Metabolic Flexibility to Predict Lifestyle Interventions Outcomes

Obesity Clinical Trial

— MEPHISTO  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06329349
• Other study ID #: EK VP57/0/2023
• Status: Recruiting
• Phase: N/A
• Start date: January 2, 2024
• Est. completion date: April 1, 2026

Study information

• Verified date: March 2024
• Source: Charles University, Czech Republic
• Contact: Jan Gojda, PhD
• Phone: +420267163031
• Email: jan.gojda[@]lf3.cuni.cz
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: April 1, 2026
• Est. primary completion date: December 12, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 25 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Obesity

Intervention

Other:
• Exercise
12 weeks, 3 times a week of progressive endurance aerobic exercise (150 to 400kcal AEE per session)
• Combined Exercise + Diet
12 weeks, 25% caloric reduction, based on PMID: 37069434

Locations

Country	Name	City	State
Czechia	Faculty of Sports Science	Prague
Czechia	Third Medical Faculty,Charles University	Prague
Czechia	University Hospital Kralovske Vinohrady	Prague

Sponsors (3)

Lead Sponsor	Collaborator
Charles University, Czech Republic	EXCELES LX22NPO5104, CarDia, Ministry of Health, Czech Republic

Country where clinical trial is conducted

Czechia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Primary	Change in metabolic flexibility (MetFlex (?RQ 200-0))	change in metabolic flexibility measured as ?RQ (respiratory quotient) during glucose clamp	18 months
Primary	Change in insulin sensitivity	change in insulin sensitivity measured as glucose infusion rate (GIR) during glucose clamp	18 months
Secondary	Glucose tolerance relate to primary outcomes changes	fasting/2h oral glucose tolerance test glycemia positively relate to weight loss.	18 months
Secondary	HbA1c relate to primary outcomes changes	HbA1c positively relate to weight loss.	18 months
Secondary	Insulin sensitivity relate to primary outcomes changes	GIR positively relate to weight loss.	18 months