Gastrointestinal toxicity due to chemotherapeutic drugs is a major cause of morbidity and mortality in cancer patients. Mucositis and diarrhea are the most significant enterotoxicities. Lesions associated with mucositis result in pain, decreased quality of life, increased length of hospitalization, higher risk of infection, and modification of anti-neoplastic treatment regimens (Sonis et al., 2004; Sharma et al., 2005; Lee et al., 2014). The pathophysiology of chemotherapy-induced mucositis remains unclear and involves a complex and dynamic array of biological events (Logan et al., 2007; Lee et al., 2014). Some studies have suggested a five-stage process, including an initiation phase, a message generation phase, a signaling and amplification phase, an ulceration phase, and a spontaneous healing phase (Sonis et al., 2004; Logan et al., 2007). The pathophysiology might include decreased villi length and disruption of crypt cell homeostasis, and several pathogenic elements are involved, including direct toxicity, a change in the balance of bowel microbial flora, oxidative stress, apoptosis, hypoproliferation, and abnormal inflammation. Recent studies have revealed that chemotherapeutics affect the intestinal microbial composition (Stringer et al., 2009a,b) and fecal microbiota (Touchefeu et al., 2014). However, no well-established or up-to-date therapeutic strategy is available to manage chemotherapy-induced intestinal mucositis (Sharma et al., 2005). Thus, the development of an effective intervention against chemotherapy-related mucositis is urgently needed for oncological supportive care.
Probiotics are live microorganisms that, similar to certain drugs or food supplements, help maintain a beneficial microbial balance in the digestive tract of humans and other hosts. Probiotics have been tested in multiple indications, including gastrointestinal disorders (for the prevention and treatment of infectious and antibiotic-induced diarrhea), treatment of liver insufficiency, lactose intolerance, inflammatory bowel disease, irritable bowel syndrome, and anti-tumorigenic activities (Liong, 2008; Jacouton et al., 2017). Certain strains of Lactobacillus have been recommended in the treatment and prevention of diarrhea and inflammatory bowel disease to improve the integrity of the intestinal tissue (Eizaguirre et al., 2002). Experimental and clinical evidence suggest that probiotics might have a beneficial effect on the toxicity of anticancer therapy (Mego et al., 2013). The most commonly used probiotic organisms are lactic acid bacteria, especially those belonging to the genus Lactobacillus. We previously demonstrated that Lactobacillus attenuates the barrier disruption of intestinal epithelial cells caused by Salmonella lipopolysaccharide administration and ameliorates chemotherapy-induced intestinal mucositis in a healthy mouse model (Yeung et al., 2013, 2015). Thus, probiotics, by manipulating gut microbiota, may ameliorate inflammation, and protect the epithelium by maintaining intestinal epithelial integrity and reduce the severity of mucositis.
Our previous researches have reported anti-inflammatory effects of the probiotic strain Lactobacillus casei variety rhamnosus (Lcr35) on lipopolysaccharide-induced inflammation and epithelial barrier dysfunction in a co-culture model using Caco-2/peripheral blood mononuclear cells (Fang et al., 2010). Furthermore, we recently demonstrated that this strain attenuates chemotherapy-induced intestinal mucositis in healthy mice (Yeung et al., 2015). The 5-FU-induced diarrhea and damage in jejunal villi was ameliorated following Lcr35 administration. Lcr35 suppressed the upregulation of pro-inflammatory cytokines expression in intestinal mucositis tissues following 5-FU treatment. No bacterial translocation was found in the safety study of Lcr35 (Yeung et al., 2015). However, the beneficial role of Lactobacillus casei variety rhamnosus in FOLFOX-induced intestinal mucositis of colorectal cancer model remains to be assessed. Subcutaneously injected colorectal carcinoma murine models have been widely used in translational research (Liu et al., 2005; Doi et al., 2010; Kim et al., 2012; Evans et al., 2016; Gordon et al., 2017). In the current study, we further investigated the protective effect of Lactobacillus casei variety rhamnosus on intestinal mucosal injury induced by 5-FU-based chemotherapy (FOLFOX) in subcutaneously injected colon cancer mice. Our results revealed that probiotic Lcr35 did not interfere anti-tumor effect of FOLFOX. Lcr35 ameliorated diarrhea and repaired intestinal mucosa damage following FOLFOX treatment. The possible mechanism(s) of Lcr35 was also elucidated.
Lactobacillus casei variety rhamnosus (Lcr35) (Antibiophilus®) was diluted in sterile saline and administered by oral gavage. The mice received 100 ?L of saline or suspension containing 1 x 103-7 CFU of the probiotics cocktail daily during the experiment. Lactobacillus casei variety rhamnosus (Lcr35) (Antibiophilus®) was diluted in sterile saline and administered by oral gavage. The mice received 100 ?L of saline or suspension containing 1 x 103-7 CFU of the probiotics cocktail daily during the experiment.
Our colorectal cancer murine model with intestinal mucositis induced by FOLFOX may be an effective model to investigate the mechanisms underlying intestinal injury and its possible interaction with drugs. The development of FOLFOX-induced mucositis involves changes in gut microbiota and might be “driven” by the activation of NF-?B. Activated NF-?B results in apoptotic signals and pro-inflammatory cytokine production, sequentially contributing to gastrointestinal injury. By modulation of the gut microbiota and proinflammatory responses with suppression of intrinsic apoptosis, Lcr35 mitigated FOLFOX-induced mucositis and may serve as an alternative therapeutic strategy for the prevention or management of chemotherapy-induced mucositis in future.
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