Inhibition of intestinal biotin absorption by chronic alcohol feeding: cellular and molecular mechanisms

Abstract

The water-soluble vitamin biotin is essential for normal cellular functions and its deficiency leads to a variety of clinical abnormalities. Mammals obtain biotin from exogenous sources via intestinal absorption, a process mediated by the sodium-dependent multivitamin transporter (SMVT). Chronic alcohol use in humans is associated with a significant reduction in plasma biotin levels, and animal studies have shown inhibition in intestinal biotin absorption by chronic alcohol feeding. Little, however, is known about the cellular and molecular mechanisms involved in the inhibition in intestinal biotin transport by chronic alcohol use. These mechanisms were investigated in this study by using rats and transgenic mice carrying the human full-length SLC5A6 5'-regulatory region chronically fed alcohol liquid diets; human intestinal epithelial Caco-2 cells chronically exposed to alcohol were also used as models. The results showed chronic alcohol feeding of rats to lead to a significant inhibition in carrier-mediated biotin transport events across jejunal brush border and basolateral membrane domains. This inhibition was associated with a significant reduction in level of expression of the SMVT protein, mRNA, and heterogenous nuclear RNA. Chronic alcohol feeding also inhibited carrier-mediated biotin uptake in rat colon. Studies with transgenic mice confirmed the above findings and further showed chronic alcohol feeding significantly inhibited the activity of SLC5A6 5'-regulatory region. Finally, chronic exposure of Caco-2 cells to alcohol led to a significant decrease in the activity of both promoters P1 and P2 of the human SLC5A6 gene. These studies identify for the first time the cellular and molecular parameters of the intestinal biotin absorptive processes that are affected by chronic alcohol feeding.

Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms

“…Wild-type and transgenic mice carrying the full-length human SLC5A6 promoter fused to the firefly luciferase reporter gene, previously generated and characterized by this laboratory (37), were used (approval for their use was obtained from the Institutional Animal Care Use Committee of the Long Beach VA Medical Center). Mice were fed Lieber-DeCarli ethanol-liquid diet (Dyets, Bethlehem, PA) [ethanol provided 25% of total ingested calories and was introduced gradually; calories were increased by 5% every day until we achieved 25% (25)] for 4 wk as described by us recently (44,46). Control littermates (sex-matched that had similar basal firefly luciferase mRNA expression) were pair-fed with the same liquid diet but without ethanol (maltose-dextrin replaced ethanol isocalorically).…”

“…This in turn predisposes the organ to the effect of stress conditions/ injurious agents or to other cell biological events causing injury (i.e., alcohol "sensitizes" or "primes" the pancreas to subsequent injury) (16,19,30,31,33). Chronic alcohol exposure was recently shown to negatively impact biotin transport events in intestinal and renal epithelial cells (45,46), effects that may contribute to the observed low biotin levels found in chronic alcoholics (4,12). The effect that chronic alcohol exposure has on the physiology of biotin uptake by PAC is not known.…”

Conditional knockout of the Slc5a6 gene in mouse intestine impairs biotin absorption

“…Biotin deficiency and suboptimal levels occur in patients with inborn errors of biotin metabolism (6,39), patients with inflammatory bowel diseases (10,40), those on long-term therapy with anticonvulsant drugs (reviewed in Refs. 4,14,15), where inhibition in intestinal biotin absorption is believed to be a contributing factor (33,27), patients on long-term parenteral nutrition (11,19), and in substantial numbers of alcoholics (5,9), where impairment in intestinal biotin absorption process is believed to be a contributing factor (38).…”

Recent advances in transport of water-soluble vitamins in organs of the digestive system: a focus on the colon and the pancreas

“…Other studies have shown that chronic alcohol exposure leads to a significant inhibition of colonic carrier-mediated biotin uptake (95). The mechanism through which chronic alcohol exposure causes inhibition of colonic biotin uptake is not clear but could be similar to that found in other intestinal epithelia mediated (at least in part) via a transcriptional mechanism(s) (95).…”