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

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. Metagenomic analysis identified high strain-level dynamics in response to EEN cessation, and hundreds of bacterial gene functions with significant changes in abundance. 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. EEN-like and fiber-repleted dietary model conditions, respectively, induced individual 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. ### Competing Interest Statement DHaller served on the Microbiome Expert Panel from Reckitt Benckiser Health Limited. TS received lecture honoraria from Nutricia and MSD and travel support from Abbvie and Ferring outside the submitted work. ### Clinical Trial German Clinical Trials Register accession No. DRKS00013306 ### Funding Statement Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – project number 395357507 (SFB 1371, Microbiome Signatures) and The Leona M. and Harry B. Helmsley Charitable Trust (project numbers 2847 and 2304–05970). TS is supported by the Medical & Clinician Scientist Program (MCSP) of the Faculty of Medicine at LMU Munich. Salary for DHäcker was supported by the National Research Foundation, Prime Minister’s Office, Singapore under its Campus for Research Excellence and Technological Enterprise (CREATE) programe. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: ethics approval Ludwig-Maximilians University of Munich, approval No. 17-801 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes