Genetic and transcriptomic landscape of colonic diverticulosis.

OBJECTIVE: Colonic diverticulosis is a prevalent condition among older adults, marked by the presence of thin-walled pockets in the colon wall that can become inflamed, infected, haemorrhage or rupture. We present a case-control genetic and transcriptomic study aimed at identifying the genetic and cellular determinants underlying this condition and the relationship with other gastrointestinal disorders. DESIGN: We conducted DNA and RNA sequencing on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We investigated variation in the transcriptome associated with diverticulosis and further integrated this variation with single-cell RNA-seq data from the human intestine. We also integrated our expression quantitative trait loci with genome-wide association study using Mendelian randomisation (MR). Furthermore, a Polygenic Risk Score analysis gauged associations between diverticulosis severity and other gastrointestinal disorders. RESULTS: We discerned 38 genes with differential expression and 17 with varied transcript usage linked to diverticulosis, indicating tissue remodelling as a primary diverticula formation mechanism. Diverticula formation was primarily linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1 and TNFSF13, with potential causal effects on diverticulosis. Notably, ENTPD7 upregulation was confirmed in diverticulosis cases. Additionally, diverticulosis severity was positively correlated with genetic predisposition to diverticulitis. CONCLUSION: Our results suggest that tissue remodelling is a primary mechanism for diverticula formation. Individuals with an increased genetic proclivity to diverticulitis exhibit a larger numbers of diverticula on colonoscopy.

A Systematic Review of Epidemiology and Outcomes Associated with Local Surgical and Intersphincteric Ligation Procedures for Complex Cryptoglandular Fistulas.

INTRODUCTION: This systematic literature review (SLR) assessed incidence/prevalence of cryptoglandular fistulas (CCF) and outcomes associated with local surgical and intersphincteric ligation procedures for CCFs. METHODS: Two trained reviewers searched PubMed and Embase for observational studies evaluating the incidence/prevalence of cryptoglandular fistula and clinical outcomes of treatments for CCF after local surgical and intersphincteric ligation procedures for CCF. RESULTS: In total 148 studies met a priori eligibility criteria for all cryptoglandular fistulas and all intervention types. Of those, two assessed incidence/prevalence of cryptoglandular fistulas. Eighteen reported clinical outcomes of surgeries of interest in CCF and were published in the past 5 years. Prevalence was reported as 1.35/10,000 non-Crohn's patients, and 52.6% of non-IBD patients were found to progress from anorectal abscess to fistula over 12 months. Primary healing rates ranged from 57.1% to 100%; recurrence occurred in a range of 4.9-60.7% and failure in 2.8-18.0% of patients. Limited published evidence suggests postoperative fecal incontinence and long-term postoperative pain were rare. Several of the studies were limited by single-center design with small sample sizes and short follow-up durations. DISCUSSION: This SLR summarizes outcomes from specific surgical procedures for the treatment of CCF. Healing rates vary according to procedure and clinical factors. Differences in study design, outcome definition, and length of follow-up prevent direct comparison. Overall, published studies offer a wide range of findings with respect to recurrence. Postsurgical incontinence and long-term postoperative pain were rare in the included studies, but more research is needed to confirm rates of these conditions following CCF treatments. CONCLUSION: Published studies on the epidemiology of CCF are rare and limited. Outcomes of local surgical and intersphincteric ligation procedures show differing success and failure rates, and more research is needed to compare outcomes across various procedures. (PROSPERO; registration number CRD42020177732).