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  • src inhibitors Currently ursodeoxycholic acid UDCA is the on

    2022-01-14

    Currently, ursodeoxycholic src inhibitors (UDCA) is the only recommended and widely used drug in the treatment of CFLD. However, the clinical efficacy of UDCA is controversial. The most recent Cochrane review only identified a small number of trials assessing the effectiveness of UDCA [92]. The authors concluded that there is ‘currently insufficient evidence to justify its routine use in cystic fibrosis’. UDCA treatment is often started early in life to prevent severe CFLD and related complications. This was also challenged by the results of a recent study, showing that treatment with UDCA started earlier in life had no effect on development of severe CFLD [13]. The effects of UDCA on BA homeostasis and FXR signaling have not been fully elucidated. UDCA increases hepatocellular and cholangiocellular secretion thereby increasing bile flow and reducing biliary toxicity [93]. UDCA is also suggested to decrease hepatic steatosis in mice [[94], [95], [96]]. In obese subjects UDCA was reported to lower FGF19 and subsequently increase hepatic bile acid synthesis [97]. The authors explained this as UDCA having FXR antagonistic effects which was supported by showing decreased FXR activation in an avidin biotin complex DNA-assay. However, in vitro assays suggest UDCA has neither FXR agonistic nor antagonistic properties [96,98]. UDCA is readily absorbed and constitutes a predominant part of the BA pool in UDCA treated patients (from 40% in PBC treated patients [99] to almost 90% in obese src inhibitors patients [97]), which is likely to contribute to the effects on the FXR-FGF15/19 axis. Fujita et al. showed a clear decrease in relative and absolute levels of muricholic acid levels in mouse livers after UDCA treatment, arguing the beneficial effects on hepatic steatosis (at least in mice) might be due to a reduction of the FXR antagonistic muricholic acid species [96]. FXR agonism has been shown to protect against hepatoxicity in a rat model of intrahepatic cholestasis [100]. In that study a systemic FXR agonist (i.e. GW4064) was used and effects could therefore be at least partly due to hepatic FXR activation. Direct evidence of the benefits of intestinal FXR-FGF15/19 signaling has been shown by Modica et al. [101] who demonstrated that transgenic overexpression of intestinal FXR or administration of FGF19 in mice protects against liver damage in three different models of cholestasis. The beneficial effects were attributed to a reduced BA pool size and more hydrophilic (i.e. less cytotoxic) biliary BA composition. However, FGF19 is a growth factor and is also associated with the induction of liver proliferation and growth of cancer cells [102]. To overcome the potential tumorigenic effects of FGF19, a modified variant of FGF19 (M70) has been produced, with reduced tumorigenicitiy but retained benefits in cholestatic liver disease in mice [103,104]. These results make intestinal FXR an interesting target in developing treatment and prevention strategies for CFLD. Unfortunately, CF mice have not been an ideal model for CFLD. Recently, however, other potentially more useful CF animal models have been developed, including the CF pig which already shows signs of CFLD at birth [105,106]. CF pigs could therefore be interesting to study CFLD [107,108].
    Modulating bile acid homeostasis to improve gastrointestinal outcomes in cystic fibrosis CF patients often display SIBO or colonic dysbiosis. Not only do these conditions generate direct symptoms including abdominal discomfort, diarrhea and flatulence, they also increase the risk of developing metabolic abnormalities and liver disease [109]. The relationship between BAs and intestinal microbiota is complex, with mutual interactions [87,110]. In the CF intestine, inspissated mucus accumulates, making it easier for harmful bacteria to thrive [27]. Other factors contributing to an altered microbial profile include a low intestinal pH due to reduced bicarbonate secretion, a longer intestinal transit time and exposure to antibiotics that CF patients frequently receive for (suspected) pulmonary infections. Interestingly, bacterial overgrowth itself has also been suggested to contribute to mucus secretion. Antibiotic treatment aimed at eradication of bacterial overgrowth in Cftr mice reduced mucus accumulation without a major effect on mucin gene expression, suggesting a more direct role for bacteria on mucus secretion by intestinal epithelium [111].