Metabolic Flexibility to Predict Lifestyle Interventions Outcomes (MEPHISTO)

Whole Body and Gut Microbiome Metabolic Flexibility to Predict Lifestyle Intervention Outcomes

Weight loss is a cornerstone of diabetes (T2D) management, yet in clinical practice, its delivery is limited by its perceived burdensome nature and variability in response. Personalization of the interventions to increase their success rate is an unmet clinical need. The proposed project MEPHISTO (Whole body and gut microbiome metabolic flexibility to predict lifestyle intervention outcomes) would aim to identify predictive features related to successful weight loss upon sequential exercise and diet intervention in people living with obesity. To this end, the study aims to conduct a clinical trial where the investigators would implement state-of-the-art physiological phenotyping of metabolic flexibility at the whole-body level and at the level of the gut in persons with obesity before and after exercise and diet + exercise intervention to identify predictive signatures of successful weight loss

Study Overview

• Status: Recruiting
• Conditions: Obesity
• Intervention / Treatment: Other: Exercise; Other: Combined Exercise + Diet

Detailed Description

Among the influential determinants impacting the efficacy and health outcomes of an intervention is an individual's level of metabolic flexibility (MetFlex). MetFlex denotes the body's capacity to adapt in response to alterations in metabolic demands and nutrient availability [Palmer, B.F. and D.J.Clegg.Mayo Clin Proc,2022.97(4):p.761-776.]. Impaired MetFlex is evident in conditions such as obesity and diabetes, yet it may be ameliorated through lifestyle interventions such as exercise training or caloric restriction (Bergouignan et al., 2013; Huffman et al., 2012; Palmer & Clegg, 2022) similar to improvements in insulin sensitivity. However, MetFlex has not been studied as a potential mechanism associated with successfull weight loss. The decline in MetFlex, i.e. the limited cellular/tissue ability to manage excess or deficiency in energy substrates leads to compromised mitochondrial function and excessive lipid accumulation in ectopic tissues, resulting in metabolic disorders such as T2D or metabolic syndrome.

Another potential player predicting an individual's capacity to respond to lifestyle interventions is the gut microbiota (gut microbiome and metabolome, MIME). It was repeatedly shown to be among the most important sources of inter-individual variability when it comes to the development of obesity (Maruvada et al., 2017) and responsiveness to dietary intervention The microbiome does not only influence host physiology directly, e.g. through contact with immune cells, but also through the vast array of metabolites produced, i.e. the microbiota-derived metabolome (Hughes & Holscher, 2021). The composition of the gut microbiota and the microbiota-derived metabolome is largely shaped by the host's diet, as this represents the main source of substances and energy for the microbiota (https://doi.org/10.1007/s11906-017-0721-6.). It is therefore striking that published studies to date have yielded rather inconsistent results regarding dietary interventions to alter gut microbiota composition (https://doi.org/10.1016/j. orcp.2020.04.006.). The discrepancy can be explained by the large variability of individual microbiomes at the beginning of the intervention, and similarly the baseline MIME signature significantly determines weight loss success.

Here the investigators present a complex project to investigate whether whole body and gut MetFlex can be further explored and used as ex-ante predictors of successful weight loss following exercise and dietary interventions, thus providing proof of concept and paving the way to personalized lifestyle interventions.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jan Gojda, PhD; Phone Number: +420267163031; Email: jan.gojda@lf3.cuni.cz
• Study Contact Backup: Name: Jana Potočková; Phone Number: +420267163031; Email: potocko@fnkv.cz

Study Locations

• Czechia
  • Prague, Czechia, 10034
    • Recruiting
    • University Hospital Kralovske Vinohrady
    • Contact: Jan Gojda, PhD; Phone Number: +420267163031; Email: jan.gojda@lf3.cuni.cz
    • Contact: Katerina Koudelkova, MD; Phone Number: +420267163031; Email: katerina.koudelkova@fnkv.cz
  • Prague, Czechia, 10084
    • Recruiting
    • Third Medical Faculty,Charles University
    • Contact: Michaela Šiklová, PhD; Phone Number: +420267102222; Email: michaela.siklova@lf3.cuni.cz
    • Contact: PhD; Phone Number: +420267163031; Email: jan.gojda@lf3.cuni.cz
  • Prague, Czechia, 16000
    • Recruiting
    • Faculty of Sports Science
    • Contact: Michal Šteffl, PhD; Phone Number: +420220172072; Email: michal.steffl@ftvs.cuni.cz
    • Contact: Tomáš Větrovský, PhD; Phone Number: +420220172072; Email: tomas.vetrovsky@ftvs.cuni.cz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• BMI>30
• age 25-45 years

Exclusion Criteria:

• active cancer
• diabetes (medical history, fasting glycemia >7.6 and/or 2hOGTT glycemia >11.1)
• uncontrolled endocrine diseases
• corticosteroid therapy
• immune-suppressive therapy
• pregnancy
• breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; No intervention.
Experimental: Intervention; Exercise intervention	Other: Exercise; 12 weeks, 3 times a week of progressive endurance aerobic exercise (150 to 400kcal AEE per session); Other: Combined Exercise + Diet; 12 weeks, 25% caloric reduction, based on PMID: 37069434

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in metabolic flexibility (MetFlex (ΔRQ 200-0))	change in metabolic flexibility measured as ΔRQ (respiratory quotient) during glucose clamp	18 months
Change in insulin sensitivity	change in insulin sensitivity measured as glucose infusion rate (GIR) during glucose clamp	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose tolerance relate to primary outcomes changes	fasting/2h oral glucose tolerance test glycemia positively relate to weight loss.	18 months
HbA1c relate to primary outcomes changes	HbA1c positively relate to weight loss.	18 months
Insulin sensitivity relate to primary outcomes changes	GIR positively relate to weight loss.	18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiome composition relate to weight loss: exploratory outcome	Change in microbiome composition in fecal samples upon the intervention is a component of successful weight loss and/or metabolic adaptation	18 months
Metabolomic signatures relate to weight loss: exploratory outcome	Change in metabolomic signatures in fecal samples upon the intervention is a component of successful weight loss and/or metabolic adaptation	18 months

Collaborators and Investigators

• Sponsor: Charles University, Czech Republic
• Collaborators: Ministry of Health, Czech Republic; EXCELES LX22NPO5104, CarDia
• Investigators: Principal Investigator: Jan Gojda, Third Faculty of Medicine Charles University

Study record dates

Study Major Dates

• Study Start (Actual): January 2, 2024
• Primary Completion (Estimated): December 12, 2025
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: March 1, 2024
• First Submitted That Met QC Criteria: March 22, 2024
• First Posted (Actual): March 25, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: exercise; obesity; diet; metabolomic; metabolic flexibility
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity
• Other Study ID Numbers: EK VP57/0/2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: After anonymization, the data would be shared upon reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No