In addition, FGF15/19 induces hepatocyte proliferation [34] and has been recently identified as an important mediator of liver regeneration after liver resection surgery [35]. Here we show that Salmonella infection disturbs the homeostasis of the FGF15/19-FGFR4 axis by down-regulating the expression of Fgf15, Fgfr4 and Klb. To our knowledge, these results constitute the first demonstration of a

pathophysiological effect of bacterial infections over the FGF15/19-FGFR4 endocrine axis. Infection modified both the ileal expression of Fgf15 and the components of its hepatic receptor, which suggests a significant functional shutdown of the pathway. Our data rules out a direct cytopathic effect of bacteria over ileal enterocytes selleckchem as the major cause of Fgf15 mRNA reductions. Instead, it is apparent that the decline in Fgf15 expression results from impaired activation of FXR in the enterocytes. Our interpretation is strongly supported MLN4924 manufacturer by the observed low volumes of gallbladder bile and the decreased expression of Fabp6, Ostα and Nr0b2 (Shp), all well-known FXR targets. In addition, we show that the depletion of the intestinal bile acids pool by oral administration of the bile acid sequestrant cholestyramine is sufficient to significantly decrease ileal Fgf15 expression. Furthermore, intravenous infections with a Salmonella invasion mutant and with

Listeria monocytogenes, both resulting in rapid hepatic colonization and pathophysiology, lead to reductions in Fgf15 expression in the absence of significant ileal bacterial colonization or enterocyte invasion. Salmonella infection

induced a massive alteration of the hepatobiliary gene expression program. Remarkably, the mRNA and protein levels of CYP7A1, the rate-limiting enzyme in the neutral pathway of bile acids synthesis were decreased during infection, in spite of the lower levels of FGF15 which would be expected to promote the upregulation of Cyp7a1 expression. These results reveal the complexities in the regulation of Cyp7a1 expression Fenbendazole and indicates that the mechanisms of Cyp7a1 expression control are hierarchical. Infection also triggered a significant reduction of FGFR4 and βKlotho, the two proteins involved in assembling the functional receptor for FGF15 in GS-1101 research buy hepatocytes. The biology of FGFR4 and βKlotho had never before been studied in the context of a bacterial insult, and our data suggest that their function can be severely compromised by bacterial infections in vivo. The mechanisms underlying their downregulation are unclear at present but we anticipate that they are related to the pro-inflammatory cytokine burst that follows liver colonization by bacteria. It has been recently reported that TNFα represses βKlotho expression in adipocytes [36]; thus it is possible that a similar mechanism acts in hepatocytes.