Successful Dietary Therapy in Paediatric Crohn's Disease is Associated with Shifts in Bacterial Dysbiosis and Inflammatory Metabotype Towards Healthy Controls

Abstract

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.

Keywords: Crohn’s disease; Diet; inflammatory bowel disease; microbiome; treatment.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.

Figures

Figure 1.

Beta-diversity plots of Bray–Curtis distances showing a gradual correction at Weeks 0, 6, 12 remission and Week 12 non-remission for patients achieving remission in Week 6 with EEN [n = 22, 20, 14, 6, respectively] and CDED + PEN [n = 30, 28, 25, 1, respectively] compared with healthy paediatric controls [n = 26] [Permanova p = 0.001]. EEN, exclusive enteral nutrition; CDED + PEN, Crohn’s disease exclusion diet + partial enteral nutrition.

Figure 2.

LEfSe cladogram of taxa showing significant [p <0.05] differences in abundance of baseline treatment-naïve [Week 0] CD children [CDED + PEN and EEN groups, n = 52] compared with healthy controls [HC] [n = 26]. Analyses include only samples from patients reaching remission at Week 6. Each dot represents identified taxa in this data. Taxa highlighted in red are increased and highlighted in green are decreased in treatment-naïve [week 0] CD samples compared with HC. Detailed marked figure can be found in Supplementary Figure 1. CD, Crohn’s disease; EEN, exclusive enteral nutrition; CDED + PEN, Crohn’s disease exclusion diet + partial enteral nutrition; LEfSe, linear discriminant analysis of effect size.

Figure 3.

LEfSe cladogram of taxa showing significant [p

Figure 4.

Changes in relative abundance [incl. standard deviation] of selected Proteobacteria across time points for children on CDED + PEN and EEN compared to healthy controls. EEN, exclusive enteral nutrition; CDED + PEN, Crohn’s disease exclusion diet + partial enteral nutrition.

Figure 5.

Metabotype 1 community structure. Cytoscape visualisation of the community structure identified from BioMiCo analysis of Metabotype 1 samples using taxa identified in 16S rRNA gene data. Nodes represent predominate taxa identified in the analysis, with size showing the summed posterior probability of the contribution of those taxa across assemblages. Edges indicate taxa that co-occurred in an assemblage.

Figure 6.

Metabotype 2 community structure. Cytoscape visualisation of the community structure identified from BioMiCo analysis of metabotype 2 samples using taxa identified in 16S rRNA gene data. Nodes represent predominate taxa identified in the analysis, with size showing the summed posterior probability of the contribution of those taxa across assemblages. Edges indicate taxa that co-occurred in an assemblage.