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Serotonin Reuptake Inhibitors Protect the Intestinal Mucosa from the Effects of Chemotherapy
*Michaela C Bamdad, *Neeru Gandotra, *John J Tackett, *Eleanor D Muise, *Robert A Cowles
Yale University School of Medicine, Department of Surgery, New Haven, CT

Objective:
Chemotherapy affects rapidly dividing cells such as those lining the small intestinal mucosa. Serotonin (5-HT), an important enteric signaling molecule, has been shown to accelerate enterocyte turnover. Deletion of the serotonin reuptake transporter (SERT) or the use of selective serotonin reuptake inhibitors (SSRI) result in 5-HT excess and increased growth parameters, such as villus height and crypt depth. We hypothesized that enhanced enteric 5-HT stimulates mucosal growth and mitigates chemotherapy-induced epithelial injury.
Design:
Intervention study.
Setting:
Laboratory.
Participants:
8-week old male mice (n=12).
Interventions:
Mice lacking SERT (SERT-KO) and wild-type littermates (WTLM) received an intraperitoneal injection of vincristine (2 mg/kg) or saline and were euthanized 2 days later. In another group, WTLM received the SSRI citalopram subcutaneously for 24 hours prior to vincristine injection and continued throughout the experiment. Terminal ileum was harvested, fixed, and stained.
Main Outcome Measures:
Body weight, villus height, crypt depth, and mucosal injury score.
Results:
Exposure of mice to vincristine resulted in a 10% decrease in body weight. Vincristine caused villus blunting in WTLM (194vs172um) and SERT-KO (250vs214um) mice compared with saline-injected controls. Citalopram rescued villus height in vincristine-treated WTLM (240vs172um), to levels exceeding control (240vs194um). Crypt depth was increased after vincristine treatment only in mice with 5-HT excess. Vincristine caused mucosal injury in WTLM (0.81vs0.14) and SERT-KO (0.59vs0.16) mice, compared to saline-injected controls. Mice that received citalopram prior to vincristine had lower injury scores than vincristine-treated WTLM and SERTKO mice (0.40vs0.81 and 0.40vs0.59, respectively).
Conclusions:
Excess 5-HT mitigates mucosal injury following vincristine administration. This effect was greater in mice treated with SSRI than in mice genetically lacking SERT. These effects may be due to enhanced enterocyte proliferation.


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