TY - JOUR
T1 - Successful DietaryTherapy in Paediatric Crohn’s Disease is Associated with Shifts in Bacterial Dysbiosis and Inflammatory MetabotypeTowards Healthy Controls
AU - Verburgt, Charlotte M.
AU - Dunn, Katherine A.
AU - Ghiboub, Mohammed
AU - Lewis, James D.
AU - Wine, Eytan
AU - Boneh, Rotem Sigall
AU - Gerasimidis, Konstantinos
AU - Shamir, Raanan
AU - Penny, Susanne
AU - Pinto, Devanand M.
AU - Cohen, Alejandro
AU - Bjorndahl, Paul
AU - Svolos, Vaios
AU - Bielawski, Joseph P.
AU - Benninga, Marc A.
AU - de Jonge, Wouter J.
AU - van Limbergen, Johan E.
N1 - Funding Information: JVL was supported by a Canadian Institutes of Health Research [CIHR]-Canadian Association of Gastroenterology-Crohn’s Colitis Canada New Investigator Award [2015–2019], a Canada Research Chair Tier 2 in Translational Microbiomics [2018–2019] and a Canadian Foundation of Innovation John R. Evans Leadership fund [awards #35235 and #36764], a Nova Scotia Health Research Foundation [NSHRF] establishment award [2015–2019], an IWK Health Centre Research Associateship and a CIHRSPOR-Chronic Diseases grant [Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects: the IMAGINE-SPOR chronic disease network], by the Wetenschappelijke Adviesraad of Stichting Steun Emma kinderziekenhuis, and by a Clinical Network Research Award from the Crohn’s and Colitis Foundation [#585718]. EW was supported by grants from the Crohn’s and Colitis Foundation and Crohn’s Colitis Canada as well as CIHR. Nestlé Health Science kindly provided Modulen to all participating sites to ensure uniformity of the formula used among participants, and provided the formula to enrolled patients for the duration of the study. The conduct of the study in Canada [Halifax, Edmonton] was supported by local divisional funds, a Women and Children’s Health Research Institute [WCHRI] Research Capacity Building Award [EW], a Canadian Institutes of Health Research [CIHR] New Investigator award [JVL], and Canada Research Chair Tier 2 in Translational Microbiomics [JVL]. The funders of the study had no role in the design of the study, data collection or analysis, interpretation of data, writing of the report, or in the decision to submit the paper for publication. None of the funders had access to the data. The authors would like to thank all participating children and their families. The authors also thank Arie Levine for design of the diet and his contribution to the study, as well as the many colleagues in paediatric gastroenterology and nutrition at all participating sites, who made this study possible: in Tel Aviv [Tamar Pfeffer-Gik who initially coordinated the study and Chen Sarbagili Shabat], Halifax [Anthony Otley, Mohsin Rashid, Angela Noble, Jessica Connors, Jennifer Haskett, Lisa Parkinson-McGraw, Brad MacIntyre], Edmonton [Hien Huynh, Matthew Carroll, Alexandra Petrova, Min Chen, Jessica Wu]. Antonia Harvey, registered dietitian, and M. Whebby, research assistant, modified the CDED recipes for use in Canada and maintained the Canadian CDED study website, supervised by Shannan Grant, Department of Applied Human Nutrition, Mount Saint Vincent University. Publisher Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - Background and aims: Nutritional therapy with the Crohn’s Disease Exclusion Diet + Partial Enteral Nutrition [CDED+PEN] or Exclusive Enteral Nutrition [EEN] induces remission and reduces inflammation in mild-to-moderate paediatric Crohn’s disease [CD]. We aimed to assess if reaching remission with nutritional therapy is mediated by correcting compositional or functional dysbiosis. Methods: We assessed metagenome sequences, short chain fatty acids [SCFA] and bile acids [BA] in 54 paediatric CD patients reaching remission after nutritional therapy [with CDED + PEN or EEN] [NCT01728870], compared to 26 paediatric healthy controls. Results: Successful dietary therapy decreased the relative abundance of Proteobacteria and increased Firmicutes towards healthy controls. CD patients possessed a mixture of two metabotypes [M1 and M2], whereas all healthy controls had metabotype M1. M1 was characterised by high Bacteroidetes and Firmicutes, low Proteobacteria, and higher SCFA synthesis pathways, and M2 was associated with high Proteobacteria and genes involved in SCFA degradation. M1 contribution increased during diet: 48%, 63%, up to 74% [Weeks 0, 6, 12, respectively.]. By Week 12, genera from Proteobacteria reached relative abundance levels of healthy controls with the exception of E. coli. Despite an increase in SCFA synthesis pathways, remission was not associated with increased SCFAs. Primary BA decreased with EEN but not with CDED+PEN, and secondary BA did not change during diet. Conclusion: Successful dietary therapy induced correction of both compositional and functional dysbiosis. However, 12 weeks of diet was not enough to achieve complete correction of dysbiosis. Our data suggests that composition and metabotype are important and change quickly during the early clinical response to dietary intervention. Correction of dysbiosis may therefore be an important future treatment goal for CD.
AB - Background and aims: Nutritional therapy with the Crohn’s Disease Exclusion Diet + Partial Enteral Nutrition [CDED+PEN] or Exclusive Enteral Nutrition [EEN] induces remission and reduces inflammation in mild-to-moderate paediatric Crohn’s disease [CD]. We aimed to assess if reaching remission with nutritional therapy is mediated by correcting compositional or functional dysbiosis. Methods: We assessed metagenome sequences, short chain fatty acids [SCFA] and bile acids [BA] in 54 paediatric CD patients reaching remission after nutritional therapy [with CDED + PEN or EEN] [NCT01728870], compared to 26 paediatric healthy controls. Results: Successful dietary therapy decreased the relative abundance of Proteobacteria and increased Firmicutes towards healthy controls. CD patients possessed a mixture of two metabotypes [M1 and M2], whereas all healthy controls had metabotype M1. M1 was characterised by high Bacteroidetes and Firmicutes, low Proteobacteria, and higher SCFA synthesis pathways, and M2 was associated with high Proteobacteria and genes involved in SCFA degradation. M1 contribution increased during diet: 48%, 63%, up to 74% [Weeks 0, 6, 12, respectively.]. By Week 12, genera from Proteobacteria reached relative abundance levels of healthy controls with the exception of E. coli. Despite an increase in SCFA synthesis pathways, remission was not associated with increased SCFAs. Primary BA decreased with EEN but not with CDED+PEN, and secondary BA did not change during diet. Conclusion: Successful dietary therapy induced correction of both compositional and functional dysbiosis. However, 12 weeks of diet was not enough to achieve complete correction of dysbiosis. Our data suggests that composition and metabotype are important and change quickly during the early clinical response to dietary intervention. Correction of dysbiosis may therefore be an important future treatment goal for CD.
KW - Crohn’s disease
KW - Diet
KW - inflammatory bowel disease
KW - microbiome
KW - treatment
UR - http://www.scopus.com/inward/record.url?scp=85147046942&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/ecco-jcc/jjac105
DO - https://doi.org/10.1093/ecco-jcc/jjac105
M3 - Article
C2 - 36106847
SN - 1873-9946
VL - 17
SP - 61
EP - 72
JO - Journal of Crohn's and Colitis
JF - Journal of Crohn's and Colitis
IS - 1
ER -