Abstract
Background and aimsHuman colonoid cultures maintained under low-calcium (0.25 mM) conditions undergo differentiation spontaneously and, concomitantly, express a high level of tight junction proteins, but not desmosomal proteins. When calcium is included to a final concentration of 1.5–3.0 mM (provided either as a single agent or as a combination of calcium and additional minerals), there is little change in tight junction protein expression but a strong up-regulation of desmosomal proteins and an increase in desmosome formation. The aim of this study was to assess the functional consequences of calcium-mediated differences in barrier protein expression.MethodsHuman colonoid-derived epithelial cells were interrogated in transwell culture under low- or high-calcium conditions for monolayer integrity and ion permeability by measuring trans-epithelial electrical resistance (TEER) across the confluent monolayer. Colonoid cohesiveness was assessed in parallel.ResultsTEER values were high in the low-calcium environment but increased in response to calcium. In addition, colonoid cohesiveness increased substantially with calcium supplementation. In both assays, the response to multi-mineral intervention was greater than the response to calcium alone. Consistent with these findings, several components of tight junctions were expressed at 0.25 mM calcium but these did not increase substantially with supplementation. Cadherin-17 and desmoglein-2, in contrast, were weakly-expressed under low calcium conditions but increased with intervention.ConclusionsThese findings indicate that low ambient calcium levels are sufficient to support the formation of a permeability barrier in the colonic epithelium. Higher calcium levels promote tissue cohesion and enhance barrier function. These findings may help explain how an adequate calcium intake contributes to colonic health by improving barrier function, even though there is little change in colonic histological features over a wide range of calcium intake levels.
Highlights
An intact colonic barrier is necessary for gastrointestinal health [1,2,3,4,5,6]
trans-epithelial electrical resistance (TEER) values were high in the low-calcium environment but increased in response to calcium
Cadherin-17 and desmoglein-2, in contrast, were weakly-expressed under low calcium conditions but increased with intervention. These findings indicate that low ambient calcium levels are sufficient to support the formation of a permeability barrier in the colonic epithelium
Summary
An intact colonic barrier is necessary for gastrointestinal health [1,2,3,4,5,6]. The intact barrier prevents permeation of toxins, soluble antigens, lipopolysaccharides and other inflammatory initiators across the intestinal wall, while inhibiting infiltration of bacteria and other particulate matter into the interstitium. Along the lateral surface (i.e., beneath the apical surface) are desmosomes [9,10], which provide anchoring sites for intermediate filaments and are necessary for cohesive strength In addition to these two cell-cell adhesional complexes are the adherens junctions [11,12,13]. These junctional complexes are comprised of cadherin family members and mediate homotypic cell-cell attachment Their formation between adjacent epithelial cells is a rapid event and thought to be necessary for the establishment and organization of other junctional complexes. They may contribute to cohesive strength directly or indirectly. The aim of this study was to assess the functional consequences of calcium-mediated differences in barrier protein expression
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