Gastrointestinal dysfunction and enteric neurotoxicity following treatment with anticancer chemotherapeutic agent 5‐fluorouracil

Background The use of the anticancer chemotherapeutic agent 5‐fluorouracil (5‐FU) is often limited by nausea, vomiting, constipation, and diarrhea; these side‐effects persist long after treatment. The effects of 5‐FU on enteric neurons have not been studied and may provide insight into the mechanisms underlying 5‐FU‐induced gastrointestinal dysfunction. Methods Balb/c mice received intraperitoneal injections of 5‐FU (23 mg/kg) 3 times/week for 14 days. Gastrointestinal transit was analysed in vivo prior to and following 3, 7, and 14 days of 5‐FU treatment via serial x‐ray imaging. Following 14 days of 5‐FU administration, colons were collected for assessment of ex vivo colonic motility, gross morphological structure, and immunohistochemical analysis of myenteric neurons. Fecal lipocalin‐2 and CD45+ leukocytes in the colon were analysed as markers of intestinal inflammation. Key Results Short‐term administration of 5‐FU (3 days) increased gastrointestinal transit, induced acute intestinal inflammation and reduced the proportion of neuronal nitric oxide synthase‐immunoreactive neurons. Long‐term treatment (7, 14 days) resulted in delayed gastrointestinal transit, inhibition of colonic migrating motor complexes, increased short and fragmented contractions, myenteric neuronal loss and a reduction in the number of ChAT‐immunoreactive neurons after the inflammation was resolved. Gross morphological damage to the colon was observed following both short‐ and long‐term 5‐FU treatment. Conclusions & Inferences Our results indicate that 5‐FU induces accelerated gastrointestinal transit associated with acute intestinal inflammation at day 3 after the start of treatment, which may have led to persistent changes in the ENS observed after days 7 and 14 of treatment contributing to delayed gastrointestinal transit and colonic dysmotility.