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  • The importance of FXR FGF signaling in BA homeostasis is

    2021-09-06

    The importance of FXR-FGF15/19 signaling in BA homeostasis is illustrated by various BA malabsorption syndromes. Clinically, BA malabsorption causes diarrhea due to high BA concentrations in the colon that lead to secretion of water and electrolytes and stimulation of propulsive contractions [36]. Patients with primary BA diarrhea, a condition in which BA malabsorption occurs in the absence of ileal or other obvious GI disease, display lower levels of FGF19 and higher levels of 7α-hydroxy-4-cholesten-3-one (C4), a surrogate marker for BA synthesis [37,38]. Additionally, in a murine model of BA malabsorption it has been shown that Fxr activation or Fgf15 administration reduces fecal BA Terazosin [39]. Even though CF patients display BA malabsorption, (BA) diarrhea is rare and constipation due to inspissated mucus and delayed intestinal transit is more common (further explained in section 6). However, BA malabsorption in CF patients does result in impaired FXR-FGF19 signaling. Our group recently demonstrated that plasma FGF19 levels are lower and C4 levels higher in CF patients with a G551D gating-mutation as compared to healthy controls [40]. Conversely, improving CTFR function by treatment with the CFTR potentiator ivacaftor, altered the levels of these parameters towards normality, supporting a role for CFTR involvement in BA homeostasis. These results also indicate the possibility of using plasma C4 and FGF19 as surrogate biomarkers for CFTR function in the GI tract in CF. This is important as currently GI markers in CF are limited and/or difficult to obtain [41]. BA homeostasis has been more extensively studied in CF mouse models than in CF patients. Debray et al. showed that Cftr mice have lower ileal expression levels of Fgf15 compared to wild type controls, while having similar fecal BA excretion rates [42]. Interestingly, most other studies in CF mouse models showed an about 3-fold increase in fecal BA excretion, similar to what has been observed in CF patients, but did not directly assess FXR-FGF15/19 signaling [31,32]. This discrepancy in fecal BA excretion might be explained by genotypic and dietary differences between studies and requires further investigation [43]. Indeed, unpublished data from our group confirms lower ileal expression levels of Fgf15 in combination with increased hepatic Cyp7a1 levels in Cftr mice, supporting the disruption of FXR-FGF15/19 signaling. The exact mechanism underlying the impaired FXR-FGF15/19 signaling in CF, however, remains unknown. In wild type mice it has been shown that uptake of BAs by Asbt activates Cftr [31]. Altered functionality or expression of ASBT might also be involved in BA malabsorption in CF. However, results on ileal Asbt expression in murine CF models have been conflicting, [31,42,44], likely due to differences in experimental setups. Additionally, gene expression might not adequately reflect protein expression or activity. When looking at protein abundance, Debray et al. [42] found decreased expression of Asbt by western blot in Cftr mice, while Bijvelds et al. [31] showed a robust Asbt immunohistochemistry staining pattern and intensity in both Cftr and F508del-Cftr mice indistinguishable from WT mice. The regulation of ASBT expression is complex and can be influenced by many factors including intestinal BA concentrations and microbial composition [33]. ASBT expression is under a negative feedback regulation by intestinal BA concentrations in mice and humans [45,46]. The proposed mechanism of this feedback regulation is that BAs activate FXR in the enterocyte which leads to subsequent small heterodimer partner (SHP) and liver receptor homologue-1 (LRH-1) activation which downregulate ASBT expression. This hypothesis is supported by the fact that BA depletion by feeding mice a BA binding resin increased Asbt expression [47]. However, Debray et al. showed, besides decreased Asbt expression in Cftr mice, a decrease in expression of ileal Fxr target genes, Fgf15 and Shp, arguing against suppression of ASBT by FXR [42]. Conversely, while decreased intestinal BA concentrations seemed to induce ASBT expression, Stravitz et al. showed an induction of Asbt gene and protein expression in rats by feeding cholic acid or perfusing the intestine with taurocholic acid [48]. Intestinal dysbiosis or SIBO could contribute to altered ASBT expression in CF. Germfree or antibiotic treated mice generally show higher expression levels of Asbt and a decrease in fecal BA excretion [[49], [50], [51]]. Higher expression levels of Asbt were also observed more proximal in the intestine when mice were treated with antibiotics, regulated through reduced expression of the transcription factor Gata4 [50].