Gut microbiota and IBD: causation or correlation?

Abstract

A general consensus exists that IBD is associated with compositional and metabolic changes in the intestinal microbiota (dysbiosis). However, a direct causal relationship between dysbiosis and IBD has not been definitively established in humans. Findings from animal models have revealed diverse and context-specific roles of the gut microbiota in health and disease, ranging from protective to pro-inflammatory actions. Moreover, evidence from these experimental models suggest that although gut bacteria often drive immune activation, chronic inflammation in turn shapes the gut microbiota and contributes to dysbiosis. The purpose of this Review is to summarize current associations between IBD and dysbiosis, describe the role of the gut microbiota in the context of specific animal models of colitis, and discuss the potential role of microbiota-focused interventions in the treatment of human IBD. Ultimately, more studies will be needed to define host-microbial relationships relevant to human disease and amenable to therapeutic interventions.

Figures

Figure 1. Colonic inflammation in IBD and link to the gut microbiota

Colonic inflammation stimulates IFNγ production, which generates reactive oxygen species (ROS) by phagocytic innate immune cells. These radicals eventually form products for anaerobic respiration. Facultative anaerobes utilize these products to outgrow, causing decreases in bacterial diversity. The dysbiotic microbiota might further encourage the outgrowth of fungi, especially Candida, which can in turn exacerbate inflammation via chitin and β -glucan antigen-presenting cell (APC) activation of the type 1 T helper (TH1) pathway. Similarly, the dysbiotic microbiota are associated with increased bacteriophage richness and abundance, which can in turn modify the bacterial microbiota via gene transfer. DMSO, dimethyl sulfoxide; TMAO, trimethylamine N-oxide.

Figure 2. Pro-inflammatory and anti-inflammatory effects of the gut gut microbiota

Pathogenic microorganisms are sensed via Toll-like receptors (TLR) and NOD-like receptors (NLR) on innate immune cells (dendritic cells (DCs), macrophages), Paneth cells and epithelial cells. This process leads to differentiation of type 17 T helper (TH17) cells and type 3 innate lymphoid cells (ILC3s) under the influence of transforming growth factor (TGF)β, IL-6 and IL-1β, and activation of the IL-23 inflammatory pathway. TLR and NLR signalling also leads to NF-κB and inflammasome activation, secretion of pro-inflammatory cytokines, and type 1 T helper (TH1) cell activation. Ultimately, these inflammatory responses lead to epithelial damage, loss of mucus-secreting goblet cells, and bacterial translocation, which further stimulates the inflammatory response. Anti-inflammatory bacteria are also sensed via TLR and NLR; however, this process leads to regulatory T (Treg)-cell differentiation via TGFβ, retinoic acid (RA) and the aryl hydrocarbon receptor (AhR) signalling. Treg cells exert their immunoregulatory function via IL-10 secretion. Moreover, NF-κB and inflammasome activation lead to secretion of anti-apoptotic factors and antimicrobial peptides, alongside recruitment of stromal and myeloid cells necessary for epithelial repair. Finally, IgA (produced by B cells) prevents colitogenic bacteria from penetrating the mucus layer.