TNFSF15 Polymorphism and Diverticulitis of the Colon: Another Step Toward a More Tailored Approach in a Complex Disease
In their excellent article, Connelly et al1 showed that single nuclear polymorphism rs7848647 of the TNFSF15 gene is strongly linked to complicated diverticulitis, advising the use of this marker in surgical decision-making. The meaning of this discovery deserves an in-depth analysis for its possible influence on clinical practice.
The TNFSF15 gene plays an important role in modulating the adaptive immune response. In particular, in humans it is linked to the occurrence of mucosal inflammation, because its expression is correlated with severity of gut mucosal inflammation as its transcript was several times more abundant in RNA from mucosal biopsies taken from inflamed areas than in those taken from noninflamed areas in Crohn disease (CD).2 Significantly, polymorphism of this gene seems to be overexpressed in CD but not in ulcerative colitis.3
Discovering the link between TNFSF15 gene polymorphism and complicated diverticulitis seems to be the last piece toward completing the puzzle of inflammation in diverticular disease. In fact, several inflammatory findings in diverticular disease are now clearly identified: it shows significant microscopic inflammatory infiltrate, linked to the severity of the disease4; it shows enhanced expression of TNFα5; it shows increased neuropeptides expression in mucosal biopsies after acute diverticulitis, which may reflect resolved prior acute inflammation and persistent chronic inflammation6; both persisting endoscopic and histological inflammation have been identified as significant risk factors for diverticulitis recurrence.7
Further data support the hypothesis that complicated diverticular disease, namely diverticulitis, resembles CD: both diseases can develop stenosis and fistulas; both diseases show significant fibrosis. In particular, both diseases show unbalanced expression of matrix metalloproteinases and their inhibitors’ (TIMPs) protein expression in the bowel wall, with enhanced expression of matrix metalloproteinases and significant upregulation of TIMPs.8; both show imbalance of the framework TNFα/SD1/bFGF.9 This framework promotes correct tissue reparation after damage: if there is an imbalance between the 3 molecules, low-grade inflammation may evolve toward full-thickness fibrotic intestinal wall; finally, both diseases show polymorphism of the TNFSF15 gene.1–3
Since this surprising similarity, the clinical approach has to be reconsidered bearing in mind the lesson of CD. Current guidelines recommend an individualized approach in advising elective sigmoid colectomy after recovery from uncomplicated acute diverticulitis. Moreover, they recommend that elective colectomy should typically be considered after the patient recovers from an episode of complicated diverticulitis, and also that routine elective resection based on young age (<50 years) should be no longer recommended.10 But looking at the aforementioned data, our medical or surgical approach to diverticulitis should be more tailored. If we have an older patient, medical treatment to prevent diverticulitis recurrence can still be recommended even if he already experienced 2 or 3 episodes of uncomplicated diverticulitis; but if we have a younger patient, with imbalance of the framework TNFα/SD1/bFGF, and polymorphism rs7848647 of the TNFSF15 gene, the patient namely has a higher risk of developing fibrosis and therefore complications in the future, elective surgery has to be at least considered even if the patient is at the first episode of uncomplicated diverticulitis.