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Comparative Study
. 2015 Dec;110(12):1718-29; quiz 1730.
doi: 10.1038/ajg.2015.357. Epub 2015 Nov 3.

Extensive Modulation of the Fecal Metagenome in Children With Crohn's Disease During Exclusive Enteral Nutrition

Christopher Quince  1 , Umer Zeeshan Ijaz  2 , Nick Loman  3 , A Murat Eren  4 , Delphine Saulnier  5 , Julie Russell  2 , Sarah J Haig  2 , Szymon T Calus  3 , Joshua Quick  3 , Andrew Barclay  6 , Martin Bertz  5 , Michael Blaut  5 , Richard Hansen  6 , Paraic McGrogan  6 , Richard K Russell  6 , Christine A Edwards  7 , Konstantinos Gerasimidis  7
Affiliations
Comparative Study

Extensive Modulation of the Fecal Metagenome in Children With Crohn's Disease During Exclusive Enteral Nutrition

Christopher Quince et al. Am J Gastroenterol. 2015 Dec.

Abstract

Objectives: Exploring associations between the gut microbiota and colonic inflammation and assessing sequential changes during exclusive enteral nutrition (EEN) may offer clues into the microbial origins of Crohn's disease (CD).

Methods: Fecal samples (n=117) were collected from 23 CD and 21 healthy children. From CD children fecal samples were collected before, during EEN, and when patients returned to their habitual diets. Microbiota composition and functional capacity were characterized using sequencing of the 16S rRNA gene and shotgun metagenomics.

Results: Microbial diversity was lower in CD than controls before EEN (P=0.006); differences were observed in 36 genera, 141 operational taxonomic units (OTUs), and 44 oligotypes. During EEN, the microbial diversity of CD children further decreased, and the community structure became even more dissimilar than that of controls. Every 10 days on EEN, 0.6 genus diversity equivalents were lost; 34 genera decreased and one increased during EEN. Fecal calprotectin correlated with 35 OTUs, 14 of which accounted for 78% of its variation. OTUs that correlated positively or negatively with calprotectin decreased during EEN. The microbiota of CD patients had a broader functional capacity than healthy controls, but diversity decreased with EEN. Genes involved in membrane transport, sulfur reduction, and nutrient biosynthesis differed between patients and controls. The abundance of genes involved in biotin (P=0.005) and thiamine biosynthesis decreased (P=0.017), whereas those involved in spermidine/putrescine biosynthesis (P=0.031), or the shikimate pathway (P=0.058), increased during EEN.

Conclusions: Disease improvement following treatment with EEN is associated with extensive modulation of the gut microbiome.

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Conflict of interest statement

Guarantor of the article: Konstantinos Gerasimidis, PhD, MSc, BSc.

Specific author contributions: K.G., C.Q., N.L., R.K.R., C.A.E., and P.M. contributed to study concept and design; K.G., S.J.H., S.T.C., J.Q., J.R., D.S., and M.B. contributed to acquisition of data; all authors contributed to the analysis and interpretation of data, drafting, and critical revision of the manuscript for important intellectual content; A.M.E., C.Q., N.L., and U.Z.I. contributed to bioinformatics and statistical analysis; K.G., A.B., R.K.R., C.A.E., and P.M. obtained funding; K.G., J.R., S.J.H., J.Q., and M.B. contributed to technical aspects of the study; K.G., C.Q., C.A.E., N.L., and R.K.R. contributed in study supervision.

Potential conflicts of interest: R.K. Russell has received speaker's fees, travel support, and participated in medical board meetings with Nestle. P. McGrogan received speaker fees, travel support, and participated in medical board meetings with Nestle. The remaining authors declare no conflict of interest.

Financial support: The study and K. Gerasimidis were funded by the Greek State Scholarship Foundation, the Hellenic Foundation of Gastroenterology, and Nutrition, the Barr Endowment Fund, the Yorkhill Children's Foundation, and the Crohn's in Childhood Research Association. C. Quince is funded by an MRC fellowship as part of the CLIMB consortium Grant Ref: MR/L015080/1. U.Z. Ijaz is funded by NERC IRF NE/L011956/1. R K Russell is supported by an NHS Research Scotland career fellowship award and MRC grant for PICTS (G0800675).

Figures

Figure 1
Figure 1
Genus Shannon diversity, in richness equivalents (a), and non-metric multidimensional scaling (NMDS) of operational taxonomic unit (OTU) community structures (b) for each EEN sample time for the Crohn's disease (CD) children and healthy controls. (a) Diversity, in species equivalents, decreased during exclusive enteral nutrition (EEN; P=0.037) and was higher in healthy children vs. CD children at time A (P=0.009). (b) NMDS plot using Bray–Curtis distances of the 3% OTU community structures.
Figure 2
Figure 2
Relative abundance of the 20 most abundant bacterial genera (a), operational taxonomic units (OTUs) (b), and MetaPhlAn species from shotgun metagenome samples (c) for each exclusive enteral nutrition (EEN) sample time for the Crohn's disease (CD) children and healthy controls. OTUs assignments see Supplementary Table S14.
Figure 3
Figure 3
Log abundance of OTU3 (Bifidobacterium spp.) (a), OTU122 (Atopobium spp.) (b), and OTU4 (Ruminoccocus gnavus) (c) as a function of days on EEN discriminated by subject. Adjusted P-values: OTU122=0.0338; OTU3=0.00573; OTU4=0.0897. A full color version of this figure is available at the American Journal of Gastroenterology journal online. EEN, exclusive enteral nutrition; OTU, operational taxonomic unit.
Figure 4
Figure 4
KEGG module Shannon diversity for each EEN sample time and participant (a) and log relative abundance of modules that significantly changed during EEN (b). (a) Diversity was not impacted during EEN (P=0.260), but there was a difference between H and CD before EEN (P=0.05). (b): M00123, biotin biosynthesis, P=0.005; M00127, thiamine biosynthesis, P=0.0166; M00299, spermidine/putrescine transport system, P=0.0307; M00022, shikimate pathway, P=0.058. P-values are based on linear regressions of KEGG module log relative abundance against days on EEN with subject-dependent intercepts for 11 children with at least two shotgun metagenome samples. Benjamini–Hochberg false discovery rate was used to adjust significance values for multiple comparisons. All modules with a mean abundance >1.0 × 10−9 were tested; only those with adjusted P-value <0.1 are shown. A full color version of this figure is available at the American Journal of Gastroenterology journal online. CD, Crohn's disease; EEN, exclusive enteral nutrition; KEGG, Kyoto Encyclopedia of Genes and Genomes.
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References

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