BackgroundInsomnia persists as a prevalent sleep disorder among middle-aged and older adults, significantly impacting quality of life and increasing susceptibility to age-related diseases. It is classified into objective insomnia (O-IN) and paradoxical insomnia (P-IN), where subjective and objective sleep assessments diverge. Current treatment regimens for both patient groups yield unsatisfactory outcomes. Consequently, investigating the neurophysiological distinctions between P-IN and O-IN is imperative for devising novel precision interventions aligned with primary prediction, targeted prevention, and personalized medicine (PPPM) principles.Working hypothesis and methodology.Given the emerging influence of gut microbiota (GM) on sleep physiology via the gut-brain axis, our study focused on characterizing the GM profiles of a well-characterized cohort of 96 Italian postmenopausal women, comprising 54 insomniac patients (18 O-IN and 36 P-IN) and 42 controls, through 16S rRNA amplicon sequencing. Associations were explored with general and clinical history, sleep patterns, stress, hematobiochemical parameters, and nutritional patterns.ResultsDistinctive GM profiles were unveiled between O-IN and P-IN patients. O-IN patients exhibited prominence in the Coriobacteriaceae family, including Collinsella and Adlercreutzia, along with Erysipelotrichaceae, Clostridium, and Pediococcus. Conversely, P-IN patients were mainly discriminated by Bacteroides, Staphylococcus, Carnobacterium, Pseudomonas, and respective families, along with Odoribacter.ConclusionsThese findings provide valuable insights into the microbiota-mediated mechanism of O-IN versus P-IN onset. GM profiling may thus serve as a tailored stratification criterion, enabling the identification of women at risk for specific insomnia subtypes and facilitating the development of integrated microbiota-based predictive diagnostics, targeted prevention, and personalized therapies, ultimately enhancing clinical effectiveness.