Influence of Age and Frailty on Intestinal and Hepatic Bile Acid Transport in Male C57BL/6 Mice
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Bile acids regulate their own synthesis as well as glucose and lipid metabolism. Bile acid homeostasis is maintained in part by enterohepatic circulation, which requires the concerted activity of multiple transporters, namely the apical sodium-dependent bile acid transporter (ASBT) and organic solute transporter (OST) α/β in the ileum, and the Na+-taurocholate cotransporting polypeptide (NTCP) and bile salt export pump (BSEP) in the liver. Limited data suggest that intestinal bile acid absorption decreases with aging, but this has never been measured experimentally. Age-related changes in the expression of bile acid transporters have also been described, albeit, the data are limited. Importantly, nothing is known about the influence of frailty on bile acid transport – frailty being defined as an increased vulnerability to adverse health outcomes. We hypothesized that intestinal bile acid absorption decreases with increasing age and frailty and that there is a decreased expression of transporters involved in enterohepatic bile acid circulation. Here we measured intestinal bile acid absorption in Ussing chambers and the mRNA expression by qPCR of ileal (Asbt, Ostα/β, Fgf15 and Fxr) and hepatic (Ntcp, Bsep, Fxr, and Cyp7a1) bile acid transporters and regulatory proteins as a function of age and frailty level in male C57BL/6 mice (89-953 days of age). A non-invasive frailty assessment was conducted on individual mice prior to experiments. There was a significant positive linear correlation between age and frailty index score (R2=0.718, p<0.0001, n=21). The intestinal bile acid absorption rate decreased in a linear manner with both increasing age (R2=0.383, p=0.006, n=18) and frailty index score (R2=0.328, p=0.013, n=18). The intestinal bile acid absorption rate was 52% significantly lower in the older cohort of mice (mean age of 752 days old, n=12) compared to the younger cohort (mean age of 151 days old, n=9) (p=0.0006, unpaired two-tailed t-test). There was a modest decrease in the intestinal expression of Asbt, Ostα/β and Fxr with increasing age and frailty index score, which was not significant by linear regression analysis. However, the expression of Asbt was lower in the older compared to the younger cohort of mice (p=0.028, unpaired two-tailed t-test), but the expression of other genes did not differ between the two cohorts. There was also a modest decrease in the expression of the hepatic transporters as a function of increasing age and frailty index score. However, the only relationships that were significant were a negative linear correlation between age and Ntcp expression (R2=0.265, p=0.017, n=19), and between age and Oatp1b2 expression (R2= 0.274, p=0.015, n=21). Indeed, the expression of Ntcp and Oatp1b2 was significantly lower in the older compared to the younger cohort of mice (p=0.0125 and p=0.016, respectively). Together, these data indicated that intestinal bile acid absorption decreases with increasing age and frailty level. This effect is likely due to a decreased expression of intestinal bile acid transporters, Asbt and Ostα/β. The decrease in Ntcp and Oatp1b2 expression in older mice suggested that hepatic bile acid handling is also sensitive to age. Thus, enterohepatic circulation of bile acids likely diminishes with age and frailty, which could impact bile acid homeostasis, and pharmacokinetics and pharmacodynamics of drugs.