Exclusive enteral nutrition mediates gut microbial and metabolic changes that are associated with remission in children with Crohn\u2019s disease

Kay Diederen,Anje A Te Velde,Victoria Auyeung,Alan W Walker,Wouter J De Jonge,James Kinross,Dirk R De Waart,Theodorus B M Hakvoort,Marc A Benninga,Angelika Kindermann,Josef Wagner,Jia V Li,Gillian E Donachie,Tim G De Meij,Jurgen Seppen,Sigrid E M Heinsbroek

doi:10.1038/s41598-020-75306-z

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.

Highlights

A nutritional intervention, exclusive enteral nutrition (EEN) can induce remission in patients with pediatric Crohn’s disease (CD)
We report a comprehensive analysis of the fecal microbiota and metabolome during a course of EEN therapy in patients with CD
Limited by our relatively small number of samples, our results suggest that increased proportional abundance of taxa such as Bifidobacterium longum, Dorea longicatena, and Blautia obeum may indicate a lower chance of disease remission following EEN

Summary

Introduction

A nutritional intervention, exclusive enteral nutrition (EEN) can induce remission in patients with pediatric Crohn’s disease (CD). Trimethylamine, cadaverine, bile salts and amino acids could play a role in the mechanism by which EEN induces remission. Exclusive enteral nutrition (EEN) is the treatment of choice for patients with pediatric Crohn’s disease (CD) in Europe[1] It is efficacious as corticosteroids in inducing clinical remission in children and adolescents with active C D2,3 and superior in inducing mucosal h ealing[4]. Two recent papers show that diets with either partial E EN17 or mimicking EEN composition with more solid ingredients[18], are effective as EEN in inducing remission in patients with pediatric CD These p apers[17,18] are important because the novel nutritional therapies are better tolerated and would be beneficial for a larger number of patients. The findings reported provide evidence that changes in the microbiota and metabolome could be causative in inducing remission in patients with pediatric CD disease

Objectives

Results

Discussion

Conclusion