Tourette syndrome (TS) is a neuropsychiatric disorder characterized by involuntary motor and vocal tics. Emerging evidence suggests that microRNA (miRNA) regulation and the gut-brain axis (GBA) may contribute to TS pathophysiology. Lactiplantibacillus plantarum PS128 (PS128) is a well-studied psychobiotic strain known to influence brain function through neurotransmitter modulation. This double-blind, randomized, placebo-controlled trial investigated the efficacy of a 12-week PS128 intervention on clinical symptoms-including tic severity, attention, and gastrointestinal discomfort-alongside circulating miRNA expression and gut microbiota composition in children aged 4-18 years with TS. Clinical outcomes were assessed using the Yale Global Tic Severity Scale (YGTSS), Clinical Global Impression (CGI), Visual Analogue Scale of Gastrointestinal Discomfort (VAS-GI), Continuous Performance Test (CPT), and neuropsychological assessments. Blood-based miRNA profiling and fecal microbiota analyses were conducted to explore potential mechanisms. Seventy-three participants completed the study. Improvements in YGTSS, CGI, and neuropsychological outcomes were comparable between groups. The primary endpoint, reduction in YGTSS score, did not differ significantly between groups. However, the PS128 group exhibited significantly greater reductions in gastrointestinal symptoms, particularly upper abdominal pain, and showed a trend toward improved attentional performance on the CPT. miRNA sequencing identified eight differentially expressed miRNAs following PS128 intervention, which were predicted to be involved in nervous system development and synaptic regulation. The qRT-PCR validation confirmed significant upregulation of miR-199a-3p and miR-143-3p in the PS128 group compared with placebo. Fecal microbiota analysis revealed increased Lactiplantibacillus abundance after PS128 intervention, which positively correlated with miR-199a-3p expression and negatively correlated with CGI scores. No intervention-related adverse events were reported. Despite no significant effect on core tic severity, PS128 improved gastrointestinal and attentional symptoms with accompanying GBA molecular changes, supporting further investigation as an adjunctive therapy for pediatric TS.
