Rapamycin Inhibition of mTOR Reduces Levels of the Na+/H+ Exchanger 3 in Intestines of Mice and Humans, Leading to Diarrhea

We conclude that rapamycin suppresses NHE3 activity through 2 distinct mechanisms: by autophagic degradation of NHE3 as a consequence of long-term exposure to therapeutic levels of rapamycin; and by acute inhibition of surface expression of NHE3 by high levels of serum rapamycin. These 2 distinct routes (Figure 7) could act together to severely inhibit NHE3 activity, contributing to the development of diarrhea in renal transplant recipients. Given that rapamycin and its analogs have been used increasingly in many medical conditions, including cancer, autoimmune dysfunction, and organ transplantation, understanding the mechanisms of rapamycin-associated diarrhea has at least 3 significant clinical and economic implications. First, this noninfectious etiology should be considered when the serum rapamycin level is higher than baseline. Second, understanding and controlling the factors that lead to serum spikes of rapamycin could reduce the incidence of rapamycin-associated diarrhea significantly. Finally, an understanding of the mechanisms of rapamycin-associated diarrhea may lead to the identification of compensating therapeutic practices that can mitigate the negative effects of this valuable family of immunosuppressive drugs.