Globally, more than 15 million infants are born preterm or very-preterm, causing an epidemic with a major economic burden. Preterm infants are more likely to develop neurological and gastrointestinal issues that has life-long health consequences. We previously reported the existence of six specific microbial profiles (enterotypes) in the gut microbiome of preterm and very preterm infants and established a robust link between these enterotypes and the clinical and neurodevelopmental outcomes. However, the potential role of microbial communities in these outcomes have not been fully investigated. The objective of the present work is to evaluate a potential crosstalk between gut microbiome and host in very-preterm infants. Preterm and very preterm infants (median gestational age = 28 weeks; n=60) were selected from the EPIPAGE2 French national cohort with more than 40 clinical variables. Fecal samples at 1 month of age were analyzed for microbiome composition anddiversity (via 16S rRNA gene sequencing), and the host transcriptome and metabolomes (global approach via LC/MS), . We observed a strong association between Staphylococcus dominated enterotype and poor overall prognosis. Host transcriptome analysis showed that 113 genes were differentially expressed between the six enterotypes and they were associated with the dominant species of each enterotype. Among these genes, the ones for Calprotectin synthesis (S100A8 and S100A9) were expressed more strongly in cluster driven by Escherichia as opposed to the clusters driven by Staphylococcus or the cluster without any detectable bacteria. Calprotectin is an antimicrobial product of immune cells, therefore it has a critical role in first line of defense in infants. It is also known that calprotectin is increased at birth in the gut of healthy preterm and full-term infants up to 3 months of life. Our analysis showed that fecal calprotectin could be a strong biomarker of intestinal and immune health in preterm infants.