Role of Bile Acids for Regulation of Aquaporins in Rodent Large Intestine

Abstract

Bile acids (BAs) affect water transport in the colon, as evident in Bile acid malabsorption (BAM). In BAM patients, an increased production of BAs or a decrease in the capacity for BA reabsorption in the ileum cause BAs to overflow into the colon, where they lead to diarrhoea through mechanisms that are yet to be determined. Although there is evidence for expression of specific water channels (AQPs) in the colon, results from different studies have been contradictory. A connection between BAs and AQPs has not been described. Here we profiled mRNA and protein levels of AQPs in the colons of rodents and examined the short and long‐term effects of naturally occurring BAs on the expression of AQPs in human colonic T84 and HT29 epithelial cells. In colonic epithelial cells isolated from rats, AQP1, ‐3, ‐4, ‐7 and ‐8 were detected at the mRNA level by RT‐PCR, with AQP1,‐3 and ‐8 expression confirmed at the protein level by immunohistochemistry (IHC). In mouse AQP1, ‐4 and ‐8 mRNA and protein were detected by RT‐PCR and IHC. Compared to the proximal segment, AQP3, ‐4, ‐7, ‐8 mRNAs were expressed at higher levels in the distal half of the rat colon as seen by RT‐qPCR. In T84 and HT‐29 cells, the BA sodium deoxycholate increased AQP3‐mRNA expression in a time‐dependent manner. Furthermore, the BA sodium ursodeoxycholate or the Farnesoid X receptor agonist GW4064 increased AQP8 mRNA in T84 cells. In conclusion, AQPs likely have a spatiotemporal expression profile in the rodent large intestine. Cell line studies suggest that specific BAs may alter AQP expression in the large intestine, and as such AQPs may play a role in BAM syndromes. The study was supported by The Danish Council for Independent Research, MEMBRANES and Gangstedfonden.

Bile acid diarrhea – as bad as it gets?

“…First, stimulation of intracellular mediators, mainly cAMP: DCA increased rabbit colon mucosal adenylate cyclase activity in a dose-dependent manner [17,18]. Second, BAs increase water secretion by upregulating expression of colonic aquaporin channels in rat colon [19]. Other mechanisms include enteroendocrine mechanisms such as increased serotonin-induced secretion [20], neurocrine secretion through activation of TGR5 and submucosal cholinergic neurons [21], decreased water absorption in human colon [22], and increased mucosal permeability (based on biochemical tests as well as scanning electron microscopy) in response to di-alpha hydroxy bile acids (CDCA, DCA) in the rabbit colon in vivo [23].…”