Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Inflamm Bowel Dis. 2024 Aug 1;30(8):1379-1388. doi: 10.1093/ibd/izae003.
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.
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.
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.
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.
锰转运蛋白 ZIP8（A391T；rs13107325）的致病性突变会增加克罗恩病的风险。ZIP8 调节锰稳态，鉴于宿主和常驻微生物之间对金属的共同需求，ZIP8 A391T 携带者的微生物组发生改变引起了广泛关注。尽管 ZIP8 A391T 与回肠疾病之间存在关联，但先前的研究并未检查回肠微生物组。
在这里，我们使用儿科风险分层研究 (RISK) 队列对来自回肠和直肠黏膜的 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群落组成之间的关联。
我们发现，ZIP8 A391T 携带者回肠黏膜中映射到韦荣球菌的序列变异减少。先前的人类研究表明，韦荣球菌对胆汁酸丰度敏感。因此，我们假设 ZIP8 A391T 携带者的胆汁酸稳态存在差异调节。使用 ZIP8 A391T 的小鼠模型，我们证明肝脏和粪便中的总胆汁酸增加，成纤维细胞生长因子 15 (Fgf15) 信号降低，这与我们的假设一致。我们在 1000IBD 队列中证实了 FGF19 的失调，发现具有回结肠克罗恩病的 ZIP8 A391T 携带者的血浆 FGF19 水平较低。
在寻找克罗恩病患者的特定基因型治疗范例的过程中，这些数据表明针对 ZIP8 A391T 携带者的 FGF19 途径。异常的胆汁酸代谢可能先于克罗恩病的发生，并优先研究锰稳态、胆汁酸代谢和信号转导以及复杂的回肠克罗恩病之间的相互作用。
