Intestinal calcium absorption: Mechanisms of absorpion and adaptations to diet-induced iron deficiency

To maintain calcium homeostasis, controlling intestinal calcium absorption is vital, and the paracellular pathway is known to predominantly mediate calcium absorption under normal dietary conditions. While the segmental profile of the transcellular pathway has provided important insights into the mechanisms of calcium absorption in the different segments of the small intestine, there is limited information regarding the paracellular pathway. In the current study, the segmental profile of paracellular calcium absorption and the underlying mechanisms were investigated in vivo. Paracellular calcium absorption was shown to be highest in the duodenum, however, the expression profile of the calcium-permeable claudin-2 and -12 were similar in all segments of the small intestine. Interestingly, the expression profile of claudin-15, speculated to mediate solvent drag-induced calcium absorption, mirrored the segmental differences in paracellular calcium transport. Additionally, based on the inverse relationship between iron and calcium transport, the impact of diet-induced iron deficiency on the intestinal and renal mechanisms of calcium homeostasis was investigated. Iron deficiency increased paracellular calcium absorption in the duodenum, and this was associated with upregulated duodenal claudin-2 and vitamin D receptor (VDR) expression. In addition, renal claudin-2 levels were upregulated in iron-deficient animals, even though urinary calcium excretion or serum calcium levels were unchanged. Since intestinal iron absorption mainly occurs in the duodenum, it is speculated that low cellular iron or high divalent metal transporter 1 (DMT1) levels may be linked to the increase in duodenal calcium absorption in iron deficiency. To test this speculation, deferoxamine, known to reduce cellular iron levels, resulted in upregulated VDR protein, while erythropoietin- 4 induced increase in DMT1 protein had no impact on VDR in Caco-2 cells. Therefore, it is hypothesised that reduced cellular iron increases VDR-mediated paracellular calcium absorption via claudin-2. This mechanism may be targeted to increase intestinal calcium absorption in patients with hypocalcaemia or bone disease

Diet‐induced iron deficiency in rats impacts small intestinal calcium and phosphate absorption

Aims: Recent reports suggest that iron deficiency impacts both intestinal calcium and phosphate absorption, although the exact transport pathways and intestinal segment responsible have not been determined. Therefore, we aimed to systematically investigate the impact of iron deficiency on the cellular mechanisms of transcellular and paracellular calcium and phosphate transport in different regions of the rat small intestine. Methods: Adult, male Sprague‐Dawley rats were maintained on a control or iron deficient diet for two weeks and changes in intestinal calcium and phosphate uptake were determined using the in situ intestinal loop technique. The circulating levels of the hormonal regulators of calcium and phosphate were determined by ELISA, while the expression of transcellular calcium and phosphate transporters, and intestinal claudins were determined using qPCR and western blotting. Results: Diet‐induced iron deficiency significantly increased calcium absorption in the duodenum but had no impact in the jejunum and ileum. In contrast, phosphate absorption was significantly inhibited in the duodenum and to a lesser extent the jejunum, but remained unchanged in the ileum. The changes in duodenal calcium and phosphate absorption in the iron deficient animals were associated with increased claudin 2 and 3 mRNA and protein levels, while levels of parathyroid hormone, fibroblast growth factor‐23 and 1,25‐dihydroxy vitamin D3 were unchanged. Conclusion: We propose that iron deficiency alters calcium and phosphate transport in the duodenum. This occurs via changes to the paracellular pathway, whereby upregulation of claudin 2 increases calcium absorption and upregulation of claudin 3 inhibits phosphate absorption

Artificial sweeteners disrupt tight junctions and barrier function in the intestinal epithelium through activation of the sweet taste receptor, T1R3

The breakdown of the intestinal epithelial barrier and subsequent increase in intestinal permeability can lead to systemic inflammatory diseases and multiple-organ failure. Nutrition impacts the intestinal barrier, with dietary components such as gluten increasing permeability. Artificial sweeteners are increasingly consumed by the general public in a range of foods and drinks. The sweet taste receptor (T1R3) is activated by artificial sweeteners and has been identified in the intestine to play a role in incretin release and glucose transport; however, T1R3 has not been previously linked to intestinal permeability. Here, the intestinal epithelial cell line, Caco-2, was used to study the effect of commonly-consumed artificial sweeteners, sucralose, aspartame and saccharin, on permeability. At high concentrations, aspartame and saccharin were found to induce apoptosis and cell death in intestinal epithelial cells, while at low concentrations, sucralose and aspartame increased epithelial barrier permeability and down-regulated claudin 3 at the cell surface. T1R3 knockdown was found to attenuate these effects of artificial sweeteners. Aspartame induced reactive oxygen species (ROS) production to cause permeability and claudin 3 internalization, while sweetener-induced permeability and oxidative stress was rescued by the overexpression of claudin 3. Taken together, our findings demonstrate that the artificial sweeteners sucralose, aspartame, and saccharin exert a range of negative effects on the intestinal epithelium through the sweet taste receptor T1R3