Jonathan Chapman, PhD

TITLE: The Gut Microbiome in Preterm Infant Health and Disease: A New Role for Clostridium Species Early-life gut microbiome development plays a critical role in shaping short- and long-term health. Preterm infants born with <32 weeks of gestation undergo altered gut microbiome development, driven by the complex care needs arising from their physiological, anatomical and immunological immaturity. Receipt of breast milk is the main driver of infant microbiome composition and can protect against pathologies with high risks of mortality and morbidity, through the provision of multiple bioactive factors. These include human milk oligosaccharides (HMOs), which are carbohydrates that cannot be digested by the infant host but are instead metabolised by a narrow group of gut bacteria, principally Bifidobacterium species. These strains support pathogen resistance, gut barrier function and immune development. But while HMO metabolism in Bifidobacterium is well characterised, the full scope of HMO-utilising species that colonise preterm infants remains unclear. Through combining multi-omics and patient-derived intestinal organoid models, we show for the first time that Clostridium species isolated from preterm infants, in particular Clostridium perfringens lacking the toxin perfringolysin O (pfoA^-), metabolise HMOs, producing short-chain fatty acids, tryptophan catabolites and other beneficial metabolites. Furthermore, cell-free supernatants from such C. perfringens showed inhibitory effects on common infant pathobionts, generally promoted growth of beneficial microbes, enhanced mitochondrial bioenergetic function in preterm intestine-derived organoids, and suppressed the inflammatory response in an organoid co-culture model. These findings reveal a previously undescribed role for pfoA^- C. perfringens strains in gut microbiome-mediated immune education during early life, expand our understanding of HMO-metabolising microbes and lay the groundwork for novel prebiotic and postbiotic therapies.