Heat-Treated Limosilactobacillus fermentum PS150 Improves Sleep Quality with Severity-Dependent Benefits: A Randomized, Placebo-Controlled Trial.

Background: Insomnia is prevalent and difficult to treat safely over the long term. Given the role of the microbiota-gut-brain axis in melatonin and hypothalamic-pituitary-adrenal (HPA) regulation, and preclinical evidence for Limosilactobacillus fermentum PS150, we evaluated whether a heat-treated formulation (HT-PS150) could improve sleep and modulate endocrine/circadian markers in adults with poor sleep. Methods: In a randomized, double-blind, placebo-controlled trial, 84 adults aged 20-60 years with PSQI ≥ 5 and ISI < 22 were assigned to receive either placebo or HT-PS150 for eight weeks. Outcomes included patient-reported sleep (PSQI, ISI), anxiety/depression (GAD-7, PHQ-9), quality of life (QLESQ-SF), gastrointestinal symptoms (VAS-GI), wrist actigraphy (Fitbit Inspire 3), and sleep-relevant biomarkers measured from urine, saliva, and/or blood samples (melatonin, cortisol, orexin, serotonin, GABA, and/or norepinephrine). Repeated measures were analyzed using generalized estimating equations. An exploratory proportional regulation analysis classified individual biomarker changes as up- or down-regulated and compared proportions between study arms. Per-protocol analyses required ≥80% compliance. Results: Improvements in the primary outcomes, PSQI and ISI, were observed over time in both groups, while no significant group × time interactions were detected. In exploratory proportional analyses, a higher proportion of participants in the HT-PS150 group exhibited up-regulated nocturnal melatonin secretion and improved daytime plasma orexin levels, as well as a tendency toward greater reductions in nocturnal salivary cortisol compared with placebo. In subgroup analyses with higher baseline insomnia severity (ISI ≥ 8), HT-PS150 was associated with greater improvements in PSQI (notably sleep duration and efficiency) and reduction in anxiety (GAD-7) upon post hoc testing. Conclusions: Although group mean scores on sleep symptom scales did not differ significantly in the full cohort, HT-PS150 appeared to modulate sleep-wake regulation by enhancing nocturnal melatonin secretion, attenuating HPA-axis activity, and stabilizing wakefulness. Clinical benefits were most evident among participants with greater baseline symptom burden, suggesting potential utility in more symptomatic populations.