Longitudinal Gut Microbiome Dynamics in Human CTLA-4 pathway Deficiencies: A One-Year Interventional Metagenomic Study

BackgroundCTLA-4 haploinsufficiency (CHAI) and LRBA deficiency cause severe immune dysregulation including enteropathy. Abatacept, a CTLA-4-immunoglobulin fusion protein, targets the underlying pathway defect, but its impact on the gut microbiome remains undefined. MethodsWe performed longitudinal shotgun metagenomics (MetaPhlAn4/HUMAnN3) on stool samples from patients enrolled in the ABACHAI clinical trial, collected at pre-treatment baseline and months 3, 6, and 12. Healthy individuals from the same household served as controls. Compositional and functional microbiome changes were analyzed using linear mixed-effects models and MaAsLin3, and correlated with organ-specific CHAI Morbidity Scores. ResultsAt baseline, patients showed significantly reduced alpha diversity (Shannon index, p=0.0029) and distinct community composition (PERMANOVA p=0.0001) compared to healthy controls, characterised by enrichment of oral-associated taxa (Veillonella, Streptococcus, Lacrimispora) and depletion of butyrate-producing commensals (Ruminococcus, Oscillibacter, Dysosmobacter). Functionally, the baseline metagenome exhibited broad reductions in amino acid and SCFA biosynthesis alongside enrichment of purine salvage and folate pathways. During treatment, beta diversity shifted significantly with treatment duration (Aitchison PERMANOVA R2=0.103, p=0.015), with within-patient community turnover peaking at month 6 ({Delta}=0.216, p=0.006). Longitudinal analyses demonstrated progressive decreases in disease-enriched taxa (Veillonella, Lacrimispora) and recovery of commensals (Collinsella, Adlercreutzia). FDR-significant reductions in microbial folate and purine biosynthesis pathways were observed over the treatment course. Gut CHAI domain severity correlated inversely with butyrate-producer abundance and positively with oral taxon enrichment. ConclusionIn CTLA-4 pathway insufficiency patients, abatacept therapy is associated with an improvement of enteropathy and a progressive, measurable gut microbiome restructuring, positioning microbiome dynamics as a candidate biomarker of treatment response in this monogenic immune dysregulation disorder.