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Background & Aims: Diverticulitis is the chronic inflammation of diverticula. Whether the pathophysiology of earlier-onset patients differs from later-onset patients is unknown. We profiled the colonic transcriptomes of these two patient populations to gain insight into the molecular underpinnings of diverticulitis. Methods: We conducted deep RNA sequencing (RNA-seq) on colonic segments surgically resected from earlier-onset (<42 years old, n=13) and later-onset (>65 years old, n=13) diverticulitis patients. We used bioinformatic approaches to cluster the patients based on the relationship of differentially expressed genes and to inform on the molecular pathways that segregated the clusters. Results: Principal component analysis identified three patient clusters; diverticulitis later-onset (DVT-LO), diverticulitis mixed-onset (DVT-MO), and diverticulitis earlier-onset (DVT-EO). The patients comprising DVT-EO, which was the majority of earlier-onset patients, displayed increased expression of anti-viral response genes. This finding was confirmed using an independent weighted co-expression network analysis (WGCNA) of differentially expressed genes. Conclusions: We found that the majority of patients with earlier-onset disease contained elevated expression of host genes involved in the anti-viral response. Thus, susceptibility to a viral pathogen may offer one explanation why some individuals develop diverticulitis at an earlier age. [ABSTRACT FROM AUTHOR]

Individuals with diverticula or outpouchings of the colonic mucosa and submucosa through the colonic wall have diverticulosis, which is usually asymptomatic. In 10-25% of individuals, the diverticula become inflamed, resulting in diverticulitis. Very little is known about the pathophysiology or gene regulatory pathways involved in the development of diverticulitis. To identify these pathways, we deep sequenced RNAs isolated from full-thickness sections of sigmoid colon from diverticulitis patients and control individuals. Specifically for diverticulitis cases, we analyzed tissue adjacent to areas affected by chronic disease. Since the tissue was collected during elective sigmoid resection, the disease was in a quiescent state. A comparison of differentially expressed genes found that gene ontology (GO) pathways associated with the immune response were upregulated in diverticulitis patients compared with nondiverticulosis controls. Next, weighted gene coexpression network analysis was performed to identify the interaction among coexpressed genes. This analysis revealed RASAL3, SASH3, PTPRC, and INPP5D as hub genes within the brown module eigengene, which highly correlated (r = 0.67, P = 0.0004) with diverticulitis. Additionally, we identified elevated expression of downstream interacting genes. In summary, transcripts associated with the immune response were upregulated in adjacent tissue from the sigmoid colons of chronic, recurrent diverticulitis patients. Further elucidating the genetic or epigenetic mechanisms associated with these alterations can help identify those at risk for chronic disease and may assist in clinical decision management. [ABSTRACT FROM AUTHOR]

Background & Aims: Both genetic and environmental factors contribute to the development and persistence of ulcerative colitis (UC). As supported by differential responses to therapy, multiple subclasses of disease likely comprise UC. We reasoned that profiling the colonic transcriptomes may offer one approach to molecular subtype UC. Methods: We conducted RNA-sequencing (RNA-seq) on full-thickness colonic tissues from 26 UC patients undergoing colectomy. Hierarchal clustering from transcriptomic data identified disease subsets. Subsets were characterized using differential gene expression analysis, cell type deconvolution, and network analysis. Results: We identified two UC subsets that were distinguished by 957 differentially expressed genes. Cluster 1 was enriched in genes associated with intestinal epithelial cell (IEC) differentiation, while cluster 2 was enriched in genes associated with epithelial-to-mesenchymal transition (EMT) and inflammatory responses. Cluster 1 was associated with an extended time from diagnosis to colectomy [hazard ratio = 0.45 (95% CI: 0.14-0.88); p=0.03]. Of cluster 1 genes, elevated MUC5B, MUC4, and MUC2 expression displayed the strongest correlation with increased time to surgery [hazard ratio = 0.37 (95% CI: 0.11-0.61); p=0.0044]. Conclusions: Our transcriptome analysis indicates that UC can be sub-classified into at least two molecular signatures. We found that elevated mucin gene expression correlated with prolonged time to colectomy following diagnosis. This work identified MUC5B, MUC4, and MUC2 as potential prognostic indicators of disease severity, as reflected in time to surgery after diagnosis. [ABSTRACT FROM AUTHOR]