Crohn's Disease-Associated Pathogenic Mutation in the Manganese Transporter ZIP8 Shifts the Ileal and Rectal Mucosal Microbiota Implicating Aberrant Bile Acid Metabolism.
Crohn's Disease-Associated Pathogenic Mutation in the Manganese Transporter ZIP8 Shifts the Ileal and Rectal Mucosal Microbiota Implicating Aberrant Bile Acid Metabolism.
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DOI：
10.1093/ibd/izae003
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发表时间：
2024-01
影响因子：
4.9
通讯作者：
Kristi Briggs;Vartika Tomar;Nicholas Ollberding;Y. Haberman;A. Bourgonje;Shixian Hu;Lara Chaaban;L. Sunuwar;R. Weersma;L. Denson;Joanna Melia
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作者：
Kristi Briggs;Vartika Tomar;Nicholas Ollberding;Y. Haberman;A. Bourgonje;Shixian Hu;Lara Chaaban;L. Sunuwar;R. Weersma;L. Denson;Joanna Melia
背景：锰转运蛋白ZIP8(A391T；rs13107325)的致病突变增加了克罗恩病的风险。ZIP8调节锰的动态平衡，鉴于宿主和驻留微生物对金属的共同需求，人们对ZIP8 A391T载体中微生物群的变化非常感兴趣。尽管回肠疾病与ZIP8A391T之间存在关联，但先前的研究尚未对回肠微生物组进行检查。方法采用儿科风险分层研究(RISK)队列，对回肠和直肠黏膜的16S核糖体RNA基因测序数据进行二次分析，以研究ZIP8 A391T携带者状态与微生物区系组成的关系。结果在ZIP8A391T携带者回肠黏膜中发现定位于韦氏杆菌的序列变异减少。先前的人体研究已经证明了韦洛氏菌对胆汁酸丰度的敏感性。因此，我们假设胆汁酸稳态在ZIP8A391T携带者中受到不同的调节。使用ZIP8 A391T的小鼠模型，我们证明了肝脏和粪便中总胆汁酸的增加和成纤维细胞生长因子15(Fgf15)信号的减少，这与我们的假设一致。我们证实了1000IBD队列中FGF19的异常调节，发现患有回结肠克罗恩病的ZIP8 A391T携带者血浆FGF19水平较低。结论在寻找针对克罗恩病患者的基因特异性治疗方案时，这些数据建议以ZIP8A391T携带者中的FGF19通路为靶点。胆汁酸代谢异常可能先于克罗恩病的发展，并优先研究锰稳态、胆汁酸代谢和信号转导与复杂的回肠克罗恩病之间的相互作用。
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.