A Novel Microbiota Targeted-Strategy for the Management of Chemotherapy-Induced Intestinal Mucositis

Chemotherapy-induced intestinal mucositis (CIM) is one of the most common and invalidating side effect of cancer therapy. Loss of mucosal integrity and gut barrier dysfunction are the initial factors of the development of intestinal mucositis. The severe nature of intestinal mucositis can lead to a reduction or cessation of cancer treatment that negatively impacts patient’s quality life. Despite numerous promising preclinical investigations have been proposed for the management of CIM, most treatments failed when translated into the clinics, thus there is an urgent need to develop strategies to alleviate the off-target effects of chemotherapeutics. Poorly absorbable antibiotics, for their lower toxicity and good safety profile, piqued interest as potential strategies to prepare the gastrointestinal tract to chemotherapy treatment. An antibiotic that has limited absorption and exerts its action on the gastrointestinal (GI) tract, has been selected as candidate to better characterize its action in CIM. A new polymorphic form -b of the selected Antibiotic was tested versus the gold standard form -a in mice challenged with the chemotherapeutic drug 5-Fluoracil, to mimic CIM manifestations. The treatment with Antibiotic -a or -b, by regulating gut microbiota composition, ameliorated CIM signs preserving tissue architecture, cell proliferation and mucus layer and protecting the intestinal barrier integrity, assessed both morphologically by increased Zona occludens-1 expression and functionally by reducing FITC-dextran particles diffused from intestinal lumen to the blood circulation. Moreover, the treatment with Antibiotic -a or -b did not show any effects on 5-Fluoracil activity in ApcMin/+C3arKO mice, a genetic mouse model of colorectal cancer, providing evidence of its potential usage to limit intestinal mucositis on colorectal cancer patients without interfering with chemotherapy regimen. Preliminary experiments on ex vivo human colon mucosa explants have revealed that antibiotic treatment was able to preserve intestinal architecture and protect the mucosa from damage induced by bacterial endotoxins. Our findings showed that the selected antibiotic treatment supports novel microbiota-targeted strategy for the management of intestinal mucositis associated with anticancer therapy.