Exclusive Enteral Nutrition Initiates Individual Protective Microbiome Changes to Induce Remission in Pediatric Crohn’s Disease

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Summary Exclusive enteral nutrition (EEN) is the first-line therapy for pediatric Crohn’s disease (CD), but protective mechanisms remain unknown. We established a prospective pediatric cohort to characterize the function of fecal microbiota and metabolite changes of treatment-naïve CD patients in response to EEN. Integrated multi-omics analysis identified network clusters from individually variable microbiome profiles, with Lachnospiraceae and medium chain fatty acids as protective features. Bioorthogonal non-canonical amino acid tagging selectively identified bacterial species in response to medium chain fatty acids. Metagenomic analysis identified high strain-level dynamics in response to EEN. Functional changes of diet-exposed fecal microbiota were further validated in a combined approach using gut chemostat cultures and microbiota transfer into germ-free Il10 -deficient mice. Dietary model conditions induced individual patient-specific strain signatures to prevent or cause IBD-like inflammation in gnotobiotic mice. Hence, we provide evidence that EEN therapy operates through explicit functional changes of temporally and individually variable microbiome profiles.

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