Abstract
Gastrointestinal epithelial barrier loss due to tight junction (TJ) dysfunction and bile acid‐induced diarrhea are common in patients with inflammatory diseases. Although excess colonic bile acids are known to alter mucosal permeability, few studies have compared the effects of specific bile acids on TJ function. We report that the primary bile acid, chenodeoxycholic acid (CDCA), and its 7α‐dehydroxylated derivative, lithocholic acid (LCA) have opposite effects on epithelial integrity in human colonic T84 cells. CDCA decreased transepithelial barrier resistance (pore) and increased paracellular 10 kDa dextran permeability (leak), effects that were enhanced by proinflammatory cytokines (PiC [ng/mL]: TNF α[10] + IL‐1ß[10] + IFN γ[30]). CDCA reversed the cation selectivity of the monolayer and decreased intercellular adhesion. In contrast, LCA alone did not alter any of these parameters, but attenuated the effects of CDCA ± PiC on paracellular permeability. CDCA, but not PiC, decreased occludin and not claudin‐2 protein expression; CDCA also decreased occludin localization. LCA ± CDCA had no effects on occludin or claudin expression/localization. While PiC and CDCA increased IL‐8 production, LCA reduced both basal and PiC ± CDCA‐induced IL‐8 production. TNF α + IL1ß increased IFN γ, which was enhanced by CDCA and attenuated by LCA. CDCA±PiC increased production of reactive oxygen species (ROS) that was attenuated by LCA. Finally, scavenging ROS attenuated CDCA's leak, but not pore actions, and LCA enhanced this effect. Thus, in T84 cells, CDCA plays a role in the inflammatory response causing barrier dysfunction, while LCA restores barrier integrity. Understanding the interplay of LCA, CDCA, and PiC could lead to innovative therapeutic strategies for inflammatory and diarrheal diseases.
Highlights
Bile acids synthesized from cholesterol in the liver are secreted into the intestine where they aid in fat digestion and can serve as signaling molecules (Alrefai and Gill 2007; Hofmann 2009)
Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society
With the caveat that a comprehensive examination of all bile acids on epithelial permeability is beyond the scope of any single study, of the four major bile acids, we examined whether chenodeoxycholic acid (CDCA) and its dehydroxylated product, lithocholic acid (LCA), affect barrier integrity in T84 cells based on the following rationale
Summary
Bile acids synthesized from cholesterol in the liver are secreted into the intestine where they aid in fat digestion and can serve as signaling molecules (Alrefai and Gill 2007; Hofmann 2009). The Yin and Yang of Bile Acid Action (CA), are formed in the liver, and in the intestine they sequentially undergo deconjugation and dehydroxylation by bacterial hydrolases. The latter step results in the formation of secondary bile acids, deoxycholic acid (DCA) from CA and lithocholic acid (LCA) from CDCA, with the bulk of LCA formation occurring in the colon. While the 5% of bile acids (lmol/L range) entering the colon under normal conditions modulate cell proliferation, gut-associated immunity, motility, and ion transport (Alrefai and Gill 2007; Hofmann 2009), it does not increase fluid secretion
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