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

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.

Analysis and Interpretation of the Human Microbiome

“…16S sequencing is much broader and gives little or no information about subspecies and antibiotic sensitivities that are important to the clinicians. Most publications relate to disease in which host-microbe interaction is likely to play a role in disease pathogenesis and ongoing disease flare; these are mostly chronic conditions such as inflammatory bowel disease (IBD), 4,[16][17][18] asthma, [19][20][21] skin conditions, 22 and cancers. [23][24][25] The immunomodulatory effect of the microbiome seems likely to hold a key to understanding several diseases, and correlation of host gene expression (transcriptome) with the microbiome and microbial gene expression may yield useful insights.…”

“…[23][24][25] The immunomodulatory effect of the microbiome seems likely to hold a key to understanding several diseases, and correlation of host gene expression (transcriptome) with the microbiome and microbial gene expression may yield useful insights. 16,18,26 Trials have begun to look at the effect of specific modulatory diets on the gut microbiome, largely in the context of IBD 17,27 and IBS. 28 These have revealed initial dysbiosis with changes in diversity through treatment and have started to understand the functional impact, such as on short-chain fatty acid synthesis.…”

New treatments for ulcerative colitis: do we have pediatric data?

“…In Crohn's disease exclusive enteral nutrition (EEN) leads to a broad reduction in bacterial abundance, probably driven by a reduction in available colonic substrate [19]. This therapeutic approach has not historically been shown to be effective in UC but there are now a series of studies set to re-explore this.…”

Vitamin A to reduce gut leak and GVHD?

“…Enteral nutrition significantly modulates the microbiota in pediatric Crohn disease but, because microbiota diversity becomes even more narrow, there remains a need to better understand what exactly correlates with clinical improvement. 7 These observations together with the well-known negative side effects of corticosteroids and other immunosuppressive agents should propel us to explore gentler and potentially equally efficacious alternative therapies to prevent or treat gut GVHD.…”