This is a non-randomized, concurrent, parallel-controlled clinical trial. The objective of this trial is to determine the relationship between weight loss responsiveness to semaglutide in obese patients and their gut microbiota.

Obesity has gradually emerged as a major public health concern. Although the GLP-1 receptor agonist semaglutide is used for chronic weight management in obese patients, significant individual variability exists in its weight-loss efficacy, and the underlying mechanisms remain unclear. Our preliminary studies have revealed that the low-response group to semaglutide exhibits significantly reduced plasma drug concentrations accompanied by a marked increase in the abundance of Prevotella copri (P. copri). Colonization with P. copri was found to attenuate semaglutide's weight-reducing effects in obese mice while decreasing its plasma concentration. In vitro experiments demonstrated an 85% degradation rate of semaglutide after 24-hour co-cultivation with P. copri. Based on these findings, we hypothesize that intestinal P. copri may produce specific enzymes that metabolize semaglutide, thereby influencing its therapeutic efficacy. This project aims to investigate the individual variability in semaglutide response through multi-omics approaches including fecal metagenomic sequencing. Utilizing in vitro bacterial screening platforms combined with gut microbiota gene knockout/heterologous expression systems, protein isolation-activity tracking, and structural characterization, we will elucidate the mechanisms underlying gut microbiota-mediated semaglutide resistance from microbial, animal, and clinical perspectives. The outcomes may identify novel therapeutic targets to overcome semaglutide resistance in weight management.

Inclusion Criteria:

• Age 18-60 years
• BMI ≥ 30 kg/m²
• At least one self-reported unsuccessful attempt at lifestyle weight loss

Exclusion Criteria:

• Weight change (self-reported) > 5% in the past 3 months prior to screening
• Use of any medication for obesity indication in the past 3 months prior to screening.
• Use of antidiabetic medications in the past 3 months, or HbA1c ≥ 6.5%, or a history of Type 1 or Type 2 diabetes.
• Use of immunosuppressants, corticosteroids, antidiarrheal drugs, antibiotics, probiotics, lipid-lowering medications, and/or other gastrointestinal motility drugs in the past 3 months prior to screening.
• A history of endocrine-related overweight or obesity diagnoses, such as Cushing's syndrome.
• Triglycerides ≥ 500 mg/dL (5.65 mmol/L) at screening.
• Known clinically significant gastric emptying abnormalities (e.g., severe diabetic gastroparesis or gastric outlet obstruction), gastrointestinal diseases, or surgical history.
• Thyroid dysfunction.
• History of mental illness.
• History or family history of multiple endocrine neoplasia or medullary thyroid cancer, or calcitonin ≥ 6 pg/mL.
• Abnormal liver function at screening, defined as alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 3*ULN.
• Abnormal kidney function at screening, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.75m².
• History of cardiovascular disease.
• History of malignancy.
• Pregnancy or breastfeeding.
• Any other physiological, psychological, or other conditions deemed by the investigator as unsuitable for participation in the trial.