Olusanya, Oluwatobi Ife-Oluwa; (2022) Intestinal calcium absorption: Mechanisms of absorpion and adaptations to diet-induced iron deficiency. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

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.

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