Pathophysiology of Crohn's disease inflammation and recurrence

Abstract

Chron's Disease is a chronic inflammatory intestinal disease, first described at the beginning of the last century. The disease is characterized by the alternation of periods of flares and remissions influenced by a complex pathogenesis in which inflammation plays a key role. Crohn's disease evolution is mediated by a complex alteration of the inflammatory response which is characterized by alterations of the innate immunity of the intestinal mucosa barrier together with a remodeling of the extracellular matrix through the expression of metalloproteins and increased adhesion molecules expression, such as MAcCAM-1. This reshaped microenvironment enhances leucocytes migration in the sites of inflammation, promoting a T_H1 response, through the production of cytokines such as IL-12 and TNF-α. IL-12 itself and IL-23 have been targeted for the medical treatment of CD. Giving the limited success of medical therapies, the treatment of the disease is invariably surgical. This review will highlight the role of inflammation in CD and describe the surgical approaches for the prevention of the almost inevitable recurrence.

Keywords: Crohn’s disease; Crohn’s disease recurrence; Intestinal inflammatory diseases; Surgery.

Fig. 1

Immuno-mediated pathogenesis of Crohn’s disease. Crohn’s disease is a multifactorial pathology in which a major role is played by alterations at the level of immunity and inflammation. Innate immunity is involved in terms of defects in the mucous barrier (Mut2 and FUT2 genes) while adaptive immunity relies on a T_H1 lymphocitic response and T_REG cells mediated by cytokines like TNF-α, IL-12, IL-34 and IL-23. The increased migration to the sites of inflammation is also determined by a reshaping of the extra cellular matrix through the action of metalloproteins (MMP-1 and MMP-3) and the overexpression of adhesion molecules such as MAcCAM-1 and integrin α4β4. Finally, also the host pathogen interaction between the intestinal epithelium and the microbiota has been linked to the evolution of the disease. Picture Created with BioRender.com

Fig. 2

Medical treatments of Crohn’s disease. Many medical options for the treatment of Crohn’s disease are available, but still not resolutive. Among them, anti-inflammatory drugs as mesalazine, antibiotics such as fluorochinolones and metronidazole and immunosuppressants (methotrexate). More targeted treatment options are directed towards TNF-α (Infliximab, Adalimumab, Certolizumab) or against integrins (Vedolimumab) and interleukins IL-12 and IL-23 (Ustekinumab). Picture created with BioRender.com