Gut Microbiota, Mitochondrial Function and Metabolic Health in Obesity

February 25, 2025 updated by: Celia Bañuls

Effect of a Very Low-calorie Diet on Microbiota, Oxidative Stress, Inflammatory and Metabolomic Profile in Metabolically Healthy and Unhealthy Obese Subjects

It has been suggested that individuals with the condition known as metabolically healthy obesity (MHO) may not have the same increased risk of developing metabolic abnormalities as their non-metabolically healthy counterparts. In addition, to date, the identification of metabolic biomarkers and microbiota underlying the MHO state is limited. In this study, our goal is to provide insight into the underlying metabolic pathways affected by obesity. To achieve this, we will compare the metabolic profile, inflammatory parameters and mitochondrial function, as well as metabolomic analysis and differential expression of microbiota in obese patients categorized as metabolically healthy vs. non healthy. In parallel, the effect of a hypocaloric diet on obese subjects' metabolism and microbiota will be assessed to approve their use in the treatment of said disorder. Specifically, we propose an observational, clinical-basic, comparative and interventional study in a population of 80 obese (BMI>35 kg/m2) patients clustered in two groups according to the presence or absence of altered metabolism (altered fasting glycemia, hypertension, atherogenic dyslipidemia). Anthropometric and clinical variables and biological samples (serum, plasma, peripheral blood cells and feces) will be collected for the determination of biochemical parameters (glucose, lipid and hormonal profile by enzymatic techniques) and protein-based peripheral biomarkers of mitochondrial function [total and mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential, glutathione levels by static cytometry], markers of mitochondrial dynamics [Mitofusin 1 (MFN1), Mitofusin 2 (MFN2), Mitochondrial fision protein 1 (FIS1) and Dynamin-related protein 1 (DRP1) by RT-PCR and Western Blot], markers of inflammation [Interleukin 6 (IL6), Tumoral necrosis factor alpha (TNFα), IL1b, adiponectin, resistin, plasminogen activator inhibitor 1 (PAI-1), Monocyte chemoattractant protein-1 (MCP-1), caspase 1 and NLRP3 by Western Blot and technology XMAP), metabolomic assay (NMR spectroscopy and PLS-DA), as well as gut microbiota content and diversity (16S rRNA, MiSeq sequencing). Finally, we will evaluate the effect of a dietary weight loss intervention on these biomarkers.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

109

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Valencia, Spain, 46020
        • FISABIO

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients with BMI≥30kg/m2, with at least 5 years of diagnosed obesity evolution.
  • Patients have had stable body weight (±2 kg) during the 3 months prior to the study.

Exclusion Criteria:

  • All patients with acute or chronic inflammatory diseases, neoplasic disease, secondary causes of obesity (uncontrolled hypothyroidism, Cushing's syndrome), and established liver and kidney failure (according to transaminase levels ±2 SD of the mean and estimated glomerular filtration rate using the CKD-EPI formula >60) will be excluded.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Very low-calorie diet Intervention
Dietary supplement: very low-calorie diet
Subjects undergo two cycles of a very-low-calorie diet (VLCD) for 6 weeks each, alternating with a hypocaloric diet (12 weeks). The dietetic intervention consists of a VLCD using a liquid formula (Optisource Plus, Nestlé S.A., Vevey, Switzerland), providing 52.8 g protein, 75.0 g carbohydrates, 13.5 g fat, 11.4 g fiber, and essential vitamins and minerals based on Recommended Dietary Allowances (RDA). This formula supplies 2738 kJ/day (654 kcal/day), replacing the participants' three daily meals. Following this and before the second VLCD cycle, a dietician performs an individualized nutritional assessment to calculate the resting energy expenditure, and personalized hypocaloric diets were prepared, reducing 500 kcal for each individual on their daily caloric expenditure, maintaining the recommended intake of each of the macronutrients (55% carbohydrates, 30% fats and 15% proteins) for 12-weeks.
Other Names:
  • VLCD

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Analyze the changes in the diversity of the intestinal microbiota after dietetic intervention.
Time Frame: 5 years
To assess the alpha-diversity of the intestinal microbiota, defined as the average diversity of species in an ecosystem, the Shannon index will be used. The results are interpreted as follows: values less than 2 are considered low in diversity and values greater than 3 are high in species diversity.
5 years
Evaluate the differences in the diversity of the intestinal microbiota depending on whether patients present metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUHO).
Time Frame: 5 years
To asses the differences in alpha-diversity of the intestinal microbiota in both groups, it will be evaluated whether there are significant differences between the Shannon indices of the two groups. The classification of patients between MHO and MUHO will be carried out using the following criteria: MUHO will be considered when patients with obesity present ≥2 metabolic abnormalities, and MHO with ≤1 metabolic abnormalities; the following cardiovascular risk factors are considered metabolic abnormalities: elevated blood pressure (defined as either SBP ≥130 mm Hg, DBP ≥85 mm Hg, or treatment with antihypertensive medications), elevated triglycerides (as fasting triglyceride concentration ≥1.7 mmol/l), low HDL-C levels (defined as HDL-C <1.04 mmol/l, in men, <1.29 mmol/l/l in women, or treatment with lipid-lowering medications), dysglycemia (fasting plasma glucose 5.6 to 6.9 mmol/l, and/or and insulin resistance as HOMA-IR >3.8).
5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluate significant changes in body fat mass percentage after the dietetic intervention.
Time Frame: 2 years
Percentage of body fat mass will be measured by bioelectrical impedance. It is considered to be high when ≥25% in men and ≥30% in women. A significant improvement will be considered when notable differences are observed in the mean values between groups measured through p-value (<0.05) with a 95% confidence interval.
2 years
Assess significant changes in high-sensitivity C-reactive protein (hs-CRP) as an inflammatory parameter after the dietetic intervention.
Time Frame: 2 years
Participants will be considered to have achieved an improvement in high-sensitivity C-reactive protein levels if they normalize its value (normality values defined between 0 and 1.69mg/dl).
2 years
Evaluate significant changes in C3 protein as an inflammatory parameter after the dietetic intervention.
Time Frame: 2 years
Participants will be considered to have achieved an improvement in C3 protein if they normalize its value (normality values defined between 81 and 157mg/dl).
2 years
Assess significant changes in plasmatic homocysteine as an inflammatory parameter after the dietetic intervention.
Time Frame: 2 years
Participants will be considered to have achieved an improvement in plasmatic homocysteine if they normalize its value (normality values defined between 5 and 15µmol/L).
2 years
Evaluate significant changes in interleukin 1-beta (IL-1B) levels as a pro-inflammatory molecule after the dietetic intervention.
Time Frame: 2 years
IL-1B levels will be measured using the Luminex® 200 analyzer system. A significant improvement will be considered when notable differences are observed in the mean values between groups measured through p-value (<0.05) with a 95% confidence interval.
2 years
Evaluate significant changes in interleukin 6 (IL-6) levels as a pro-inflammatory molecule after the dietetic intervention.
Time Frame: 2 years
IL-6 levels will be measured using the Luminex® 200 analyzer system. A significant improvement will be considered when notable differences are observed in the mean values between groups measured through p-value (<0.05) with a 95% confidence interval.
2 years
Evaluate significant changes in tumor necrosis factor alpha (TNF-alpha) levels as a pro-inflammatory molecule after the dietetic intervention.
Time Frame: 2 years
TNF-alpha levels will be measured using the Luminex® 200 analyzer system. A significant improvement will be considered when notable differences are observed in the mean values between groups measured through p-value (<0.05) with a 95% confidence interval.
2 years
Assess significant changes in superoxide dismutase (SOD) levels after the dietetic intervention.
Time Frame: 2 years
Superoxide dismutase levels will be measured using the Luminex® 200 analyzer system. A significant improvement will be considered when notable differences are observed in the mean values between groups measured through p-value (<0.05) with a 95% confidence interval.
2 years
Analyze the significant differences between metabolomic profile before and after the dietetic intervention.
Time Frame: 2 years
NMR spectra will be used to obtain spectra from serum samples from the cohort. In order to evaluate if there will be significant differences after the dietetic intervention, a PLS-DA model for discrimination between basal and post intervention levels will be performed. Scores plots will be calculated with a 95% confidence interval.
2 years
Evaluate if there is a significant reduction after the dietetic intervention in total ROS levels.
Time Frame: 2 years
Total ROS levels will be assessed by a flow cytometry assay. A significant improvement will be considered when notable differences are observed in the mean values between groups measured through p-value (<0.05) with a 95% confidence interval.
2 years
Assess if there is a significant reduction after the dietetic intervention in glutathione levels.
Time Frame: 2 years
Total glutathione levels will be assessed by a flow cytometry assay. A significant improvement will be considered when notable differences are observed in the mean values between groups measured through p-value (<0.05) with a 95% confidence interval.
2 years
Analyze if there is a significant change after the dietetic intervention in total free radicals and superoxide levels.
Time Frame: 2 years
Total free radicals and superoxide content will be assessed by a flow cytometry assay. A significant improvement will be considered when notable differences are observed in the mean values between groups measured through p-value (<0.05) with a 95% confidence interval.
2 years
Analyze if there is a significant reduction after the dietetic intervention in mitochondrial ROS production.
Time Frame: 2 years
Mitochondrial ROS production will be assessed by a flow cytometry assay. A significant improvement will be considered when notable differences are observed in the mean values between groups measured through p-value (<0.05) with a 95% confidence interval.
2 years
Evaluate if there is a significant improvement after the dietetic intervention in mitochondrial membrane potential.
Time Frame: 2 years
Mitochondrial membrane potential will be assessed by a flow cytometry assay. A significant improvement will be considered when notable differences are observed in the mean values between groups measured through p-value (<0.05) with a 95% confidence interval.
2 years
Analyze the proportion of subjects achieving at least 10% reduction in weight compared with baseline.
Time Frame: 5 years
Proportion of subjects achieving at least 10% reduction in weight after the dietetic intervention (6 months).
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Celia Bañuls

Collaborators

Instituto de Salud Carlos III

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2019

Primary Completion (Actual)

December 31, 2023

Study Completion (Actual)

August 31, 2024

Study Registration Dates

First Submitted

February 2, 2024

First Submitted That Met QC Criteria

February 19, 2024

First Posted (Actual)

February 28, 2024

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

February 25, 2025

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PI18/00932

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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