Asowata, Evans Ohenhen; (2019) Mechanisms of Intestinal Phosphate Absorption and the Effect of Diet-induced Iron Deficiency on Phosphate Homeostasis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Intestinal phosphate absorption occurs via a sodium-dependent mechanism, known to be NaPi-IIb-mediated, and a sodium-independent mechanism, thought to be mediated via the paracellular pathway. Emerging evidence suggests that the paracellular pathway is likely to be more dominant and that this pathway is regulated by NHE3. Studies in rats, mice and humans have shown some species differences in the efficacy of both NaPi-IIb and NHE3 inhibitors on intestinal phosphate absorption, thus, the suitability of rodents as experimental models to study phosphate absorption is uncertain. Furthermore, recent reports suggest that alterations in iron levels influence phosphate homeostasis, although there are conflicting reports regarding how it affects intestinal phosphate absorption. In this study, the mechanisms of phosphate absorption in the small intestine of rats, mice and humans were compared, and the effect of diet-induced iron deficiency on these mechanisms was investigated. The result showed a similar profile for intestinal NHE3 in rats and humans, suggesting that the rat is a more appropriate model to study the mechanisms of paracellular phosphate absorption. Using in vivo and in vitro uptake experiments, iron deficiency was demonstrated to significantly inhibit phosphate absorption in the duodenum and jejunum of rats. The findings of this study demonstrated that NaPi-IIb expression or activity was unaffected by iron deficiency. However, while the sodium-independent phosphate transport pathway was most affected in the duodenum, NHE3 activity was inhibited in the jejunum, in response to iron deficiency. Interestingly, iron deficiency resulted in increased expression of duodenal claudin 3, while also causing the expected upregulation of DMT1 in the duodenum and jejunum. It is therefore hypothesised that increased DMT1 expression, in addition to the inhibition of jejunal NHE3 activity by iron deficiency, may locally impact phosphate absorption by a mechanism involving the accumulation of intracellular protons leading to the sealing of the paracellular pathway.

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