The PCOME Trial: Synergistic Effects of Lactobacillus crispatus containing Probiotic and Metformin on Insulin Resistance, Inflammation and Gut Microbiome in Polycystic Ovary Syndrome - Open-Label, Randomized Controlled Trial Protocol (Preprint)
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BACKGROUND: Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder driven by a complex interplay of hyperandrogenism, insulin resistance, and chronic low-grade inflammation.
BACKGROUND: Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder driven by a complex interplay of hyperandrogenism, insulin resistance, and chronic low-grade inflammation. While Metformin addresses systemic insulin sensitivity, it leaves the upstream trigger of gut dysbiosis and mucosal endotoxemia unmanaged. This study introduces a distinct therapeutic paradigm by combining Metformin with a strain-specific formulation of Lactobacillus crispatus to target the gut-metabolic axis directly. Unlike generic probiotic blends, L. crispatus actively mitigates gastrointestinal inflammation through specialized Surface Layer Proteins (SLPs) that physically reinforce the epithelial barrier against lipopolysaccharide (LPS) translocation, alongside strain-derived hydrogen peroxide production that upregulates host mucosal PPAR- γ to block NF-kB driven cytokine transcription (TNF-α and IL-6). By dampening this localized inflammatory cascade, this metabolic-inflammatory regimen aims to protect IRS-1 signaling, alleviate hyperinsulinemia, to restore normal ovarian steroidogenesis. OBJECTIVE Primary Objective The PCOME Study is to compare the change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) from baseline to 3 months across the three intervention groups—Probiotic, Metformin, and Combination therapy—in women diagnosed with PCOS. Secondary Objectives The PCOME Study aims to evaluate the impact of the three intervention regimens (Probiotic, Metformin, and Combination therapy) on the following parameters at 3 months: 1. Inflammatory and Gut Health Markers • Serum and fecal calprotectin levels • Serum acylated ghrelin (AGH) levels • Fecal short-chain fatty acid (SCFA) concentrations • Serum zonulin levels (as a marker of intestinal permeability) 2. Gut Microbiome Profile • Alpha diversity (e.g., richness and evenness) • Beta diversity (community structure) • Differential abundance of key bacterial taxa, including Lactobacillus, Bifidobacterium, Akkermansia muciniphila, and the Bacteroidetes/Firmicutes ratio 3. Metabolic and Hormonal Markers • Additional markers of insulin resistance: fasting glucose, fasting insulin, and glycated hemoglobin (HbA1c). • Markers of hyperandrogenism: total testosterone, free androgen index (FAI), and sex hormone-binding globulin (SHBG) 4. Clinical and Anthropometric Outcomes • Body mass index (BMI) and waist-hip ratio (WHR) • Assessment of hirsutism using the modified Ferriman-Gallwey score • Menstrual regularity METHODS This open-label, randomized, hospital-based trial at AIIMS Bhubaneswar will assess the effects of probiotic and/or metformin therapy in women aged 18–40 years diagnosed with PCOS per Rotterdam criteria. A total of 138 participants will be randomized equally into three groups: probiotics only, metformin only, and combination therapy. The 3-month intervention includes metformin (1000 mg/day) and a specified Lactobacillus crispatus containing probiotic (2 capsules/day). The primary outcome is the change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Key secondary outcomes include changes in serum/fecal calprotectin, AGH, total testosterone, and fecal microbiome profile. RESULTS Not ready yet CONCLUSIONS This trial will provide critical, mechanistic evidence on whether the targeted, strain-specific action of L. crispatus can work synergistically with Metformin to heal the intestinal mucosal barrier, arrest systemic endotoxemia, and rescue disrupted gut-brain-endocrine signaling. By validating this novel metabolic-inflammatory regimen against localized (calprotectin) and systemic (AGH, HOMA-IR) endpoints, this study intends to establish a highly integrated, microbiome-targeted therapeutic strategy capable of optimizing long-term metabolic and reproductive health outcomes in women with PCOS. CLINICALTRIAL CTRI/2025/09/094113
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