BACKGROUND: Polycystic ovary syndrome (PCOS) affects 9% to 12% of reproductive-age women worldwide, with higher prevalence reported in India. Its pathophysiology involves insulin resistance, hyperandrogenism, and chronic low-grade inflammation, increasingly linked to gut dysbiosis and lipopolysaccharide-driven toll-like receptor 4 signaling. Elevated calprotectin and suppressed acylated ghrelin (AGH) reflect this inflammatory-metabolic disruption. While metformin remains standard therapy, it does not address underlying gut dysbiosis. Lactobacillus crispatus, with its antibacterial and immunomodulatory properties, is a promising but untested gut-targeted adjunct. This trial evaluates whether combining metformin with L. crispatus supplementation improves metabolic and inflammatory outcomes beyond either therapy alone. OBJECTIVE: This study aims to compare probiotic, metformin, and combination therapy for reducing insulin resistance in PCOS over 12 weeks and assess their effects on gut barrier integrity, microbiome composition, hyperandrogenemia, glycemic control, and clinical outcomes. METHODS: This open-label randomized, hospital-based trial at the All India Institute of Medical Sciences, Bhubaneswar, will assess the effects of probiotic and/or metformin therapy in women aged 18 to 40 years diagnosed with PCOS per Rotterdam criteria. A total of 135 participants will be randomized equally into 3 groups: probiotics only, metformin only, and combination therapy. The 3-month intervention includes metformin (1000 mg per day) and a specified L. crispatus-containing probiotic (2 capsules per day). The primary outcome is the change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Key secondary outcomes include changes in serum and fecal calprotectin, AGH, total testosterone, and fecal microbiome profile. RESULTS: Participant recruitment began in January 2026. As of August 30, 2026, 26 of the planned 135 participants had been enrolled. Enrollment and data collection are projected to conclude by December 2026; statistical analysis will begin after database lock, with study completion anticipated by June 2027 and publication targeted for mid- to late 2027. CONCLUSIONS: This trial will provide critical, mechanistic evidence on whether the targeted action of L. crispatus can work additively 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 and HOMA-IR) end points, 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.