Multiomic features associated with mucosal healing and inflammation in paediatric Crohn's disease.

Henry Taylor,Julian R Marchesi,Ailsa L Hart,Jm Fell,Jenny Epstein,Rocio C Seoane,Jia V Li,Jose Ivan Serrano‐Contreras,Julie A K Mcdonald

doi:10.1111/apt.16086

Abstract

The gastrointestinal microbiota has an important role in mucosal immune homoeostasis and may contribute to maintaining mucosal healing in Crohn's disease (CD). To identify changes in the microbiota, metabolome and protease activity associated with mucosal healing in established paediatric CD METHODS: Twenty-five participants aged 3-18 years with CD, disease duration of over 6 months, and maintenance treatment with biological therapy were recruited. They were divided into a low calprotectin group (faecal calprotectin <100 μg/g, "mucosal healing," n = 11), and a high calprotectin group (faecal calprotectin >100 μg/g, "mucosal inflammation," n = 11). 16S gene-based metataxonomics, 1 H-NMR spectroscopy-based metabolic profiling and protease activity assays were performed on stool samples. Relative abundance of Dialister species was six-times greater in the low calprotectin group (q = 0.00999). Alpha and beta diversity, total protease activity and inferred metagenomic profiles did not differ between groups. Pentanoate (valerate) and lysine were principal discriminators in a machine-learning model which differentiated high and low calprotectin samples using NMR spectra (R2 0.87, Q2 0.41). Mean relative concentration of pentanoate was 1.35-times greater in the low calprotectin group (95% CI 1.03-1.68, P = 0.036) and was positively correlated with Dialister. Mean relative concentration of lysine was 1.54-times greater in the high calprotectin group (95% CI 1.05-2.03, P = 0.028). This multiomic study identified an increase in Dialister species and pentanoate, and a decrease in lysine, in patients with "mucosal healing." It supports further investigation of these as potential novel therapeutic targets in CD.

Highlights

Crohn's disease (CD) is a chronic inflammatory disease caused by an inappropriate immunological response to the gastrointestinal microbiota in genetically susceptible individuals
In paediatric CD Weinstein-Nakar et al[7] found faecal calprotectin levels under 100 μg/g were predictive of mucosal and transmural healing
This study aims to identify changes in the microbiota which are associated with mucosal healing in established paediatric CD and to investigate the functional implications of these changes using inferred metagenomics, 1H-NMR metabolomics and protease activity assays

Summary

Introduction

Crohn's disease (CD) is a chronic inflammatory disease caused by an inappropriate immunological response to the gastrointestinal microbiota in genetically susceptible individuals. Transmural inflammation throughout the gastrointestinal tract causes pain, bleeding, weight loss and diarrhoea; resulting in long-term complications such as stricture and fistula formation. Adequate suppression of inflammation results in mucosal healing, which is associated with improved long-term outcomes.[1,2] Low faecal calprotectin levels are a well validated non-invasive marker of mucosal healing in CD.[3,4,5,6] The faecal calprotectin threshold which defines mucosal healing has not been universally agreed, studies support values in the range of 100300 μg/g,3-8 with a value of 100 μg/g used most frequently.[9] In paediatric CD Weinstein-Nakar et al[7] found faecal calprotectin levels under 100 μg/g were predictive of mucosal and transmural healing

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