Crohn's Disease-Associated Pathogenic Mutation in the Manganese Transporter ZIP8 Shifts the Ileal and Rectal Mucosal Microbiota Implicating Aberrant Bile Acid Metabolism

Kristi Briggs, Vartika Tomar, Nicholas Ollberding, Yael Haberman, Arno R. Bourgonje, Shixian Hu, Lara Chaaban, Laxmi Sunuwar, Rinse K. Weersma, Lee A. Denson, Joanna M.P. Melia*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1379-1388
Number of pages10
JournalInflammatory Bowel Diseases
Volume30
Issue number8
DOIs
StatePublished - 1 Aug 2024

Funding

FundersFunder number
Johnson and Johnson
Dr Maria Oliva-Hemker
Biostatistics, Epidemiology and Data Management Core at Johns Hopkins
School of Medicine, Johns Hopkins University
American Gastroenterological Association
Seres Pharmaceutical
Samenwerkende Gezondheidsfondsen
Pfizer
National Institutes of HealthDK114478
National Institutes of Health
Johns Hopkins Specialized Center for Research Excellence in Sex DifferencesU54AG062333
Doris Duke Early Clinician2020147
Crohn's and Colitis FoundationLSHM18057-SGF
Crohn's and Colitis Foundation

    Keywords

    • bile acids
    • Crohn's disease
    • manganese
    • Veillonella
    • ZIP8

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