Sambataro, Fabio

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are increasingly conceptualized as multisystem neurodevelopmental conditions involving behavioral, gastrointestinal, immune, and metabolic alterations. The microbiota–gut–brain axis (MGBA) has been proposed as a key framework linking these systems, although evidence from human studies remains heterogeneous and inconclusive. We conducted a structured narrative review of pediatric human studies investigating the microbiota-gut-brain axis (MGBA) in ASD and ADHD, excluding preclinical and animal studies. PRISMA 2020 principles were used as a transparency framework to support reporting of study identification, screening, and eligibility. Observational, cohort, and interventional studies were synthesized with particular attention to study design, methodology, associations with standardized clinical scales, dietary factors, and therapeutic implications. Across ASD ( n = 90), most studies were observational, predominantly cross-sectional or case-control in designs, reporting consistent associations between ASD symptom severity and gastrointestinal symptoms, intestinal permeability, immune activation, and dietary selectivity. Evidence in ADHD ( n = 21) was substantially more limited and largely observational. Diet emerged as a major modulating and confounding factor in microbiota–behavior associations. Interventional studies involving probiotics, microbiota transfer therapy, and other gut-directed approaches showed more consistent improved gastrointestinal outcomes but showed modest and heterogeneous effects on core ASD symptoms, often limited to subgroups with prominent gastrointestinal comorbidities. To strengthen interpretation of interventional findings, randomized trial reports and non-randomized interventional studies were appraised according to study design, whereas the predominantly heterogeneous observational literature was interpreted narratively. Overall, this review suggests that MGBA alterations may be better conceptualized as modifiers of symptom expression, particularly in ASD and with only emerging relevance in ADHD, rather than as disorder-specific causal mechanisms. This interpretation underscores the need for stratified, longitudinal, and clinically informed research frameworks, in line with the focus of the present research topic.

Abstract Introduction Observational studies have reported associations between hypnotic use and increased risk of cognitive decline. These findings may reflect confounding from insomnia severity, healthcare utilization, and comorbidity burden. We evaluated whether hypnotic exposure is independently associated with incident mild cognitive impairment (MCI) or dementia after rigorous adjustment, including a comprehensive propensity score (PS) and Apolipoprotein E (APOE) ε4 status. Methods We conducted a retrospective cohort study using a biobank sample with linked electronic health records and genetic data. Hypnotic exposure was derived from orders data and categorized as unexposed (n=27,055), single prescription (n=4243), shorter-term use (n=3999), long-term use (≥6 orders for ≥1 year; n=3214), and by drug class: benzodiazepines (n=376), Z-drugs (n=6222), trazodone (n=2395), and mixed exposure (≥2 classes; n=2435). Incident MCI/dementia diagnoses (ICD-9/10) occurring ≥12 months after initial prescription constituted outcomes. The PS modeled likelihood of receiving hypnotics based on demographics; sleep-related conditions; healthcare utilization (record length, visit frequency, diagnostic burden); psychiatric comorbidities; alcohol use and chronic pain. Hypnotic users were 1:2 matched to unexposed individuals on age, sex, healthcare utilization, and PS. Cox proportional hazards models with a 60-month lag tested associations of exposure category, duration, and class with outcomes. Models adjusted for all PS covariates, cardiovascular risk score, and APOE ε4 status. Results Matched but unadjusted analyses suggested slightly higher hazards of MCI/dementia among hypnotic users versus unexposed (HR=1.08; CI=0.99–1.18). However, after PS adjustment and APOE ε4 inclusion, hypnotic users showed significantly lower hazards (HR=0.81; CI=0.74–0.89). Class-specific analyses indicated reduced hazards for Z-drugs (HR=0.83; CI=0.74–0.93), trazodone (HR=0.71; CI=0.60–0.86), and mixed users (HR=0.79; CI=0.68–0.91), with all classes showing lower hazards than benzodiazepine-only users. Long-term hypnotic use was associated with lower hazards than no prescription (HR=0.69; CI=0.61–0.80), single prescription (HR=0.81; CI=0.68–0.97), or short-term use (HR=0.76; CI=0.65–0.90). Conclusion The elevated cognitive risk among hypnotic users appears largely attributable to underlying clinical/utilization factors rather than hypnotic exposure itself. After comprehensive confounding control, all hypnotic classes except benzodiazepines demonstrated lower risk of MCI/dementia. These findings underscore the need for rigorous adjustment in studies of insomnia pharmacotherapy and suggest potential protective effects of certain hypnotics that warrant further investigation. Support (if any) None