Association among genetic predisposition, gut microbiota, and host immune response in the etiopathogenesis of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder that affects thousands of people around the world. These diseases are characterized by exacerbated uncontrolled intestinal inflammation that leads to poor quality of life in affected patients. Although the exact cause of IBD still remains unknown, compelling evidence suggests that the interplay among immune deregulation, environmental factors, and genetic polymorphisms contributes to the multifactorial nature of the disease. Therefore, in this review we present classical and novel findings regarding IBD etiopathogenesis. Considering the genetic causes of the diseases, alterations in about 100 genes or allelic variants, most of them in components of the immune system, have been related to IBD susceptibility. Dysbiosis of the intestinal microbiota also plays a role in the initiation or perpetuation of gut inflammation, which develops under altered or impaired immune responses. In this context, unbalanced innate and especially adaptive immunity has been considered one of the major contributing factors to IBD development, with the involvement of the Th1, Th2, and Th17 effector population in addition to impaired regulatory responses in CD or UC. Finally, an understanding of the interplay among pathogenic triggers of IBD will improve knowledge about the immunological mechanisms of gut inflammation, thus providing novel tools for IBD control.

Figure 1. Intestinal immune response in the development of inflammatory bowel disease (IBD). The immune surveillance of the intestine is composed of several cell types, including dendritic cells (DCs), macrophages (MΦ), natural killer (NK) cells, natural killer T (NKT) cells, innate lymphoid cells (ILCs) and intraepithelial lymphocytes (IEL). All these components are altered in some way during IBD. The breakdown of immunological tolerance causes recognition of the intestinal microbiota by the local immune system, activating the inflammatory cascade. The physical/chemical barriers composed by IEL, Paneth cells (PC), microfold cells (M cells) or their products are impaired during the disease and fail to restrain bacterial invasion. In lamina propria (LP), DCs capture and recognize bacterial antigens by projecting their dendrites into the intestinal lumen between intestinal epithelial cells (IEC), while in the Peyer's patches (PP) the antigens become available to DCs through M cells. Afterwards, the LP and PP DCs migrate to the mesenteric lymph nodes (MLN) and present the antigens to naive T cells (Th0). Meanwhile, the PP DCs may also present antigens to Th0 cells located in the follicles. The antigen presentation in the presence of the cytokines interleukin (IL)-12 or IL-23/IL-6/transforming growth factor-beta (TGF-β) leads to polarization of Th0 cells into a pro-inflammatory Th1 or Th17 profile, respectively, which are increased due to low number or function of regulatory T cells (Treg). Th1 and Th17 cells secrete cytokines such as tumor necrosis factor (TNF), interferon γ (IFN-γ), IL17A, IL-17F and IL-21, which in turn contribute to tissue injury and excessive inflammatory response, especially in Crohn's disease. In addition, cytokines such as IL-4, IL-33, IL-25 and thymic stromal lymphopoietin (TSLP) directly or indirectly contribute to the differentiation of Th0 cells into Th2 profile in ulcerative colitis, which may also be under low control of Tregs. The red arrows indicate components that are altered in IBD. The red crosses indicate the absence or reduced function in IBD. It is noteworthy that cytokines and immune mechanisms depicted in the figure are shown according to the scope and information presented in this review. Thus, the mediators described here can also be synthesized from other cell sources as well as other immune pathways may contribute to IBD pathogenesis.