Neonatal Jaundice and the Infant Gut Microbiome: An Integrated Shotgun Metagenomics and Bidirectional Mendelian Randomization Study in Xinjiang

Muqing Niu¹Jinyong Pan¹Yan Guo¹Fengling Zhang¹Hua Guan²Xiaoping Yang²Hu Li¹Heyun Xiong¹Yan Zhang¹Yonglin Chen^1*

• ¹First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, China
• ²Xinjiang Production and Construction Corps Hospital, Urumqi, China

Background: Neonatal jaundice is a common condition, yet inter-individual variation in its onset and severity cannot be fully explained by traditional clinical risk factors. Emerging evidence suggests that the infant gut microbiome may modulate bilirubin metabolism, but its compositional and functional signatures in jaundiced neonates remain incompletely defined. This study aimed to characterize the taxonomic and functional features of the gut microbiome in neonatal pathologic jaundice and to explore potential causal links using Mendelian randomization (MR). Methods: We conducted a case–control study of term infants with pathologic jaundice and matched healthy controls. Stool samples were subjected to shotgun metagenomic sequencing to assess microbial diversity, taxonomic composition, functional gene repertoires, and carbohydrate-active enzyme families, and publicly available genome-wide association study summary statistics were used to perform bidirectional MR between microbiome-related traits and neonatal jaundice. Results: Alpha diversity indices did not differ significantly between groups, whereas beta diversity based on Bray– Curtis dissimilarity showed clear separation of jaundiced and control infants, indicating a restructured microbial community rather than a simple loss of richness. Jaundiced neonates exhibited increased relative abundance of Gram-negative taxa, including Escherichia coli, and reduced levels of putatively beneficial genera such as Bifidobacterium and Lactobacillus. Functionally, pathways involved in bile acid synthesis and metabolism, carbohydrate and energy metabolism, and cofactor and vitamin biosynthesis were enriched in the jaundiced group, accompanied by marked shifts in carbohydrate-active enzyme profiles. Forward MR suggested that several microbial metabolic pathways exert genetically predicted effects on jaundice risk, whereas reverse MR provided little evidence that genetic liability to jaundice substantially alters microbiome traits. Conclusions: Neonatal pathologic jaundice is associated with distinctive compositional and functional alterations in the gut microbiome. Genetic evidence from MR supports a potential causal contribution of specific microbial pathways to jaundice risk, highlighting candidate targets for microbiome-based prevention or adjunctive therapy in early life.