Multi-omics insights into growth impairment mechanisms in children with persistent diarrhea

ABSTRACT This study aimed to elucidate the key mechanisms underlying short stature with pediatric persistent diarrhea in children (PDC) and to propose an integrated model linking the butyrate-producing gut microbial niche, short-chain fatty acids (SCFAs), Th17/Treg balance, the growth hormone-insulin-like growth factor 1 (GH-IGF-1) axis, and growth regulation. Samples from healthy controls (HCs), PDC patients without short stature (PDC-NS), and PDC patients with short stature (PDC-S) were analyzed using multi-omics profiling and machine learning-based predictive modeling. The results showed that PDC-S patients exhibited disruption of core butyrate-producing bacterial communities and related metabolic pathways, markedly reduced fecal butyrate levels, systemic Th17/Treg imbalance characterized by a pro-inflammatory state, and dual suppression of receptor- and ligand-level components of the GH-IGF-1 axis. Multi-omics machine learning identified a five-factor risk prediction panel composed of metabolic, immune, and endocrine markers, while causal inference further established butyrate as a central regulator of growth. Mouse experiments further validated that combined intervention with butyrate, Faecalibacterium prausnitzii , and recombinant human growth hormone (rhGH) ameliorated growth retardation. Overall, this study proposes a precision therapeutic strategy based on butyrate and GH co-intervention, providing new mechanistic insights and translational tools for PDC-associated short stature. IMPORTANCE The research conducted in this study holds significant implications for improving the understanding and treatment of stunted growth with persistent diarrhea in children (PDC). By unraveling the intricate pathways linking gut microbiota, immune responses, and growth hormone regulation, the study sheds light on the underlying mechanisms contributing to stunting in these vulnerable populations. The identification of key factors, such as butyrate-producing bacteria and the Th17/Treg balance, not only enhances our comprehension of PDC-related growth impairment but also offers a promising avenue for targeted interventions. The proposed integrated mechanistic model and intervention strategy pave the way for precision therapies tailored to address the specific biological mechanisms at play, potentially leading to more effective and personalized treatments for children suffering from PDC-associated stunting.