M. U. Mallicote1, O. Escobar1, C. Gayer1 1Children’s Hospital Los Angeles,Los Angeles, CA, USA
Introduction: Bile acids are known to stimulate the Farnesoid X receptor (FXR) pathway in the intestines; however, there are discrepancies in the literature about the effects of FXR activation on the intestinal barrier. FXR activation has been reported to decrease gut permeability in chronic injury models, although FXR activation is known to decrease intestinal cell proliferation. Given these inconsistencies, we hypothesize that FXR activation is detrimental to the intestinal barrier in an acute injury model.
Methods: In vivo, wild-type (WT) and global FXR knock-out (FXR-KO) mice were injected with lipopolysaccharide (LPS) or saline via intra-peritoneal route to induce intestinal injury and gavage-fed FITC-dextran. Animals were sacrificed at 16 hours. Barrier function was assessed by serum FITC levels and mRNA expression of IL-6, IL-10, TNF, and IL1b was assessed by RT-PCR.
Results: Barrier permeability in WT mice was significantly increased in LPS versus saline controls. This effect, however, was significantly attenuated in FXR-KO mice. LPS increased FXR mRNA expression in WT but not in FXR-KO. Of the cytokines tested, only TNF was elevated in both WT and FXR-KO mice injected with LPS versus saline controls. FXR-KO mice injected with LPS also showed highly elevated levels of IL-6 and IL1b whereas the WT mice did not. Interestingly, the FXR-KO mice also exhibited high levels of IL-10 an anti-inflammatory cytokine.
Conclusions: In WT mice, LPS-induced inflammation mainly leads to elevated levels of TNF. In FXR-KO mice there is elevation of IL-6, TNF, and IL1b, however intestinal barrier damage appears to be attenuated. Of note, in FXR-KO mice there was elevation of the anti-inflammatory cytokine IL-10 which may be the cause of the attenuated barrier damage we are seeing. Determining why the absence of FXR leads to IL-10 induction may lead to the development of novel therapies for regulating the intestinal epithelium during acute injury and may help prevent gut-origin sepsis.