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Sex differences in the gastrointestinal tract of rodents and humans

The rat is one of the most commonly used animals in pre-clinical studies, however, there is a lack of knowledge on the potential sex differences in rat gastrointestinal (GI) tract physiology. Consequently, key sex differences towards the translation into humans in the drug development process may be obscured. This research project aimed to uncover potential sex differences in male and female rats by the characterisation of GI tract physiology. The evaluation of luminal fluids (pH, buffer capacity, osmolality and surface tension) and the membrane efflux transporter P-glycoprotein (P-gp) were conducted in two species of rats, namely the Wistar rat and the Sprague Dawley (SD) rat. P-gp expression was also characterised in male and female human intestinal tissue to assess its correlation against rats. No distinct sex differences were observed in the characterisation of luminal fluids in Wistar and SD rats. With respect to P-gp, however, male Wistar rats expressed a statistically higher (p < 0.05) level in the jejunum and ileum when compared to female Wistar rats. The involvement of food and the factor of time were also evaluated in subsequent investigations. In the fed-state, P-gp expression decreased in the male small intestinal segments of Wistar rats. In females, however, the reverse was observed where P-gp expression significantly increased when compared to the fasted-state which returned back to control levels after 4 hours. No sex differences in intestinal P-gp expression were found in the SD rat model. Ex vivo studies using ganciclovir (a P-gp substrate) showed significant sex-dependent effects on intestinal permeation albeit specific to only Wistar rats. In addition, unlike SD rats, the intestinal expression of P-gp in Wistar rats highly correlated to that in humans. Jejunal and ileal P-gp expression in human male subjects were statistically higher (p < 0.05) than human female subjects which was similarly identified in Wistar rats. This project is the first to report a distinct sex difference in P-gp expression in Wistar rats and humans. As such, the appropriate animal model should be considered during pre-clinical drug development, especially for the oral administration of P-gp substrates. This research project also highlights that the rat is not just a rat; distinct strain differences should be considered and specifically chosen for the optimisation of pre-clinical studies, and ease of translation into human subjects.