Di Gloria L, Peruzzi M, Vasarri M, Menicatti M, Bartolucci G, Annunziata M, Bedeschi A, Ramazzotti M, Degl'Innocenti D, Nassi N.

Congenital central hypoventilation syndrome (CCHS) is a genetic disorder caused by mutations in the PHOX2B gene, characterized by impaired autonomic control of breathing and systemic consequences that may affect gut homeostasis. This study provides the first integrated multi-omics analysis in a CCHS group and matched controls, combining fecal DNA-based gut taxonomic profiling with targeted quantification of fatty acids and aromatic carboxylic acids. While overall microbial diversity and community structure remained largely preserved, significant alterations were observed in specific taxa within the CCHS group. Notably, the control group exhibited an enrichment of short-chain fatty acid (SCFA)-producing genera, which are associated with eubiotic gut ecosystems, whereas the CCHS group showed higher abundance of taxa commonly linked to inflammatory contexts. Consistently, fecal levels of beneficial SCFAs-particularly valeric acid, and to a lesser extent butyric acid-were reduced in CCHS group. These findings point to a dysbiotic gut microbiota in patients with CCHS, likely supporting putative inflammatory processes that would further worsen overall health status if confirmed. Furthermore, this work provides exploratory functional signatures for future studies aimed at understanding systemic consequences, guiding mechanistic investigations, and informing strategies to improve supportive care and long-term health outcomes in this rare patient population.