The Multifactorial Etiopathogeneses Interplay of Inflammatory Bowel Disease: An Overview

Abstract

The gastrointestinal system where inflammatory bowel disease occurs is central to the immune system where the innate and the adaptive/acquired immune systems are balanced in interactions with gut microbes under homeostasis conditions. This article overviews the high-throughput research screening on multifactorial interplay between genetic risk factors, the intestinal microbiota, urbanization, modernization, Westernization, the environmental influences and immune responses in the etiopathogenesis of inflammatory bowel disease in humans. Inflammatory bowel disease is an expensive multifactorial debilitating disease that affects thousands new people annually worldwide with no known etiology or cure. The conservative therapeutics focus on the established pathology where the immune dysfunction and gut injury have already happened but do not preclude or delay the progression. Inflammatory bowel disease is evolving globally and has become a global emergence disease. It is largely known to be a disease in industrial-urbanized societies attributed to modernization and Westernized lifestyle associated with environmental factors to genetically susceptible individuals with determined failure to process certain commensal antigens. In the developing nations, increasing incidence and prevalence of inflammatory bowel disease (IBD) has been associated with rapid urbanization, modernization and Westernization of the population. In summary, there are identified multiple associations to host exposures potentiating the landscape risk hazards of inflammatory bowel disease trigger, that include: Western life-style and diet, host genetics, altered innate and/or acquired/adaptive host immune responses, early-life microbiota exposure, change in microbiome symbiotic relationship (dysbiosis/dysbacteriosis), pollution, changing hygiene status, socioeconomic status and several other environmental factors have long-standing effects/influence tolerance. The ongoing multipronged robotic studies on gut microbiota composition disparate patterns between the rural vs. urban locations may help elucidate and better understand the contribution of microbiome disciplines/ecology and evolutionary biology in potentially protecting against the development of inflammatory bowel disease.

Keywords: Crohn’s disease; adaptive/acquired immune system; diet/nutrition; dysbiosis/dysbacteriosis); environment; ethnicity; gastrointestinal disorders; genetics; indeterminate colitis; inflammation; inflammatory bowel disease; innate immune system; intestinal microbiota; rural lifestyle; ulcerative colitis; urbanization.

Figure 1.

(A) Small intestine mucosal immune system landscape. The intestinal epithelial cell (IEC) layers form villi and crypt structures and are composed of different cell lineages. Goblet cells secrete mucus. Paneth cells, found only in the small intestine, can be found at the base of the crypts and are the main secretors of antimicrobial peptides. The base of the crypts also contains the IEC stem cell populations. Immune cells can be found in organized tissue such as Peyer’s patches and throughout the lamina propria. They include macrophages, dendritic cells, intra-epithelial lymphocytes, lamina propria effector T cells, IgA secreting plasma cells, innate lymphoid cells and stromal cells such as fibroblasts. Antigen presenting cells in Peyer’s patches or mesenteric lymph nodes interact with and activate local lymphocytes, which consequently upregulate expression of the integrin α4β7. Such cells then enter the systemic circulation but home towards the gut, in response to chemokine ligands such as CCL25. (B) Colon (large intestine) mucosal immune system. The colon has a much higher bacterial load and a markedly different immune cell composition. The colon contains only crypts, no villi. Also there are no Paneth cells, which mean that enterocytes have a much more important contribution to antimicrobial peptide production. However, there is a high prevalence of goblet cells. The mucus forms dual layers, with a thick largely sterile inner layer and a thinner outer layer. There are no Peyer’s patches. While the immune cell types present are similar to those found in the small intestine it is likely that there may be at least subtle differences. In particular natural killer T cells are found more frequently and have a more significant role in the colon. Adapted with permission from “Recent advances in inflammatory bowel disease: Mucosal immune cells in intestinal inflammation” by Cader and Kaser, Gut 2013, 62, 1653–1664, BMJ Publishing Group Limited [48].

Figure 2.

Intestinal immune system. IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; TGF, transforming growth factor; Th, helper T cell; Treg, regulatory T cell; TCR, T cell receptor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cell; TLR, toll-like receptor; NOD, nucleotide oligomerization domain. Adapted with permission from “Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies” by Kim and Cheon, Immune Netw. 2017, 17, 25–40 [46].

Figure 3.

Biologics regarding therapeutic targets (black: showed benefits; violet: no benefits). APC, antigen presenting cell; IEC, intestinal epithelial cell; TNF, tumor necrosis factor; MHC, major histocompatibility complex; TCR, T cell receptor; JAK, Janus kinase; TGF, transforming growth factor; IL, interleukin; MAdCAM, mucosal vascular addressing cell adhesion molecule. Adapted with permission from “Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies” by Kim and Cheon, Immune Netw. 2017, 17, 25–40 [46].