FIGURE 1.

Multifactorial pathophysiology of canine IBD. (A) In the normal intestinal mucosa, Toll-like receptors (TLRs) sample pathogen-associated molecular patterns (PAMPs) from commensals in the intestinal lumen, which send signals to naïve T cells to differentiate primarily into T regulatory cells, which produce anti-inflammatory cytokines, such as TGF-beta and IL-10. (B) In the case of canine IBD, microbial dysbiosis drives the messaging toward a pro-inflammatory pathway of Th cell differentiation, resulting in the production of pro-inflammatory cytokines, mainly IL-1beta. In addition, mutations in pattern recognition receptors, such as TLR5, result in hyper-responsiveness to flagellin. Since the dysbiosis in canine IBD is characterized by an increase in Enterobacteriaceae (which express flagellin), this will further increase pro-inflammatory responses of the mucosa. Moreover, the inflammatory cytokines will lead to architectural changes in epithelial cells, such as increased leakage through tight junction, and therefore increased permeability. This in turn will result in more bacteria breaching the mucosal barrier, therefore leading to a self-enhancing circle of inflammation. IL-4: Interleukin 4, IFN: Interferon, STAT3: Signal Transducer And Activator Of Transcription 3, IL-23: Interleukin-23, IL-12: Interlleukin-12, IL-27: Interleukin-27, TGF-beta: Tissue growth factor-beta, IL-10: Interleukin-10, IL-beta: Interleukin-beta.