Enterohepatic bacterial infections dysregulate the FGF15-FGFR4 endocrine axis
© Romain et al.; licensee BioMed Central Ltd. 2013
Received: 18 June 2013
Accepted: 26 October 2013
Published: 29 October 2013
Enterohepatic bacterial infections have the potential to affect multiple physiological processes of the body. Fibroblast growth factor 15/19 (FGF15 in mice, FGF19 in humans) is a hormone that functions as a central regulator of glucose, lipid and bile acid metabolism. FGF15/19 is produced in the intestine and exert its actions on the liver by signaling through the FGFR4-βKlotho receptor complex. Here, we examined the in vivo effects of enterohepatic bacterial infection over the FGF15 endocrine axis.
Infection triggered significant reductions in the intestinal expression of Fgf15 and its hepatic receptor components (Fgfr4 and Klb (βKlotho)). Infection also resulted in alterations of the expression pattern of genes involved in hepatobiliary function, marked reduction in gallbladder bile volumes and accumulation of hepatic cholesterol and triglycerides. The decrease in ileal Fgf15 expression was associated with liver bacterial colonization and hepatobiliary pathophysiology rather than with direct intestinal bacterial pathogenesis.
Bacterial pathogens of the enterohepatic system can disturb the homeostasis of the FGF15/19-FGFR4 endocrine axis. These results open up a possible link between FGF15/19-FGFR4 disruptions and the metabolic and nutritional disorders observed in infectious diseases.
KeywordsEndocrine Metabolism Enterohepatic Infection FGF15 FGF19 FGFR4 βKlotho Salmonella Listeria
Alteration of the host’s metabolism is common in infectious diseases; it can lead to patient malnutrition and the need for nutritional support [1, 2]. Infection-driven metabolic changes are characterized by an accelerated flux of glucose, lipids, proteins and amino acids that may result in net protein loss and diabetic-like hyperglycemia [1, 2]. Significant metabolic disorders have been observed in natural and experimental infections with the bacterium Salmonella enterica, including changes of the lipid and protein profiles and widespread hormonal imbalances [1, 3, 4]. In humans, Salmonella enterica serovar Typhi causes typhoid fever, a disease characterized by multi-organ bacterial colonization with common immunopathological manifestations in the gastrointestinal tract and the hepatobiliary system .
The molecular and physiological bases of the metabolic disorders observed during infection are not fully understood. In this work, we examined the disruption of the enterohepatic fibroblast growth factor 15/19 (FGF15/19)-fibroblast growth factor receptor 4 (FGFR4) endocrine axis during bacterial infections of the enterohepatic system. FGF15/19 (FGF15 in mice, FGF19 in humans) is an endocrine factor secreted by intestinal enterocytes . FGF15/19 has a crucial role in the control of whole body glucose and lipid metabolism and energy expenditure [7, 8]. It is also a key regulator of de novo synthesis of bile acids via the repression of cholesterol 7 alpha hydroxylase (CYP7A1) expression in hepatocytes . In addition, FGF15 represses the apical Na+-dependent bile acid transporter (ASBT) expression in hepatic cholangiocytes  and facilitates gallbladder filling by promoting gallbladder muscle distension . Through these functions, FGF15/19 closes an important negative feedback loop in the regulation of bile acid homeostasis. Signaling to hepatic target cells occurs through the interaction of FGF15/19 with the tyrosine kinase receptor fibroblast growth factor receptor 4 (FGFR4) and also requires the protein βKlotho. Mice genetically deficient for Fgf15, Fgfr4 or Klb (βKlotho) have similar biliary phenotypes with higher levels of CYP7A1 and increased synthesis of bile acids [6, 12–14]. Reduced FGF19 levels have been observed in patients with inflammatory bowel disease  and chronic idiopathic bile acid diarrhea . On the other hand, patients with insulin resistance and non-alcoholic fatty liver disease, as well as extrahepatic cholestasis frequently display elevated plasma levels of FGF19 [17, 18].
Using a model of murine typhoid fever, we demonstrate that Salmonella enterica infection triggers major alterations in the hepatic biliary function gene expression program, promotes accumulation of hepatic cholesterol and triglycerides and leads to a significant reduction in physiological gallbladder bile volumes. In addition, Salmonella infection causes a substantial decrease in the expression of intestinal Fgf15, accompanied by a dramatic loss of hepatic FGFR4 and βKlotho. These disturbances appear to be secondary to hepatic inflammation. Given the important role of the FGF15/19-FGFR4 endocrine axis as a central metabolic regulator, these alterations may be a major factor underlying the pathophysiology of bacterial infectious diseases.
Bacterial strains and mouse infections
Salmonella enterica serovar Typhimurium strains SL1344 (Smr) and SB103 (invA)  and Listeria monocytogenes 10403 s (Smr)  were used in this study. Bacteria were grown overnight at 37°C in LB supplemented with 100 μg/mL streptomycin. Inoculum was prepared in sterile HEPES 100 mM, NaCl 0.9%, pH 8.0. Animal protocols were approved by the Animal Care Committees of the University of British Columbia and the University of Sherbrooke. Eight weeks-old female C57BL/6 mice (The Jackson Laboratory, Bar Harbor, USA) were infected orally with 5 × 107Salmonella SL1344, intravenously with 5 × 102Salmonella SB103 or with Listeria 10403 s (2 × 109 bacteria orally and 104 intravenously). The animals were kept with food and water ad libitum through the duration of the study and were always sacrificed during the light period (10:00 AM ± 60 minutes). The bile was collected by gallbladder resection and draining by puncture. For bacterial counts, tissues were homogenized using a Mixer Mill MM400 (Retsch GmbH) followed by plating of serial dilutions in LB plates containing 100 μg/mL streptomycin. All infection experiments were done in duplicate using a total of 8–10 mice per group.
The genes analyzed in this study and the sequences of the qPCR primer sets
ATP-binding cassette, sub-family G (WHITE), member 5
ATP-binding cassette, sub-family G (WHITE), member 8
Apical sodium-dependent bile acid transporter
Bile salt export pump
Cholesterol 7 alpha hydroxylase
Fatty acid binding protein 6
Fibroblast growth factor 15
Fibroblast growth factor receptor 4
Farnesoid X receptor (nuclear receptor subfamily 1, group H, member 4)
ATP-binding cassette, sub-family B member 1a
ATP-binding cassette sub-family B member 1b
Multidrug resistance protein 2
ATP-binding cassette, sub-family C (CFTR/MRP) member 2
ATP-binding cassette, sub-family C (CFTR/MRP), member 3
ATP-binding cassette, sub-family C (CFTR/MRP), member 4
Sodium-taurocholate co-transporting polypeptide
Organic solute transporter alpha
Organic solute transporter beta
Small heterodimer partner
Scavenger receptor class B type 1
Ribosomal protein, large, P0
For histological analysis, tissue sections were fixed in 10% buffered formalin, embedded in paraffin and stained with H&E. Alternatively, samples fixed in 3.5% paraformaldehyde and frozen-embedded in OCT were used for immunofluorescent microscopy as previously described . Fluorescence was visualized using an Olympus IX81 microscope.
Cholesterol and triglyceride determinations
Cholesterol and triglycerides were assayed in liver lysates. A total of 40-100 mg of liver was homogenized with an ultra turrax (setting 5, 4 times for 15 sec) in 3 ml of chloroform:methanol (2:1), extracted twice with water, and centrifuged for 15 minutes at 3000 g. For the triglyceride assay 200 μl of the organic layer (lower phase) was removed and evaporated under N2(g). 10 μl of Thesit (Sigma-Aldrich, St Louis, MO) was added and mixed under N2(g). Water (50 μl) was added and incubated at 37°C for 1 hr with intermittent vortexing. Aliquots of 5 μl were assayed using the Serum Triglyceride Determination kit (Sigma-Aldrich, St Louis, MO) modified for a 96-well plate, calibrated with a trioleate (Sigma-Aldrich, St Louis, MO) standard curve. The cholesterol assay was performed at the same time but 500 μl of the organic layer (lower phase) was removed after the centrifugation step and evaporated under N2(g). 50 μl of isopropanol was then added to the dried down lipids and mixed by vortexing. Aliquots of 2 μl were then assayed using the Cholesterol E kit (Wako Chemicals USA, Richmond, USA).
Data processing and statistical analyses were performed using GraphPad Prism5. Student’s t test was applied to all sets of data for statistical comparisons between groups, the graphs show the means and the standard errors of the mean.
Enterohepatic infections downregulate the expression of intestinal Fgf15
To establish the role of hepatic colonization and to probe the involvement of bacterial enterocyte invasion in repressing Fgf15 expression, we carried out intravenous infections with the Salmonella invasion-deficient strain SB103 following Menendez et al.. In this type of infection, Salmonella colonization of the hepatobiliary system occurs immediately whereas colonization of the gut is delayed by 72 to 96 hours . Furthermore, the bacteria that eventually reach the intestines are unable to invade the enterocytes due to the invA mutation of this strain. As shown in Figure 2C, intravenous infection with Salmonella SB103 caused a reduction of Fgf15 transcripts abundance. Notably, such a decrease was observed with a much lower intestinal bacterial burden than those in oral infections with the wild-type strain (average 102vs. 107 cfu/mg, respectively). These results demonstrate that colonization of the hepatobiliary system by Salmonella represses the expression of intestinal Fgf15 and show that enterocyte invasion by intestinal bacteria does not play a major role on this effect.
Colonization of the hepatobiliary system by Salmonella induces local pathological damage and inflammation , which can result in impaired synthesis of bile acids and inflammation-induced cholestasis . This may in turn, compromise intestinal FXR activation and lead to inhibition of Fgf15, Fabp6, Nr0b2 and Osta expression. To test whether the depletion of bile acids would be sufficient to decrease Fgf15 expression in vivo, we fed uninfected C57BL/6 mice with a diet supplemented with the bile acid sequestrant cholestyramine. As shown in Figure 3B mice fed with cholestyramine did have significantly lower levels of Fgf15 transcripts than mice fed with a normal diet.
Salmonellainfection leads to depletion of the hepatic FGF15 receptor complex
The FGF19-FGFR4 endocrine axis is currently considered a potential intervention point for the therapy of cancer, gallstone disease, and metabolic disorders associated to the metabolic syndrome [7, 30]. Experimental administrations of FGF19 and transgenic FGF19 mice have shown decreased liver fat content, improved hepatic and serum lipid profiles, and resistance to high-fat diet-induced obesity [31–33]. In addition, FGF15/19 induces hepatocyte proliferation  and has been recently identified as an important mediator of liver regeneration after liver resection surgery . 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 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 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 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 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 ; thus it is possible that a similar mechanism acts in hepatocytes.
It is apparent that the dysregulation of the FGF15/19-FGFR4 endocrine axis components is not a general pathogenic feature of all bacteria, as infections with the enteric pathogen Citrobacter rodentium, the mouse model for human EPEC and EHEC , did not modify the expression of ileal Fgf15 (data not shown). Instead, this pathophysiological effect may be restricted to infections displaying a relevant liver involvement. Further work is still necessary to define the full impact of infections in FGF15/19 function and to determine the underlying molecular mechanisms.
Through the alteration of the hepatobiliary function, bacterial pathogens of the enterohepatic system dysregulate the homeostasis of the FGF15/19-FGFR4 endocrine axis. These revealing findings have important implications for the understanding of the pathophysiology of microbial diseases. Disruption of the FGF15/19-FGFR4 pathway may be a contributing factor to the metabolic and nutritional disorders associated with infectious diseases.
We thank Catherine Desrosiers, Melisange Roux and Elora Midavaine for technical help. This work was supported by grants to A.M. from the Fonds de Recherche du Québec-Santé (26710) and the Natural Sciences and Engineering Research Council of Canada (401949–2011), and to B.B.F. from the Canadian Institutes for Health Research. L. C. M. A. was funded by a postdoctoral fellowship from the Canadian Institutes of Health Research. A. M. is a member of the FRQS-funded Centre de Recherche Clinique Étienne-Le Bel.
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