Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

Abstract

The gastrointestinal tract is particularly vulnerable to off-target effects of antineoplastic drugs because intestinal epithelial cells proliferate rapidly and have a complex immunological interaction with gut microbiota. As a result, up to 40-100% of all cancer patients dosed with chemotherapeutics experience gut toxicity, called chemotherapeutics-induced intestinal mucositis (CIM). The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. In turn, this results in various pathologies, including ulceration, pain, nausea, diarrhea, and bacterial translocation sepsis. In addition to reducing patient quality-of-life, CIM often leads to dose-reduction and subsequent decrease of anticancer effect. Despite decades of experimental and clinical investigations CIM remains an unsolved clinical issue, and there is a strong consensus that effective strategies are needed for preventing and treating CIM. Recent progress in the understanding of the molecular and functional pathology of CIM had provided many new potential targets and opportunities for treatment. This review presents an overview of the functions and physiology of the healthy intestinal barrier followed by a summary of the pathophysiological mechanisms involved in the development of CIM. Finally, we highlight some pharmacological and microbial interventions that have shown potential. Conclusively, one must accept that to date no single treatment has substantially transformed the clinical management of CIM. We therefore believe that the best chance for success is to use combination treatments. An optimal combination treatment will likely include prophylactics (e.g., antibiotics/probiotics) and drugs that impact the acute phase (e.g., anti-oxidants, apoptosis inhibitors, and anti-inflammatory agents) as well as the recovery phase (e.g., stimulation of proliferation and adaptation).

Keywords: cancer; chemotherapeutics-induced mucositis; gastrointestinal physiology; intestinal proliferation; mucositis; stem cells; toxicity.

FIGURE 1

The pathology and timeline of chemotherapeutics-induced intestinal mucositis is primarily related to the effect of cytostatics on stem cells in the proliferation zone of the crypts: crypt base columnar (CBC) stem cells and transit amplifying daughter stem cells. Injury to the DNA of these cells causes apoptosis and initiates of a range of local tissue responses. These include generation of reactive oxygen species (ROS) and inflammation mediators, leading to further injury, inflammation, ulceration, villus and crypt atrophy, and the interstitial infiltration of luminal bacteria (commensal and pathogenic) and immune cells. After about 2 weeks the histology of the intestine is restored in humans (1 week in rodents). The green texts show potential targets for CIM intervention. The figure also shows the six different mature cell types of the intestines, the villi protrusions present in the small intestine, and the lymphatic, venous and arterial vessels. Artwork by Febe Jacobsson. EC = enterochromaffin.

FIGURE 2

Illustration of the rapid recovery (about 60 min) of the rat small intestinal blood-to-lumen 51Cr-EDTA clearance following local luminal exposure to saline (white area) and two mucosal irritants (grey area): (A) ethanol 30 min (Sommansson et al., 2013b) and (B) sodium dodecyl sulfate (SDS, anionic surfactant) 15 min (Dahlgren et al., 2018b).

FIGURE 3

Concentrations of doxorubicin in plasma and liver, heart, kidney, and intestines of mice following 5 mg/mL intravenous administration of a solution. Data from Luo et al. (2017). The high concentration of doxorubicin in all the organs shows that the side-effects of many anti-cancer drugs are not ubiquitously dose-dependent. Rather, they are associated with the tissue-specific cell proliferation rate. This is why cancer tissue and healthy intestinal tissue are typically heavily affected.