The natural history of diverticular disease (DD) is poorly known. Most accredited patho-mechanisms refer to the remodeling of tunica muscularis with fibrosis and loss of colonic compliance. The contribution of oxidative stress begins to be considered.
Main purpose of the project is the advancement of knowledge in the pathophysiology of DD by focusing on the pathogenic role of gender-related oxidative stress.
Recent studies have demonstrated that pre-menopausal woman is protected by the insurgence of complicated DD thank to the contribution of estrogens. These ovarian hormones display beneficial effect able to prevent proliferative, fibrotic and oxidative imbalance. Furthermore, they also positively influence the abundance of mitochondrial DNA and mitochondrial functions.
To improve the knowledge of the specific gender-related oxidative neuromuscular alterations involved in DD, we will perform detailed analysis on human colonic specimens obtained from patients with different stage of disease (i.e . patients undergoing surgery for complicated DD; patients with asymptomatic diverticulosis; patients without diverticula). Analysis will be conducted separately on circular and longitudinal muscle layer.
The oxidative status, the mitochondrial respiratory chain function and biogenesis, collagen imbalance and phenotype will be evaluated on tissue and isolated single cells. Different practical methodology based on immunohistochemistry, biochemical and molecular biology will be utilized, to identify biomarkers and alterations involved.
Main strengths of this project is the systematic methodological approach consistent in the evaluation of homogenous group of patients with different clinical expression of DD. The further advantage is the accuracy placed in studying simultaneously the circular and longitudinal smooth muscle layers of the same patients.
The results will be of great help to pursue tailored-therapeutic algorithm strategies.
The natural history of diverticular disease (DD) is nowadays poorly understood do to both its complexity and to the archaic and not meticulous approach utilized in the past. Much experimental and clinical evidence suggests a multifactorial pathogenesis for DD. However, data that have been collected in the last decades are difficult to interpret because obtained from heterogeneous groups of DD patients not contextualized in the current clinical classification. The peculiarity of the present study is that it has been done in a homogenous group of DD patients.
One of the main highlight of this project lies in its innovation and especially on its methodological accuracy in that a systematic and simultaneous analysis will be conducted on circular and longitudinal smooth muscle layers of the same patients and from patients with different clinical expression of DD. The results obtained with such a methodological approach will end up to determine if DD represents a primary myopathy, as originally hypothesized.
The second innovative strength of the project is the analysis of oxidative stress as the main mechanism involved in DD pathogenesis. The actual therapeutic strategies aimed to modulate gut microbiota, as rifaximin or probiotics, or to reduce mucosal inflammation, as mesalamine, present a relative poor efficacy for the prevention and recurrence of complicated DD and on clinical symptomatic management of uncomplicated DD. The main involvement of oxidative imbalance in DD might open a new pathogenic scenario that may impact therapeutic strategies that have not yet been tested in this disease.
The experimental methodology provides different approach (i.e. immunohistochemistry, biochemical and molecular biology) to study oxidative stress imbalance offering 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 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.