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    • Next to their indirect effect on ASBT expression microbiota

    2022-08-05

    Next to their indirect effect on ASBT expression, microbiota are also directly involved in BA homeostasis and FXR-FGF15/19 signaling. Different species of intestinal microbiota have the ability to biotransform BAs mainly by deconjugation and subsequent de-hydroxylation, the latter resulting in more hydrophobic secondary BAs. The various BA species have different properties regarding Protease Inhibitor Cocktail (100X in DMSO, EDTA plus) receptor and receptor activation. Many species of microbiota express bile salt hydrolase (BSH) activity which results in deconjugation of part of the luminal BAs, thereby making them unable to be reabsorbed by ASBT but, due to decreased polarity (more hydrophobic), easier to be passively reabsorbed. Germ-free mice lack the microbial ability to deconjugate BAs, resulting in higher concentrations of tauro-β-muricholic acid, a conjugated BA that acts as an Fxr antagonist that can lower Fgf15 levels [49]. CF patients and murine CF models display intestinal dysbiosis and sometimes even bacterial overgrowth, potentially affecting BA handling. Cftr mice generally show a decreased intestinal microbiota biodiversity with an increase in species associated with inflammation [52]. Decreases within the Bacteroides and Firmicutes phyla were observed in Cftr mice as well as CF patients [24]. The Firmicutes phylum contains species known to be involved in de-hydroxylation of BAs [53]. A decrease in one of the most important secondary BAs, deoxycholic acid (DCA), has been observed in feces of Cftr mice [17,32]. These observations suggest an important relation between intestinal dysbiosis in CF and BA handling. The exact role, however, of microbiota in BA homeostasis in CF remains to be elucidated.
    Bile acid homeostasis and its relation to metabolic function in cystic fibrosis BAs are primarily known as detergents with their main function to aid in digestion and absorption of fat and fat soluble vitamins. However, recent studies show that BAs also act as ligands for receptors resulting in the release of hormones that affect other metabolic processes in the body such as glucose metabolism [54]. CF patients often display metabolic abnormalities, such as hyperglycemia, hypertriglyceridemia or steatosis, and these are more common with increasing age [55]. Table 1 summarizes several of the metabolic effects of BA homeostasis and metabolic abnormalities in CF patients. Malnutrition is generally regarded as an important problem in CF management. However, due to better nutritional and supportive therapy, the prevalence of malnutrition in CF has declined and some CF patients even develop overweight or obesity [56]. A recent study showed that some CF patients display “normal weight obesity”, defined by a normal body mass index (BMI) but increased fat percentage that was associated with decreased pulmonary function [57]. BA homeostasis is also highly involved in lipid and cholesterol metabolism [54]. Conversion of cholesterol to BAs and subsequent fecal excretion is one of the main routes of cholesterol disposal. Most CF patients display serum low-density lipoprotein cholesterol (LDL-C) levels that are lower compared to control subjects of similar age [55,58]. However, some CF patients display elevated LDL-C and triglyceride levels which are associated with older age and other metabolic abnormalities such as a high BMI and lower insulin sensitivity [[62], [63], [64]]. With increasing age the incidence of CF related diabetes (CFRD) is also rising. The pathophysiology of CFRD is not completely understood but its incidence is correlated with EPI and fibrosis [65]. A combination of partial insulin deficiency and episodes of insulin resistance are often present. Interestingly, CF patients display lower levels of glucagon like peptide 1 (GLP-1), an incretin hormone regulating postprandial insulin secretion, that is improved by pancreatic enzyme replacement therapy [[59], [60], [61]]. Intestinal activation of the G-protein coupled bile acid receptor 1 (GPBAR1, GPCR19 also known as TGR5) by BAs enhances the secretion of GLP-1 [66]. Secondary BAs lithocholic acid (LCA) and DCA are the most potent naturally occurring TGR5 agonists. As these BA species are lower in murine CF models, it is tempting to speculate that TGR5 activation is reduced in CF due to impaired BA homeostasis. Unfortunately, however, no studies directly addressing this relationship have been performed.