2026 ECNP Congress

PS02-2073

Gut microbiome profiles and treatment response in treatment-naive children with ADHD

Junesung Yoon — P. Hyunwook, W. Youngtae, S. Eunice, S. Hyemin, C. Jung Kyoon, L. Taeyeop · Asan Medical Center- University of Ulsan College of Medicine, Department of Psychiatry, Seoul, Korea- Rep

2026 ECNP Congress

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder affecting approximately 8% of children worldwide. The gut-brain axis, a bidirectional communication network linking the central nervous system and the enteric nervous system, has emerged as a potential modulator of ADHD pathophysiology. Several studies have reported altered gut microbial signatures in individuals with ADHD; however, the role of the microbiome in shaping treatment outcomes remain poorly understood. Here, we aimed to characterise gut microbiome differences associated with ADHD diagnosis and treatment response.

Methods

A total of 88 Korean children aged 5–12 years were enrolled, comprising 48 with ADHD and 40 typically developing controls. Among ADHD participants with follow-up data, 26 were responders and 13 were non-responders. Fecal samples were collected at baseline and analysed using 16S rRNA gene sequencing. ADHD participants received methylphenidate or atomoxetine, and treatment response was assessed at 12 weeks. To assess within-sample and between-sample microbial diversity, alpha diversity indices and beta diversity based on Bray-Curtis dissimilarity were computed. Differentially abundant genera (DAGs) were identified using ANCOM-BC with age as a covariate. Microbial co-occurrence networks were constructed using SparCC via NetCoMi, and functional pathways were inferred using PICRUSt2. Enterotype classification was performed using partitioning around medoids on Bray-Curtis dissimilarity matrices.

Results

Alpha and beta diversity did not significantly differ between diagnostic or treatment response groups. Network analysis showed that modularity was significantly higher and edge density significantly lower in the ADHD group. Escherichia–Shigella demonstrated a stepwise increase with symptom severity, and showed a positive correlation with the GABA degradation V pathway, which was enriched in the ADHD group. Notably, microbiome features were more strongly associated with treatment response than with diagnosis, with response groups showing a greater number of DAGs and higher explained microbial variance. Among responder-enriched DAGs, the Eubacterium hallii group and Subdoligranulum—both well-established SCFA producers [1,2]—showed the largest positive effect sizes. Unsupervised clustering identified three enterotypes, one of which—E2, characterised by Ruminococcus gnavus group enrichment and Eubacterium hallii group depletion—was predominantly composed of non-responders and associated with poorer clinical improvement.

Discussion and Conclusions

Baseline microbiome features were more strongly associated with treatment response than with diagnosis, suggesting that microbial ecology may modulate pharmacological responsiveness rather than reflect disorder status. Furthermore, the ADHD network exhibited higher modularity and lower edge density, suggesting reduced microbiome resilience representing an additional dimension of dysbiosis beyond compositional differences alone. At the functional level, increased microbial GABA degradation capacity may reflect altered gut–brain signalling dynamics associated with symptom severity.

In conclusion, ADHD was associated with enrichment of pro-inflammatory Escherichia–Shigella, increased microbial GABA degradation capacity, and reduced network connectivity. Importantly, microbiome composition, functional characteristics, and enterotype structure were more strongly associated with treatment responsiveness than with diagnosis. These findings support a potential role of the gut microbiome as a modulator of pharmacological response in ADHD.

References

  1. Houtman TA, Eckermann HA, Smidt H, de Weerth C. Gut microbiota and BMI throughout childhood: the role of firmicutes, bacteroidetes, and short-chain fatty acid producers. Sci Rep 2022; 12.
  2. Jiang, L., Li, J.C., Tang, B.S., Guo, J.F., 2023. Associations between gut microbiota and Parkinson disease: A bidirectional Mendelian randomization analysis. Eur. J. Neurol. 30 (11), 3471–3477.