The natural history and pathophysiology of diverticular disease (DD) is still under definition and efforts continued to identify risk factors and to establish relative preventive strategies. The increasing socioeconomic burden of DD has become evident, and with the growth of the population age, this significant economic impact will likely continue to rise. Efforts have been made to identify risk factors to establish relative preventive strategies and to achieve more standardized treatment approaches. Recent evidence showed an increased rate of hospital admissions especially evident among women and younger individuals.
A multifactorial pathogenesis has been hypothesized for uncomplicated and complicated DD with likely different interconnections between luminal and extra-luminal colonic microenvironments that converge on the cornerstone pathophysiological mechanism of diverticula formation and complications that lies in a loss of colonic compliance with increased intraluminal pressure in colonic haustra related to a smooth muscle hypertrophy and remodeling contributing to wall fibrosis. The actual therapeutic strategies aimed to modulate luminal gut microbiota, as rifaximin or probiotics, or aimed to reduce mucosal inflammation, as mesalazine, present a relative poor efficacy both for the prevention of the first AD episode (primary prevention) and its recurrence (secondary prevention). Extra-luminal factors, namely muscle layers and visceral fat, have been studied in less details even if they appear to represent the targets of AD risk and protective factors and to be influenced by age and gender.
In the context of risk stratification, the aim of the present project is to identify possible age- and gender-dependent alterations, mainly focused on extra-luminal factors, that could contribute to DD and discriminate different pathogenic phenotypes that characterize more aggressive and complicated DD.
The economic burden of complicated DD and relative recurrence is exponentially growing with the national cost of diverticulitis-related emergency department visits in the USA, from 2006 to 2013, increased by 105% (Bollom A, Dig Dis Sci 2017, 62:2694). With the growth of the population age, this significant economic burden likely will continue to rise. As for now, the underlying mechanisms and risk factors that contribute to AD and its recurrence still need to be clarified. The actual therapeutic strategies aimed to modulate gut microbiota, as rifaximin or probiotics, or to reduce mucosal inflammation, as mesalazine, present a relative poor efficacy for the prevention of the first AD episode (primary prevention) and its recurrence (secondary prevention). A definite assessment of AD predisposing/protective factors and these relative mechanisms could greatly contribute to better address the best strategy for prevention and really further reduce health cost and improve the management of DD.
Actually, matter of debate is represented by the possible recognition of clinical/biochemical parameters that could be able to identify patients who progress from an uncomplicated to a complicated AD and to monitor the potential development of complications requiring immediate surgical intervention. As for now, the proper timing of surgical treatment of acute diverticulitis remains undetermined with surgical resection probably to be reserved to patients with severe recurrences.
It would be then useful to stratify the patients in order to separate patients that could respond to lifestyle modifications from that with more aggressive disease that could better be treated with surgery. It could be possible that besides age-dependent alterations, different pathogenic phenotypes might characterize more aggressive and complicated DD, such that observed in younger people. A better understanding of the different possible factors involved will be of great help to plan different possible therapeutic strategies.
This project offers the opportunity to study directly on diverticular human tissue the markers of pathogenic phenotypes that characterize more aggressive and complicated DD and to evaluate the possible contribution of age- and gender-dependent alterations. The results could facilitate the identification of biomarkers that could be helpful in the clinical stratifications of the patients. The identifications of markers of aggressive DD phenotypes could deeply improve the understanding of its complicated pathogenesis and will be of great help to pursue tailored-therapeutic algorithm strategies.