|Figure 1: We demonstrate that in the intestines, where PXR is expressed in intestinal epithelial
cells in a crypt-villus gradient (apical IEC), in homeostasis, dietary tryptophan-derived
bacterial metabolites (i.e. indole-3-propionic acid or IPA) tonically activate PXR
and induce a down-regulation of TLR4, and its downstream signaling pathway. This results
in modulating the abundance of TNF-α, which in turn modulates intestinal barrier function
(i.e. permeability). In the context of preserved indole concentrations, loss of PXR
(often observed in some Crohn's ileitis and UC) will promote the inflammatory response.
In corollary, with excess loss of dietary modulators (e.g., tryptophan/IPA), and/or
specific indole metabolizing bacteria (e.g., antibiotics), there is increased permeability
exacerbating underlying inflammatory pathology. In this model, restitution of signaling
homeostasis, either by reconstituting intestinal loss of PXR or indole-metabolite
producing bacteria and/or PXR activating bacterial metabolites (i.e. IPA via tryptophan
catabolism), could result in abrogating pro-inflammatory signals and loss of barrier
permeability in the context of intestinal inflammation.