The Gut–Liver Axis in Preterm Neonates: Implications of Dysbiosis-induced Liver Injury

Preterm birth, affecting approximately 13.4 million infants annually, is associated with gut–liver axis dysregulation, leading to hepatic complications. In this review, we elucidate the mechanisms linking gut microbiota dysbiosis to liver injury in preterm infants, including microbial metabolites, epigenetic modifications, and therapeutic interventions. Premature gut microbiota exhibits less diversity and a slower colonization of beneficial bacteria such as Bifidobacterium , depending on gestational age, mode of delivery, feeding, and antibiotic exposure. These factors disrupt bile acid metabolism, increase intestinal permeability, alter immune responses, and impair vagal signaling, resulting in chronic inflammation, oxidative stress, and conditions such as cholestasis and metabolic-associated steatotic liver disease (MASLD). Microbial metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and indoles, mediate epigenetic changes that further exacerbate hepatic vulnerability. Microbiota-targeted therapies, including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT), show promise in restoring eubiosis and reducing inflammatory metabolite translocation. Notably, multistrain probiotics and human milk oligosaccharides (HMOs), in particular, have been shown to influence eubiosis and decrease the translocation of inflammatory metabolites. This review underscores the necessity of personalized, multi-targeted therapeutic strategies for individual preterm infants that will promote optimal gut–liver axis function and long-term hepatic safety. Early-life biomarkers and interventions need to be identified and developed in an attempt to bridge the knowledge gap amongst this at-risk group and prevent chronic liver disease.