbiota, genetic susceptibility, and environmental contaminant exposure. This study is a randomized, controlled, parallel-group clinical trial designed to compare the effects of two dietary interventions: (1) a traditional Mediterranean diet, which includes both plant- and animal-based foods and is considered the standard of care in this setting, and (2) a Mediterranean diet exclusively based on plant-derived foods. Participants will be randomly allocated in a 1:1 ratio using a computer-generated randomization sequence with stratification by age and sex. The intervention will last 12 weeks, followed by a 4-week post-intervention follow-up period aimed at evaluating adherence, sustainability, and integration of lifestyle changes. The study adopts a pragmatic design to enhance external validity, allowing participants to follow ad libitum dietary intake within structured dietary guidelines, guided by internal hunger and satiety cues rather than strict caloric prescriptions. All participants will undergo a comprehensive baseline assessment, including clinical evaluation, dietary assessment, anthropometric measurements, blood pressure, and non-invasive liver evaluation using transient elastography with controlled attenuation parameter (CAP). Biological samples (blood, urine, feces, and hair) will be collected at baseline and at the end of the intervention to allow intra-individual comparisons. Dietary interventions will be individually tailored by registered dietitians based on participants' clinical characteristics, preferences, and estimated energy requirements. Both dietary patterns will emphasize whole, minimally processed foods and adherence to Mediterranean dietary principles. The plant-based intervention group will exclude all animal-derived foods and will receive standardized vitamin B12 supplementation to prevent deficiencies. Dietary intake will be monitored through repeated 24-hour dietary recalls conducted at multiple time points throughout the intervention, including both weekdays and weekends. Participants will also provide photographic records of meals to enhance data accuracy. Nutrient intake will be analyzed using specialized dietary analysis software. Continuous dietary counseling and support will be provided to promote adherence. Comprehensive outcome assessments will include biochemical, metabolic, inflammatory, and functional parameters. Laboratory analyses will include liver enzymes, lipid profile, glucose metabolism markers, iron status, and systemic inflammatory markers such as C-reactive protein and the neutrophil-to-lymphocyte ratio. Environmental exposure assessment will include quantification of PFAS in serum samples using high-performance liquid chromatography coupled with tandem mass spectrometry and isotopic dilution techniques. Heavy metals will be measured in hair samples using inductively coupled plasma mass spectrometry (ICP-MS/MS), providing an estimate of chronic exposure. Gut microbiota composition will be analyzed using 16S rRNA gene sequencing, focusing on diversity indices, taxonomic composition, and functional profiles. Genetic analyses will be performed on blood samples to identify polymorphisms associated with MetLD susceptibility and progression. Standardized and validated questionnaires will be used to assess physical activity, adherence to the Mediterranean diet, and quality of life. Additionally, body composition will be evaluated using bioelectrical impedance analysis, and muscle strength will be assessed using handgrip dynamometry. The primary objective of the study is to evaluate the effect of a plant-based Mediterranean diet on liver health, assessed non-invasively through elastographic and biochemical parameters. Secondary objectives include the evaluation of changes in anthropometric and cardiometabolic parameters, systemic inflammation, gut microbiota composition, genetic modulation of dietary response, and internal exposure to environmental contaminants. Data will be collected and managed using a secure electronic data capture system, ensuring data quality, confidentiality, and compliance with regulatory standards. Statistical analyses will be performed using appropriate descriptive and inferential methods, including multivariate regression models to account for potential confounders. The study will be conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. Ethical approval will be obtained from the relevant institutional review board, and all participants will provide written informed consent prior to inclusion. This study is expected to provide novel, integrative evidence on the role of dietary patterns in modulating liver health, metabolic function, environmental exposures, and host-microbiome interactions. The findings may contribute to the development of more effective, sustainable, and personalized nutritional strategies for the prevention and management of MetLD, supporting the integration of precision nutrition and planetary health into clinical practice.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
50
This dietary pattern is considered the standard of care in the study setting and includes a balanced intake of plant- and animal-derived foods, consistent with current clinical recommendations for metabolic liver disease. The diet emphasizes high consumption of vegetables, fruits, legumes, whole grains, nuts, seeds, and olive oil as the primary source of fat. Moderate intake of fish, poultry, eggs, and low-fat dairy products will be encouraged, while red and processed meats, added sugars, and ultra-processed foods will be limited.
This dietary pattern is designed and supervised by registered dietitians and emphasizes high consumption of vegetables, fruits, legumes, whole grains, nuts, seeds, and olive oil as the primary source of fat, in line with Mediterranean dietary principles. All animal-derived foods (including meat, fish, seafood, dairy products, and eggs) will be excluded. Legumes, whole grains, nuts, and seeds will serve as the main sources of protein and healthy fats. Participants will be encouraged to prioritize whole, minimally processed foods; however, plant-based alternatives to meat and dairy may be allowed in cases where necessary to support adherence.
Hospital Puerta del Hierro
Madrid, Spain
Body weight
Change from baseline to 12 weeks in body weight (kg), measured using bioelectrical impedance analysis under standardized conditions.
Time frame: Baseline and 12 weeks
Hepatic steatosis
Change from baseline to 12 weeks in hepatic steatosis measured non-invasively using transient elastography. Hepatic steatosis will be assessed by the controlled attenuation parameter (CAP, dB/m)
Time frame: Baseline and 12 weeks
Liver stiffness
Change from baseline to 12 weeks in liver stiffness, measured non-invasively using transient elastography. Liver stiffness will be expressed in kilopascals (kPa).
Time frame: Baseline and 12 weeks
Fat mass
Change from baseline to 12 weeks in total fat mass measured by bioelectrical impedance analysis (BIA) under standardized conditions.
Time frame: Baseline and 12 weeks
Waist circumference
Change from baseline to 12 weeks in waist circumference as a marker of central adiposity.
Time frame: Baseline and 12 weeks
Systolic blood pressure
Change from baseline to 12 weeks in systolic blood pressure (mmHg) measured using a validated device under standardized conditions.
Time frame: Baseline and 12 weeks
Diastolic blood pressure
Change from baseline to 12 weeks in diastolic blood pressure (mmHg) measured under standardized conditions.
Time frame: Baseline and 12 weeks
Fasting glucose
Change from baseline to 12 weeks in fasting plasma glucose (mg/dL) measured using standard laboratory methods.
Time frame: Baseline and 12 weeks
Fasting insulin
Change from baseline to 12 weeks in fasting insulin levels (µIU/mL) measured in blood samples.
Time frame: Baseline and 12 weeks
Total cholesterol
Change from baseline to 12 weeks in total cholesterol levels (mg/dL) measured using standard laboratory assays.
Time frame: Baseline and 12 weeks
Low-density lipoprotein cholesterol
Change from baseline to 12 weeks in low-density lipoprotein cholesterol (mg/dL)
Time frame: Baseline and 12 weeks
High-density lipoprotein cholesterol
Change from baseline to 12 weeks in high-density lipoprotein cholesterol (mg/dL)
Time frame: Baseline and 12 weeks
Triglycerides
Change from baseline to 12 weeks in triglyceride levels (mg/dL)
Time frame: Baseline and 12 weeks
Iron status
Change from baseline to 12 weeks in serum iron measured in blood samples.
Time frame: Baseline and 12 weeks
Ferritin
Change from baseline to 12 weeks in ferritin measured in blood samples.
Time frame: Baseline and 12 weeks
Transferrin saturation
Change from baseline to 12 weeks in transferrin saturation measured in blood samples.
Time frame: Baseline and 12 weeks
C-reactive protein
Change from baseline to 12 weeks in serum C-reactive protein as a marker of systemic inflammation.
Time frame: Baseline and 12 weeks
Neutrophil-to-lymphocyte ratio
Change from baseline to 12 weeks in the neutrophil-to-lymphocyte ratio calculated from complete blood count.
Time frame: Baseline and 12 weeks
Gut microbiota alpha diversity
Change from baseline to 12 weeks in gut microbiota beta diversity reflecting differences in microbial composition between samples.
Time frame: Baseline and 12 weeks
Gut microbiota taxonomic composition
Change from baseline to 12 weeks in relative abundance of bacterial taxa assessed by 16S rRNA sequencing.
Time frame: Baseline and 12 weeks
Serum PFAS concentrations
Change from baseline to 12 weeks in serum levels of per- and polyfluoroalkyl substances (PFAS), measured by HPLC-MS/MS.
Time frame: Baseline and 12 weeks
Change in hair heavy metal concentrations (lead, cadmium, mercury, arsenic)
Change from baseline to 12 weeks in heavy metal concentrations measured in hair samples using ICP-MS/MS.
Time frame: Baseline and 12 weeks
Genetic variants
Assessment of genetic polymorphisms (e.g., PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13) and their association with response to dietary intervention.
Time frame: Baseline
Health-related quality of life
Change from baseline to 12 weeks in general quality of life assessed using the 36-Item Short Form Health Survey (SF-36) questionnaire. The SF-36 is a validated instrument that evaluates health-related quality of life across multiple domains, with scores ranging from 0 to 100, where higher scores indicate better perceived health status and quality of life.
Time frame: Baseline and 12 weeks
Liver disease-specific quality of life
Change from baseline to 12 weeks in disease-specific quality of life assessed using the Chronic Liver Disease Questionnaire (CLDQ). The CLDQ is a validated instrument designed to assess quality of life in individuals with chronic liver disease, with scores ranging from 1 to 7, where higher scores indicate better quality of life and fewer symptoms.
Time frame: Baseline and 12 weeks
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