Observational Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 14, 2020; 26(22): 3098-3109
Published online Jun 14, 2020. doi: 10.3748/wjg.v26.i22.3098
Intestinal dysbiosis in pediatric Crohn's disease patients with IL10RA mutations
Ai-Juan Xue, Shi-Jian Miao, Hua Sun, Xiao-Xia Qiu, Sheng-Nan Wang, Lin Wang, Zi-Qing Ye, Cui-Fang Zheng, Zhi-Heng Huang, Yu-Huan Wang, Ying Huang
Ai-Juan Xue, Shi-Jian Miao, Hua Sun, Xiao-Xia Qiu, Sheng-Nan Wang, Lin Wang, Zi-Qing Ye, Cui-Fang Zheng, Zhi-Heng Huang, Yu-Huan Wang, Ying Huang, Department of Gastroenterology, Children’s Hospital of Fudan University, Shanghai 201102, China
Author contributions: Xue AJ, Huang Y, Miao SJ, Sun H, Qiu XX, Wang SN, Wang L, Ye ZQ, Zheng CF, Wang YH, and Huang ZH contributed to study conception and design; Xue AJ, Miao SJ, Sun H, Qiu XX, and Wang SN contributed to data acquisition and interpretation; Xue AJ contributed to the first draft of this article; Xue AJ, Miao SJ, Sun H, Qiu XX, Wang SN, Wang L, Ye ZQ, Zheng CF, Huang ZH, Wang YH, and Huang Y contributed to editing, reviewing, and final approval of the article.
Supported by the Jiujiu Charitable Trust-PIBD China.
Institutional review board statement: This study was approved by the Ethics Board of the Children's Hospital of Fudan University (2017-229, Shanghai).
Informed consent statement: Oral or written informed consent was obtained from the parents or guardians of the children prior to sample collection.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: The dataset is available from the corresponding author at yhuang2019@126.com.
STROBE statement: The authors have read the STROBE Statement, and the manuscript was prepared and revised according to the STROBE Statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Ying Huang, MD, PhD, Doctor, Department of Gastroenterology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China. yhuang2019@126.com
Received: January 6, 2020
Peer-review started: January 6, 2020
First decision: January 19, 2020
Revised: March 30, 2020
Accepted: May 28, 2020
Article in press: May 28, 2020
Published online: June 14, 2020
Research background

Several studies have employed animal models to explore the association between microbiota and interleukin (IL)10 signaling; however, limited information is available about the human microbiome. To the best of our knowledge, this is the first report of microbial dysbiosis in this sub-population of inflammatory bowel diseases (IBD) patients with IL10RA mutations.

Research motivation

Patients with IL10RA mutations had early disease onset and experienced more severe colitis. Recent studies have revealed an association between host genetic variants and gut microbial changes; in addition, the underlying interactions were found to contribute to the onset and severity of IBD. However, the role of microbiota in patients with infantile-onset IBD who have IL10 signaling defects is not clear. Our findings may facilitate further attempts to develop microbial therapeutics in these patients.

Research objectives

We aimed to characterize the microbiome in patients with IL10RA mutations and to explore the association between gut dysbiosis and disease severity. We observed a reduced diversity and increased variability of gut microbiome in patients with IL10RA mutations. We also explored the association between intestinal dysbiosis and the disease severity in these patients. Further studies should focus on the precise role of the microbiota in the etiology of IBD in terms of host genetic susceptibility; this constitutes an attractive target for a given host genome.

Research methods

Fecal samples were collected from patients who were diagnosed with loss-of-function mutations in the IL10RA gene. Age-matched volunteer children were recruited as healthy controls. Patients with Crohn's disease (CD) were used as disease controls to standardize the antibiotic exposure. Microbial DNA was extracted from the fecal samples. All analyses were based on the 16S rRNA gene sequencing data.

Research results

Seventeen patients with IL10RA mutations, 17 patients with pediatric CD, and 26 healthy children were included. Both patients with IL10RA mutations and those with CD exhibited a reduced diversity of gut microbiome with increased variability. The relative abundance of Firmicutes was substantially increased in the IL10RA group. On further comparison of the relative abundance of taxa between patients with IL10RA mutations and healthy children, 13 taxa showed significant differences. The IL10RA-specific dysbiosis indices exhibited a significant positive correlation with weighted pediatric CD activity index and simple endoscopic score for CD. This observational study was a pilot effort to characterize IL10RA-specific microbial alterations and does not permit any causal inferences.

Research conclusions

In patients with IL10RA mutations and early onset IBD, gut dysbiosis showed a moderate association with disease severity. In this study, clinical variables of IL10RA-deficient patients (such as disease course) were linked with changes in the stool microbiome, which implies potential clinical relevance of the changes in microbial populations.

Research perspectives

16S rRNA sequencing has its limitations; shotgun metagenomic sequencing with a higher taxonomic resolution may capture microbial shifts in full complexity. Further investigations may be warranted to identify the shifts in functional or metabolic capabilities of the microbiome. Prospective trials enrolling larger treatment-naive populations at high risk with longitudinal follow-up would provide insights into the role of microbes in the onset of inflammation.