Systematic Review: Outcome Prediction in Acute Severe Ulcerative Colitis.

Background and Aims: Approximately 1 in 4 patients with ulcerative colitis experiences a severe exacerbation of disease requiring hospitalization, termed acute severe ulcerative colitis (ASUC). These episodes pose a major burden on patients with ulcerative colitis and early prediction of their outcomes based on clinical data is crucial to optimize therapy. Methods: A systematic review was performed using Embase and Medline for articles between 2000 and 2023. Studies obtained from the databases were uploaded on Covidence for screening by 2 independent reviewers. Quality appraisal for each study was done using the Critical Appraisals Skills Program depending on study design. Results: A total of 48 eligible studies were included in the review. The key predictors of ASUC identified in this review included clinical, endoscopic, and radiographic biomarkers, which were summarized. The main outcomes assessed in the studies were intravenous corticosteroid failure, need for rescue therapy, and need for colectomy. Score-based predictions and some novel markers were also included in the results. Conclusion: Utilization of evidence-based predictors of outcome in ASUC could serve as a powerful tool in customizing therapeutic measures and a step forward toward personalized patient care. Despite promising candidates, there remains a significant opportunity to identify and test additional clinical and laboratory-based predictors, especially early in the hospitalization and as the clinical practice and medical therapies evolve.

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

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.

A pathogenic mutation in the manganese transporter ZIP8 A391T increases the risk of ileal Crohn's disease. Analysis of the ileal microbiome revealed decreased bile acid­sensitive microbes. Animal and human studies confirmed aberrant bile acid signaling ZIP8 A391T carriers.