Gut microbiota modulation with rifaximin and probiotic supplementation as an add-on treatment for pediatric autism spectrum disorder

Abstract

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent difficulties in social communication and interaction, together with restricted and repetitive behaviors. In recent years, the gut microbiota has received increasing attention as a potentially modifiable factor in ASD. Numerous studies report differences in gut microbial composition in children with ASD compared with typically developing children, although findings are heterogeneous and it remains unclear whether dysbiosis is a cause, a contributor, or a consequence of ASD-related factors. Proposed mechanisms are commonly framed within the microbiota–gut–brain axis, in which microbiota-related changes may influence neurodevelopment and behavior through multiple interconnected pathways. This has increased interest in microbiota-targeted strategies, including probiotics/psychobiotics, which aim to modulate gut microbial balance and function and potentially affect downstream gut–brain signaling and overall wellbeing in selected individuals. In preclinical models and in some clinical trials, these interventions have shown signals of improvement in specific gastrointestinal and behavioral outcomes, although results remain inconsistent across studies. OBJECTIVE: To evaluate whether a two-step microbiota-targeted strategy, rifaximin followed by Lactobacillus plantarum PS128, reduces ASD symptom severity in children with moderate-to-severe ASD compared with control conditions. DESIGN: Single-center, randomized, double-blind, placebo-controlled, parallel-group clinical trial with three arms conducted within the CSMIJ network in Girona, coordinated with pediatric neurology at Hospital Universitario de Girona Dr. Josep Trueta. INTERVENTION AND METHOD: Children aged 5–12 years with moderate/severe ASD (DSM-5 diagnosis and ADOS-2-based severity) will be randomized 1:1:1 to: 1.Placebo rifaximin + placebo probiotic (N=52), 2.Active rifaximin + placebo probiotic (N=52), or 3. active rifaximin + L.plantarum PS128(N=52). Treatment consists of 14 days of rifaximin/placebo followed by 12 weeks of probiotic/placebo, with an additional 2-month follow-up (total ~6 months). Randomization is stratified by age (5–8 / 9–12) and baseline severity (moderate/severe)

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