Exclusive enteral nutrition mediates gut microbial and metabolic changes that are associated with remission in children with Crohn’s disease

Abstract

A nutritional intervention, exclusive enteral nutrition (EEN) can induce remission in patients with pediatric Crohn’s disease (CD). We characterized changes in the fecal microbiota and metabolome to identify the mechanism of EEN. Feces of 43 children were collected prior, during and after EEN. Microbiota and metabolites were analyzed by 16S rRNA gene amplicon sequencing and NMR. Selected metabolites were evaluated in relevant model systems. Microbiota and metabolome of patients with CD and controls were different at all time points. Amino acids, primary bile salts, trimethylamine and cadaverine were elevated in patients with CD. Microbiota and metabolome differed between responders and non-responders prior to EEN. EEN decreased microbiota diversity and reduced amino acids, trimethylamine and cadaverine towards control levels. Patients with CD had reduced microbial metabolism of bile acids that partially normalized during EEN. Trimethylamine and cadaverine inhibited intestinal cell growth. TMA and cadaverine inhibited LPS-stimulated TNF-alpha and IL-6 secretion by primary human monocytes. A diet rich in free amino acids worsened inflammation in the DSS model of intestinal inflammation. Trimethylamine, cadaverine, bile salts and amino acids could play a role in the mechanism by which EEN induces remission. Prior to EEN, microbiota and metabolome are different between responders and non-responders.

Nutritional Therapy Strategies in Pediatric Crohn’s Disease

“…Changes in fecal microbial composition induced by EEN or CDED + PEN have been linked with remission and sustained remission [ 3 , 100 , 141 , 142 ]. In an RCT, both CDED + PEN and EEN were effective in inducing remission by week 6 and showed similar taxa changes: a decrease in Actinobacteria and Proteobacteria and an increase in Clostridia [ 3 ].…”

“…Multiple studies have described the paradoxical loss in diversity upon the start of EEN therapy in children with CD, moving even further away from healthy controls in terms of the metrics of microbiome diversity. This diversity effect reverses upon return to the free diet [ 114 , 142 , 143 , 144 ]. However, diversity is a poor measure of microbiome complexity, as patients who do not achieve or sustain remission have been shown to expand Proteobacteria and lower-species-richness (using amplicon-sequence variant analysis), which are associated with lower calprotectin [ 25 , 137 ].…”

“…Bile acids (BAs) play a principal role in regulating immune responses and bacterial community composition within the gut; changes in intestinal microbial communities can disturb intestinal BA composition [ 142 , 145 , 146 ]. Altered BA metabolism has been demonstrated in the feces of CD patients and is associated with decreased secondary BAs (secBAs) and increased primary BAs (priBAs) compared to healthy controls [ 147 , 148 ].…”

Diet and Nutrition in Pediatric Inflammatory Bowel Diseases

“…The exact mechanism through which EEN is capable of inducing mucosal healing is still unclear, but some evidence exists about the beneficial exclusion of specific dietary components, microbiome modulation, intestinal rest and direct anti-inflammatory effect of EEN [ 63 , 64 ]. Previously published trials have shown the ineffectiveness of partial enteral nutrition (PEN) associated with a free diet in inducing clinical remission, proving that dietary antigens, even in small quantities, are dangerous, thus suggesting that EEN could also work by excluding them [ 40 , 65 ].…”

“…Previously published trials have shown the ineffectiveness of partial enteral nutrition (PEN) associated with a free diet in inducing clinical remission, proving that dietary antigens, even in small quantities, are dangerous, thus suggesting that EEN could also work by excluding them [ 40 , 65 ]. After EEN administration microbiome composition has shown some modifications, including paradoxical reduction of microbial diversity and decreased proportion of presumably beneficial bacterial groups, such as Bifidobacterium spp, Firmicutes (including Faecalibacterium prausnitzii ) , Bacteroides/Prevotella and Proteobacteriaceae [ 64 , 66 , 67 ]. In particular, a significant correlation was found between the decrease of Bacteroides/Prevotella group bacteria and the clinical improvement during EEN treatment [ 68 ].…”