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Background and Objectives: Patients with Hirschsprung's disease are at risk of developing Hirschsprung-associated enterocolitis, especially in the first 2 years of life. The pathophysiology of this inflammatory disease remains unclear, and intestinal dysbiosis has been proposed in the last decade. The primary objective of this study was to evaluate in a large cohort if Hirschsprung-associated enterocolitis was associated with alterations of fecal bacterial composition compared with HD without enterocolitis in different age groups., Methods: We analyzed the fecal microbiota structure of 103 Hirschsprung patients from 3 months to 16 years of age, all of whom had completed definitive surgery for rectosigmoid Hirschsprung. 16S rRNA gene sequencing allowed us to compare the microbiota composition between Hirschsprung's disease patients with (HAEC group) or without enterocolitis (HD group) in different age groups (0-2, 2-6, 6-12, and 12-16 years)., Results: Richness and diversity increased with age group but did not differ between HD and HAEC patients, irrespective of the age group. Relative abundance of Actinobacteria was lower in HAEC than in HD patients under 2 years of age (-66%, P = 0.045). Multivariate analysis by linear models (MaAsLin) considering sex, medications, birth mode, breast-feeding, and the Bristol stool scale, as well as surgery parameters, highlighted Flavonifractor plautii and Eggerthella lenta , as well as Ruminococcus gnavus group, as positively associated with Hirschsprung-associated enterocolitis in the 0-2 years age group., Conclusion: Hirschsprung-associated enterocolitis was associated with features of intestinal dysbiosis in infants (0-2 years) but not in older patients. This could explain the highest rate of enterocolitis in this age group., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02857205, MICROPRUNG, NCT02857205, 02/08/2016., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Arnaud, Cousin, Schmitt, Petit, Parmentier, Levard, Podevin, Guinot, DeNapoli, Hervieux, Flaum, De Vries, Randuineau, David-Le Gall, Buffet-Bataillon and Boudry.)

Gut microbiota and the central nervous system have parallel developmental windows during pre and post-natal life. Increasing evidences suggest that intestinal dysbiosis in preterm infants predisposes the neonate to adverse neurological outcomes later in life. Understanding the link between gut microbiota colonization and brain development to tailor therapies aimed at optimizing initial colonization and microbiota development are promising strategies to warrant adequate brain development and enhance neurological outcomes in preterm infants. Breast-feeding has been associated with both adequate cognitive development and healthy microbiota in preterms. Infant formula are industrially produced substitutes for infant nutrition that do not completely recapitulate breast-feeding benefices and could be largely improved by the understanding of the role of breast milk components upon gut microbiota. In this review, we will first discuss the nutritional and bioactive component information on breast milk composition and its contribution to the assembly of the neonatal gut microbiota in preterms. We will then discuss the emerging pathways connecting the gut microbiota and brain development. Finally, we will discuss the promising microbiota modulation-based nutritional interventions (including probiotic and prebiotic supplementation of infant formula and maternal nutrition) for improving neurodevelopmental outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Buffet-Bataillon, Bellanger, Boudry, Gangneux, Yverneau, Beuchée, Blat and Le Huërou-Luron.)