Dysbiotic microbiota interactions in Crohn's disease

Abstract

Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects. The purpose of this review is to delve into the modification of the gut microbiota cluster network during CD progression and to discuss how this shift compromises the gut barrier integrity, granting the translocation of microbes and their products. We then complete the scope of the review by retracing gut microbiota dysbiosis interactions with the main pathophysiologic factors of CD, starting from the host's genetic background to the immune inflammatory and fibrotic processes, providing a standpoint on the lifestyle/exogenous factors and the potential benefits of targeting a specific gut microbiota.

Keywords: Crohn’s disease; bacterial translocation; dysbiosis; fibrosis; inflammation; microbiota.

Figure 1.

Interaction of microbiome, intestinal barriers, and translocating bacteria in healthy conditions and active CD. Eubiosis is characterized by stable cluster networks and full species richness which in concert with fully active healthy epithelial and secretory barriers (namely normal intestinal permeability) and normal immune responses to physiological bacterial translocation is the basis for stable remission. The proposed hypothetical scenario on pathophysiology of Crohn’s disease being at least partly primarily due to dysbiosis and loss of cluster network induced in individuals with genetic pre-disposition and/or by lifestyle/exogenous factors is visualized at the bottom. With increasing intestinal hyperpermeability and exaggerated pro-inflammatory immune response inflammation perpetuates fueling into a vitious circle of pathological bacterial translocation and further aggravation of dysbiosis. Thus, the goal of treatment put forward is restoration of eubiosis being the basis for stable remission or if not achieved for recurrence

Figure 2.

Tolerogenic microenvironment during microbiota eubiosis in healthy intestinal tissue in Crohn’s disease. In healthy colonic tissue, the gut barrier is made up of a thick mucus layer containing mucin produced by Goblet cells, sIgA produced by plasma cells, AMPs secreted by epithelial cell, and the cellular immune system (ILCs, MAIT cells, NKTs, macrophages, dendritic cells and T cells), mainly organized in Peyer’s patches. DCs and macrophages produce anti-inflammatory mediators that promote iTreg Foxp3+ expansion. Moreover, the eubiotic microbiota contributes to reduction of proinflammatory substrates induction (reduced activation of NFkB in epithelial cells) and produces SCFAs and subsequent inhibition of proinflammatory (Th1 and Th17) cell lineage activation. iTregs together with eubiotic microbiota are responsible of the predominant immunotolerance in intestinal tissue microenvironment, while ILC-derived IL-22 contributes to keep gut barrier integrity. sIgA, soluble IgA; AMPs, antimicrobial peptides; ILC, innate lymphoid cells; MAIT, mucosal associated invariant T cell; iNKT, invariant Natural Killer T cell; DC, dendritic cell; iTreg, induced regulatory T cells; NFkB, nuclear factor kappa-B; Th, T helper cell; SCFAs, short chain fatty acids, PMN, polymorphonuclear cells; TLRs, Toll-like receptors; NLRs, Nod-like receptors; IL, interleukin; RA, retinoic acid; TGF-β, transforming growth factor-β

Figure 3.

Immunogenic microenvironment during microbiota dysbiosis in inflamed intestinal tissue in Crohn’s disease. Crohn’s disease triggers induce a proinflammatory response orchestrated by tissue resident APCs activation, driving neutrophil recruitment, oxidative damage, the expansion of Th1 and Th17 populations and suppression of the regulatory T cell milieu. This environment favors the access of Tc and Trm cells to the damaged tissue. Innate lymphoid subpopulations cooperate in maintaining this immunogenic profile. Changes in gut microbiota composition and the reduction of SCFAs production contribute to the loss of tight junctions and the decrease of AMPs in the epithelial barrier, favoring an increased permeability (“leaky gut”). sIgA, soluble IgA; AMPs, antimicrobial peptides; ILC, innate lymphoid cells; MAIT, mucosal associated invariant T cell; iNKT, invariant Natural Killer T cell; DC, dendritic cell; iTreg, induced regulatory T cells; NFkB, nuclear factor kappa-B; Th, T helper cell; SCFAs, short-chain fatty acids, PMN, polymorphonuclear cells; TLRs, Toll-like receptors; Tc, T cytotoxic cell; NLRs, Nod-like receptors; IL, interleukin; ROs, reactive oxygen species; RNs, reactive nitrogen species; NETs, neutrophil extracellular traps; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-gamma; CCL, chemokine ligand; CCR, chemokine receptor; PBT, pathological bacterial translocation; PAMPs; pathogen-associated molecular patterns; AIEC, adherent invasive Escherichia coli.

Figure 4.

Intestinal fibrosis development during microbiota dysbiosis in Crohn’s disease. Mediators generated during sustained inflammation and continued PBT favored by gut barrier distortion induce myofibroblasts activation and extracellular matrix production with deposition of fibrinogen and collagen. Intestinal epithelial cells undergo EMT after activation of TLR-4 and contribute to the fibrotic context by inducing TGF-β. PBT, pathological bacterial translocation; TLRs, Toll-like receptors; ECM, extracellular matrix; EMT, epithelial to mesenchymal transition; ROs, reactive oxygen species; RNs, reactive nitrogen species; MCP-1, Monocyte Chemoattractant Protein-1; IL, interleukin; TGF-β, transforming growth factor-beta; SPF, Specific-pathogen-free; EIEC, Enteroinvasive Escherichia coli.