Molecular characterization of trace element uptake in the gastrointestinal tract

Project Summary

Essential trace elements (TE) such as selenium (Se), manganese (Mn), zinc (Zn), iron (Fe), iodine (I) and copper (Cu) are indispensable for various physiological events, being involved in enzymatic reactions, structural stabilization of proteins, and endocrine and intracellular signaling. TE deficiencies as well as supraphysiological exposures are associated with a multitude of physiological, morphological, and functional changes that are contributing to the incidence and severity of many different diseases. Therefore, adequate TE supply is a cornerstone of preventive medicine, and monitoring and potentially correcting TE imbalances in the elderly can contribute to healthy ageing.

Two fundamental aspects in these processes will be subject of this proposal. Firstly, despite clear indication for a crucial impact on intestinal resorption, molecular events by which different TE might interact during intestinal uptake, and in particular their competition for chemical interaction with the mucus layer, have been widely disregarded, so far. Consequently, work package 1 investigates the binding of TE with mucins alone, as well as their interdependence when being present in concentrations comparable to the Traceage animal diet. In work package 2 the impact of interactions between TE and the glycoproteins of the mucus layer on TE uptake will be elucidated in an in vitro model for the small intestine. Hereby, inflammation will also be considered, as inflammation is a central element of the pathological changes during aging, and there is an intertwined relationship between gastrointestinal barrier integrity, TE uptake and deficiency, and inflammation.

Secondly, there are considerable limitations for the presently used biomarkers for the status of Cu and Zn, especially when it comes to addressing the fine line between adequate and marginally deficient supply with TE. We will focus on measuring the concentration of the free ions in serum, because they represent the biologically available fraction of these TE. Therefore, in work package 3 we will develop a procedure for determining free Cu in serum samples by using low molecular weight fluorescent probes. Together with the method for determining free zinc with Zinpyr-1, which has been successfully established in the first funding phase of Traceage, we will use it to determine the concentrations of the bioavailable fractions of Zn and Cu in sera from the human cohorts EPIC-DZD (P1, Schulze) and WONDER (P2, Norman) as well as sera obtained during the animal experiments from the second funding phase of Traceage (P3, Kipp; P6, Grune).

Together, the results from this project shall contribute to a better understanding of the complex interactions during TE uptake, enabling dietary improvements towards adequate TE supply.