INTRODUCTION: To elucidate the postnatal dynamics and clinical associations of fecal calprotectin (FC) in very preterm infants, with a focus on necrotizing enterocolitis (NEC) and feeding intolerance (FI). METHODS: We performed a prospective observational cohort study in infants with a gestational age of <32 weeks or birth weight <1,500 g with weekly feces collection. The relationships between FC, NEC, and FI were investigated, adjusting for demographic and clinical factors. RESULTS: A total of 1,086 fecal samples were collected from 194 preterm infants. Postnatal FC levels of non-NEC infants were highly variable and followed an age-dependent patterned progression. FC levels were elevated in patients with NEC before and at NEC onset, distinguishing them from non-NEC infants and those at sepsis onset. Among infants without NEC or sepsis, those with FI exhibited lower FC concentrations throughout hospitalization and displayed a significant delay in reaching high FC levels after meconium compared with non-FI infants. The age to reach the first high nonmeconial FC levels was positively associated with the time to achieve full enteral feeding. DISCUSSION: Postnatal FC dynamics among premature infants followed a patterned progression but were disturbed in patients with NEC and FI. Because of the high variations, the use of FC levels in NEC diagnosis should be implemented with caution in clinical practice. FC may help understand FI and feeding progression in very preterm infants. Further research is needed to validate these findings and explore the potential clinical applications of FC in this population.

Background: Feeding intolerance (FI) is a significant concern in the care of preterm infants, impacting their growth and development. We previously reported that FI is linked to lower fecal calprotectin (FC) levels. This study aims to explore the postnatal dynamics and interplay between microbiota, metabolic profiles, and host immunity in preterm infants with and without FI. Methods: Infants with gestational age <32 weeks or birth weight <1500 g were enrolled at the Children’s Hospital of Fudan University between January 2018 and October 2020. Weekly fecal samples were analyzed for bacterial profiling, metabolome, and calprotectin levels, exploring their longitudinal development and interrelationships. Results: Of the 118 very preterm infants studied, 48 showed FI. These infants experienced an interrupted microbial–immune trajectory, particularly at 3–4 weeks of age, marked by a reduced bacterial abundance, alpha diversity, and FC levels. Metabolic changes in FI were pronounced between 3 and 6 weeks. Pantothenic acid and two polyamine metabolites were closely associated with bacterial abundance and FC levels and negatively correlated with the duration to attain full enteral feeding. Conclusions: FI infants demonstrated compromised microbiome–immune interactions, potentially influenced by specific metabolites. This research underscored the importance of early microbial and metabolic development in the pathogenesis of FI in very preterm infants.