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Among the available interventions, gut microbiota modulators (GMMs) such as probiotics and prebiotics have demonstrated significant potential in infection prevention and neuroprotection. Despite these encouraging findings, the clinical application of GMMs remains challenging due to safety concerns and inconsistent effectiveness across diverse patient populations. These factors create substantial barriers to the widespread adoption of microbiota-based therapies in clinical practice. To overcome these challenges and fully leverage the therapeutic potential of microbiota modulation, this review explores the feasibility of repurposing GMMs for managing multiple health disorders. A broad spectrum of microbiota-targeted strategies is examined, including dietary modifications, fecal microbiota transplantation, bacteriophage therapy, microbiome engineering, and immune system modulation. A particularly innovative approach involves integrating GMMs with pharmaceutical delivery systems to enhance therapeutic efficacy while mitigating potential adverse effects. This integrative strategy underscores the pivotal role of the gut microbiome in health and disease, supporting the development of precision medicine tailored to individual patient needs. By combining GMMs with targeted delivery mechanisms, this approach not only improves treatment effectiveness but also addresses critical concerns regarding safety and patient variability. Furthermore, this review outlines future research directions within the rapidly evolving field of microbiota modulation, emphasizing the necessity of comprehensive clinical trials and long-term safety evaluations. By critically assessing both the challenges and opportunities associated with microbiota-based interventions, this study provides a strategic framework for translating experimental research into viable clinical applications. A holistic approach to gut microbiota modulation has the potential to redefine treatment paradigms, offering personalized therapeutic strategies for a wide range of disorders and advancing the broader field of precision medicine.<\/jats:p>","DOI":"10.1007\/s00210-025-04155-2","type":"journal-article","created":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T23:51:22Z","timestamp":1746402682000},"page":"13397-13426","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["The microbiota-gut-brain-axis theory: role of gut microbiota modulators (GMMs) in gastrointestinal, neurological, and mental health disorders"],"prefix":"10.1007","volume":"398","author":[{"given":"Al-Hassan Soliman","family":"Wadan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa K. 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