Abstract
Diet-related obesity is associated with increased intestinal hyperpermeability. High dietary fat intake causes an increase in colonic bile acids (BAs), particularly deoxycholic acid (DCA). We hypothesize that DCA modulates the gene expression of multiple cell junction pathways and increases intestinal permeability. With a human Caco-2 cell intestinal model, we used cell proliferation, PCR array, biochemical, and immunofluorescent assays to examine the impact of DCA on the integrity of the intestinal barrier and gene expression. The Caco-2 cells were grown in monolayers and challenged with DCA at physiological, sub-mM, concentrations. DCA increased transcellular and paracellular permeability (>20%). Similarly, DCA increased intracellular reactive oxidative species production (>100%) and accompanied a decrease (>40%) in extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways. Moreover, the mRNA levels of 23 genes related to the epithelial barrier (tight junction, focal adhesion, gap junction, and adherens junction pathways) were decreased (>40%) in (0.25 mM) DCA-treated Caco-2 cells compared to untreated cells. Finally, we demonstrated that DCA decreased (>58%) the protein content of occludin present at the cellular tight junctions and the nucleus of epithelial cells. Collectively, DCA decreases the gene expression of multiple pathways related to cell junctions and increases permeability in a human intestinal barrier model.
Highlights
The increasing worldwide incidence of colon cancer is linked to obesity and the intake of saturated fatty acids [1,2,3,4]
The abundance of deoxycholic acid (DCA) is much higher than other secondary bile acid species occurring in the feces [5,6,7]
We showed that the effect of DCA on transepithelial electrical resistance (TEER) value was greater than of paracellular diffusion measurement at 0.3 mM (Figure 1)
Summary
The increasing worldwide incidence of colon cancer is linked to obesity and the intake of saturated fatty acids [1,2,3,4]. Impaired epithelial barrier function (e.g., permeation) is implicated in the etiology of several diseases including colonic inflammation and cancer [11] Various environmental factors such as high-fat diets impair the intestinal barrier including intestinal epithelial damage, mucus layer changes, and dysbiosis. These impairments result in a variety of intestinal diseases such as colon cancer [12]. DCA is considered a Molecules 2022, 27, 723 epithelial damage, mucus layer changes, and dysbiosis These impairments result in2aofv1a2riety of intestinal diseases such as colon cancer [12]. TThhee ppeerrmmeeaabbiilliittyy wwaass iinnccrreeaasseedd bbyy 1199%% aanndd 2299%% iinn CCaaccoo--22 mmoonnoollaayyeerrss ttrreeaatteedd wwiitthh 00..2255 aanndd 00..33 mmMM DDCCAA vviiaa pphheennooll rreedd mmeeaassuurreemmeenntt ccoommppaarreedd ttoo tthhaatt ooff uunnttrreeaatteedd cceellllss,, rreessppeeccttiivveellyy ((FFiigguurree 11AA,,BB)). 87%, respectively, in the cells treated with 0.25 mM and 0.30 mM DCA when compared to untreated cells (Figure 5B)
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