Abstract
The human colon is exposed to cBA, and ucBA and excess BAs can increase fluid secretion and perturb the epithelial barrier. We showed in T84 cells (AJP 305: C447, ’13) that: a) BAs preferentially stimulate Cl‐ secretion from the basolateral surface (BLM); b) Overnight exposure (O/N) to proinflammatory cytokine (PiC), decreases transepithelial electrical resistance (TER) and then, luminal (AM) BA can stimulate Cl‐ secretion. We hypothesize that high AM [BAs] directly decrease TER, and this is enhanced by PiC. Confluent T84 cells (TER >1000 Ohm.cm2) were treated with 5‐500µM BAs for 0.5‐24h + PiCs (TNFα+IL‐1ß+IFNγ). Cell viability and toxicity were assessed by Accuri flow cytometry and lactate dehydrogenase respectively and barrier function by TER and dextran fluxes. Viability and cytotoxicity were dose and time dependent. UcBAs (500μM, O/N) had higher cytotoxicity (CDCA:28.6%; DCA:27.8%) than cBAs (TCDC:15.5%; TDC:13.3%). Physiological doses (5‐50μM) were less toxic (8‐10%). O/N PiC decreased TER by ~50% and 0.5mM CDCA (20’) decreased this further by 20%. AM, not BLM CDCA (0.5mM), increased (~2‐fold) 10‐kDa blue‐dextran AM to BLM flux over time (8h); PiC increased this further (+2‐fold). In summary, AM BAs alter epithelial barrier integrity allowing luminal BAs to access the BLM and this is enhanced by PiC. This will provide the basis for future studies on the role of BA‐induced diarrhea in inflammatory diseases.Grant Funding Source: Supported by COS, Benedictine U.
Published Version
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