Metaproteomic portrait of the gut microbiome in children with Down syndrome

Down syndrome (DS), or Trisomy 21, is a genetic condition caused by an extra copy of chromosome 21, and is associated with a broad spectrum of comorbidities, including autoimmune, behavioral and gastrointestinal disorders. Because metaproteomics captures the proteins the gut microbiota (GM) actually expresses, it can clarify how the GM tracks these clinical manifestations. Forty-eight children with DS were enrolled in the study and stratified by age and comorbidity such as autoimmune thyroid diseases (AITDs), immune-related conditions, and behavioral disorders. Fecal proteins were extracted by differential centrifugation, trypsin-digested and analyzed by data-dependent nanoliquid chromatography coupled with tandem mass spectrometry, followed by MetaLab-MAG and Unipept processing. This resulted in the identification of bacterial and human protein groups (PGs), along with their label-free quantification, functional annotation, and taxonomic assignment. The GM metaproteome was shaped by age, but not by sex. In both age groups (6 ≤ years < 13 and 13 ≤ years ≤ 18), comorbidity was consistently associated with pathway down-regulation: sulfur metabolism in AITDs; glycolysis/gluconeogenesis, pyruvate metabolism, oxidative phosphorylation and butanoate metabolism in immune-related conditions; and sixteen shared amino-acid, nucleotide, sugar and glycan pathways in behavioral disorders. This functional contraction was carried by a recurring set of taxa, including the butyrogenic Faecalibacterium prausnitzii , Blautia and Ruminococcus bromii . Comorbidity in DS is accompanied by a hypofunctional, short-chain fatty acid-poor microbiota, while the fecal host proteome mirrors processes associated with T21, including matrix remodeling and interferon-skewed immunity. These findings may open new avenues for therapeutic interventions aimed at improving pathological outcomes in DS.