The Yin and Yang of bile acid action on tight junctions in a model colonic epithelium

J Sarathy, SJ Detloff, M Ao, N Khan… - Physiological …, 2017 - Wiley Online Library
J Sarathy, SJ Detloff, M Ao, N Khan, S French, H Sirajuddin, T Nair, MC Rao
Physiological Reports, 2017Wiley Online Library
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 …
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]: TNFα[10] + IL‐1ß[10] + IFNγ[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. TNFα + IL1ß increased IFNγ, 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.
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