This study is a randomized controlled trial with 120 overweight or obese (body-mass index, BMI, ≥ 24 kg/m²) participants and 20 normal-weight participants. Twelve weeks of energy-restricted nutritional and lifestyle intervention with placebo, Lactobacillus paracasei LC-19 (LC-19), or semaglutide (a glucagon-like peptide-1 receptor agonist, GLP-1RA) will be randomly conducted in the overweight or obese participants. The primary goal is to clarify the roles of LC-19 and semaglutide in weight reduction and in improving energy, glucose, and lipid metabolism, while also comparing side effects, adverse events, and long-term outcomes such as weight regain between these two interventions. In addition, the study will explore key factors affecting intervention response to provide evidence for optimizing individualized intervention strategies.
The primary goal is to clarify the roles of LC-19 and semaglutide in weight reduction and in improving energy, glucose, and lipid metabolism, while also comparing side effects, adverse events, and long-term outcomes such as weight regain between these two interventions. In addition, the study will explore key factors affecting intervention response to provide evidence for optimizing individualized intervention strategies. In this study, 120 overweight or obese participants (BMI ≥ 24 kg/m²) will be recruited and be randomly assigned to one of the three groups: an energy-restricted nutritional and lifestyle intervention + placebo group (control group), an energy-restricted nutritional and lifestyle intervention plus LC-19 group (probiotic group), or an energy-restricted nutritional and lifestyle intervention plus semaglutide injection group (GLP-1RA group), with a 12-week intervention. In addition, 20 normal-weight participants will be recruited and receive 12-week weight maintenance nutritional and lifestyle interventions. Before and after the 12-week interventions, metabolic homeostasis will be used to characterize metabolic health and to be determined using comprehensive measurements of dynamic changes in postprandial metabolic responses (including energy metabolism, multiple clinical biomarkers, metabolomic signatures, gut microbiota, genetic signatures etc.) after the standardized mixed-meal tolerance test (MMTT; 126.5 g glucose, 30.67 g fat and 34.5 g protein) in whole-room indirect calorimeter under resting conditions. In addition, data from dietary intake, anthropometric measurements, body composition, behavior questionnaires, 14-day continuous glucose monitoring, and 14-day accelerometer-based physical activity and sleep monitoring will also be collected to characterize metabolic homeostasis. During the interventions, participants will receive dietary advice, behavior guidance and nutritional and lifestyle education by dietitian and physicians. App-connected wearable devices will be utilized to monitor their dietary intakes and an app-connected scale will be used to monitor their weight changes during interventions. Additionally, at 6 months post-intervention, a follow-up assessment will be conducted, including questionnaires (consistent with the baseline visit), anthropometry (e.g., height, weight, waist and hip circumference, blood pressure, pulse), clinical laboratory tests (e.g., blood glucose, blood lipids, liver and kidney function), and stool sample collection. The study protocol has been approved by the Ethics Committee of Tongde Hospital of Zhejiang Province.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
140
Participants will receive dietary advice, behavior guidance and nutritional and lifestyle education based on dietary guidelines.
Participants will receive dietary advice, behavioral guidance and nutritional and lifestyle education by dietitian and physicians. App-connected wearable devices will be utilized to monitor their dietary intakes and App-connected scale will be used to monitor their weight changes during interventions.
Participants will receive one bag (2 g; 1 × 10¹² CFU) daily of LC-19.
participants will receive daily one bag of LC-19 (10\^12 cfu/bag).
Participants will receive prescibed semaglutide therapy
Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences
Hangzhou, Zhejiang, China
RECRUITINGChange in Body Weight (kg) from Baseline to Week 12
The change between the baseline and after 12-week intervention. Weight will be assessed using a Seca 255 scale (ScalesGalore).
Time frame: Baseline and Week 12
Change in Energy Expenditure Rate (kcal/min) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Energy expenditure rate (kcal/min) will be assessed with a whole-room indirect calorimeter (Sable).
Time frame: Baseline and Week 12
Change in Respiratory Quotient from Baseline to Week 12
The change from baseline to after the 12-week intervention. Respiratory quotient will be assessed with a whole-room indirect calorimeter.
Time frame: Baseline and Week 12
Change in Fat Oxidation Rate (g/min) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Fat oxidation rate (g/min) will be assessed with a whole-room indirect calorimeter.
Time frame: Baseline and Week 12
Change in Carbohydrate Oxidation Rate (g/min) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Carbohydrate oxidation rate (g/min) will be assessed with a whole-room indirect calorimeter.
Time frame: Baseline and Week 12
Change in Waist Circumference (cm) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Waist circumference will be assessed with a Seca 201 tape (ScalesGalore).
Time frame: Baseline and Week 12
Change in Hip Circumference (cm) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Hip circumference will be assessed with a Seca-201 tape (ScalesGalore).
Time frame: Baseline and Week 12
Change in Fat Mass (kg) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Fat mass will be assessed using dual energy x-ray absorptiometry (DXA; GE).
Time frame: Baseline and Week 12
Change in Fat-free Mass (kg) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Fat-free mass will be assessed using DXA (GE).
Time frame: Baseline (week 0) and Week 12
Change in Controlled Attenuation Parameter (CAP, dB/m) from Baseline to Week 12
The change from baseline to after the 12-week intervention. CAP will be assessed using FibroScane (Echosens). The median CAP value of 10 valid measurements will be used (IQR ≤ 30%). Reported value = Week 12 CAP minus baseline CAP; positive values indicate increased hepatic steatosis.
Time frame: Baseline and Week 12
Change in Systolic Blood Pressure (mmHg) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Systolic blood pressure will be assessed with an Omron J750 electronic monitor.
Time frame: Baseline and Week 12
Change in Diastolic Blood Pressure (mmHg) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Diastolic blood pressure will be assessed with an Omron J750 electronic monitor.
Time frame: Baseline and Week 12
Change in Heart Rate (beats/min) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Heart rate will be assessed with an Omron J750 electronic monitor.
Time frame: Baseline and Week 12
Change in Fasting Glucose (mmol/L) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Glucose will be measured using a hexokinase enzymatic assay.
Time frame: Baseline and Week 12
Change in Glucose Incremental AUC (mmol·min/L) from Baseline to Week 12
Venous blood will be collected at 0, 30, 60, 120, 180, 240, and 300 min during an oral mixed-meal tolerance test (MMTT). Glucose will be measured using a hexokinase enzymatic assay. Incremental area under the concentration-time curve (iAUC) will be calculated via the trapezoidal rule after subtracting the fasting value. Reported value = Week 12 iAUC - baseline iAUC; positive numbers indicate an increase.
Time frame: Baseline and Week 12
Change in HbA1c (%) from Baseline to Week 12
The change from baseline to after the 12-week intervention. HbA1c will be assessed using high-performance liquid chromatography.
Time frame: Baseline (Week 0) and Week 12
Change in Mean 24-h Glucose (mg/dL) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Mean 24-h glucose will be assessed using Continuous Glucose Monitoring (FreeStyle Libre 2, Abbott) for 14 consecutive days.
Time frame: Baseline and Week 12
Change in Glucose Coefficient of Variation (CV, %) from Baseline to Week 12
The change between the baseline and after 12-week intervention. Glucose CV will be calculated as (SD / mean) × 100% from continuous glucose monitoring (FreeStyle Libre 2, Abbott) over 14 consecutive days.
Time frame: Baseline and Week 12
Change in Fasting Insulin (µIU/mL) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Insuin will be measured using an electrochemiluminescence assay.
Time frame: Baseline and Week 12
Change in Insulin Incremental AUC (µIU·min/mL) from Baseline to Week 12
Venous blood will be collected at 0, 30, 60, 120, 180, 240, and 300 min during an MMTT. Insulin will be measured using an electrochemiluminescence assay. iAUC will be calculated via the trapezoidal rule after subtracting the fasting value. Reported value = Week 12 iAUC - baseline iAUC; positive numbers indicate an increase.
Time frame: Baseline and Week 12
Change in Fasting C-peptide (ng/mL) from Baseline to Week 12
The change from baseline to after the 12-week intervention. C-peptide will be measured using an electrochemiluminescence assay.
Time frame: Baseline and Week 12
Change in C-peptide Incremental AUC (ng·min/mL) from Baseline to Week 12
Venous blood will be collected at 0, 30, 60, 120, 180, 240, and 300 min during an MMTT. C-peptide will be measured using an electrochemiluminescence assay. iAUC will be calculated via the trapezoidal rule after subtracting the fasting value. Reported value = Week 12 iAUC - baseline iAUC; positive numbers indicate an increase.
Time frame: Baseline and Week 12
Change in Fasting Serum Triglycerides (mmol/L) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Serum triglycerides will be quantified using an enzymatic colorimetric assay.
Time frame: Baseline and Week 12
Change in Triglyceride Incremental AUC (mmol·min/L) from Baseline to Week 12
Venous blood will be collected at 0, 30, 60, 120, 180, 240, and 300 min during an MMTT. Triglyceride will be measured using an enzymatic colorimetric assay. iAUC will be calculated via the trapezoidal rule after subtracting the fasting value. Reported value = Week 12 iAUC - baseline iAUC; positive numbers indicate an increase.
Time frame: Baseline and Week 12
Change in Serum Fasting Total Cholesterol (mmol/L) from Baseline to Week 12
The change from baseline to after the 12-week intervention. Total cholesterol will be quantified in serum using an enzymatic colorimetric assay.
Time frame: Baseline and Week 12
Change in Total Cholesterol Incremental AUC (mmol·min/L) from Baseline to Week 12
Venous blood will be collected at 0, 30, 60, 120, 180, 240, and 300 min during an MMTT. Total cholesterol will be measured using an enzymatic colorimetric assay. iAUC will be calculated via the trapezoidal rule after subtracting the fasting value. Reported value = Week 12 iAUC - baseline iAUC; positive numbers indicate an increase.
Time frame: Baseline and Week 12
Change in Fasting Serum High-Density Lipoprotein Cholesterol (HDL-C, mmol/L) from Baseline to Week 12
The change from baseline to after the 12-week intervention. HDL-C will be quantified in serum using an enzymatic colorimetric assay.
Time frame: Baseline and Week 12
Change in HDL-c Incremental AUC (mmol·min/L) from Baseline to Week 12
Venous blood will be collected at 0, 30, 60, 120, 180, 240, and 300 min during an MMTT. HDL-c will be measured using an enzymatic colorimetric assay. iAUC will be calculated via the trapezoidal rule after subtracting the fasting value. Reported value = Week 12 iAUC - baseline iAUC; positive numbers indicate an increase.
Time frame: Baseline and Week 12
Change in Fasting Serum Low-Density Lipoprotein Cholesterol (LDL-C, mmol/L) from Baseline to Week 12
The change from baseline to after the 12-week intervention. LDL-C will be quantified in serum using an enzymatic colorimetric assay.
Time frame: Baseline and Week 12
Change in LDL-c Incremental AUC (mmol·min/L) from Baseline to Week 12
Venous blood will be collected at 0, 30, 60, 120, 180, 240 and 300 min during an MMTT. LDL-c will be measured using an enzymatic colorimetric assay. iAUC will be calculated via the trapezoidal rule after subtracting the fasting value. Reported value = Week 12 iAUC - baseline iAUC; positive numbers indicate an increase.
Time frame: Baseline and Week 12
Change in GLP-1 Incremental AUC (pg·min/mL) from Baseline to Week 12
Venous blood will be collected at 0, 30, 60, 120, 180, 240 and 300 min during an MMTT. GLP-1 will be quantified using a high-sensitivity ELISA. iAUC will be calculated via the trapezoidal rule after subtracting the fasting value.
Time frame: Baseline (Week 0) and Week 12
Change in GIP Incremental AUC (pg·min/mL) from Baseline to Week 12
Venous blood will be collected at 0, 30, 60, 120, 180, 240, and 300 min during an MMTT. GIP will be quantified using a high-sensitivity ELISA. iAUC will be calculated via the trapezoidal rule after subtracting the fasting value.
Time frame: Baseline and Week 12
Change in Ghrelin Incremental AUC (pg·min/mL) from Baseline to Week 12
Venous blood will be collected at 0, 30, 60, 120, 180, 240, and 300 min during an MMTT. Ghrelin will be quantified using a high-sensitivity ELISA. iAUC will be calculated via the trapezoidal rule after subtracting the fasting value.
Time frame: Baseline and Week 12
Change in Shannon Diversity Index from Baseline to Week 12
Fecal DNA will be extracted and subjected to shotgun metagenomic sequencing on an Illumina NovaSeq 6000 (2 × 150 bp; ≥6 Gb per sample). Reads will be taxonomically profiled using MetaPhlAn 4.0. The Shannon diversity index will be calculated for each sample. Reported value = Week 12 index - baseline index.
Time frame: Baseline and Week 12
Change in Relative Abundance of Akkermansia muciniphila (%) from Baseline to Week 12
Same sequencing workflow as above. Relative abundance (% of total classified reads) of A. muciniphila will be extracted from MetaPhlAn output. Reported value = Week 12 abundance - baseline abundance.
Time frame: Baseline and Week 12
Single Nucleotide Polymorphisms (SNPs)
Mutations at specific sites will be detected using a genotyping microarray.
Time frame: Baseline
Change in body weight from Week 12 to 6 months post-intervention
The change from the end of intervention (Week 12) to 6 months post-intervention. Weight will be assessed using a Seca-255 scale (ScalesGalore).
Time frame: Post-intervention 6 months
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