@article{b2aeda883f0a4c629828fa837c009c9f,
title = "Crohn's Disease-Associated Pathogenic Mutation in the Manganese Transporter ZIP8 Shifts the Ileal and Rectal Mucosal Microbiota Implicating Aberrant Bile Acid Metabolism",
abstract = "Background: A pathogenic mutation in the manganese transporter ZIP8 (A391T; rs13107325) increases the risk of Crohn's disease. ZIP8 regulates manganese homeostasis and given the shared need for metals between the host and resident microbes, there has been significant interest in alterations of the microbiome in carriers of ZIP8 A391T. Prior studies have not examined the ileal microbiome despite associations between ileal disease and ZIP8 A391T. Methods: Here, we used the Pediatric Risk Stratification Study (RISK) cohort to perform a secondary analysis of 16S ribosomal RNA gene sequencing data obtained from ileal and rectal mucosa to study associations between ZIP8 A391T carrier status and microbiota composition. Results: We found sequence variants mapping to Veillonella were decreased in the ileal mucosa of ZIP8 A391T carriers. Prior human studies have demonstrated the sensitivity of Veillonella to bile acid abundance. We therefore hypothesized that bile acid homeostasis is differentially regulated in carriers of ZIP8 A391T. Using a mouse model of ZIP8 A391T, we demonstrate an increase in total bile acids in the liver and stool and decreased fibroblast growth factor 15 (Fgf15) signaling, consistent with our hypothesis. We confirmed dysregulation of FGF19 in the 1000IBD cohort, finding that plasma FGF19 levels are lower in ZIP8 A391T carriers with ileocolonic Crohn's disease. Conclusions: In the search for genotype-specific therapeutic paradigms for patients with Crohn's disease, these data suggest targeting the FGF19 pathway in ZIP8 A391T carriers. Aberrant bile acid metabolism may precede development of Crohn's disease and prioritize study of the interactions between manganese homeostasis, bile acid metabolism and signaling, and complicated ileal Crohn's disease.",
keywords = "bile acids, Crohn's disease, manganese, Veillonella, ZIP8",
author = "Kristi Briggs and Vartika Tomar and Nicholas Ollberding and Yael Haberman and Bourgonje, {Arno R.} and Shixian Hu and Lara Chaaban and Laxmi Sunuwar and Weersma, {Rinse K.} and Denson, {Lee A.} and Melia, {Joanna M.P.}",
note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Published by Oxford University Press on behalf of Crohn's Colitis Foundation. All rights reserved.",
year = "2024",
month = aug,
day = "1",
doi = "10.1093/ibd/izae003",
language = "אנגלית",
volume = "30",
pages = "1379--1388",
journal = "Inflammatory Bowel Diseases",
issn = "1078-0998",
publisher = "Oxford University Press",
number = "8",
}