Understanding chemotherapy-induced intestinal mucositis and strategies to improve gut resilience

Abstract

Intestinal mucositis remains one of the most debilitating side effects related to chemotherapy. The onset and persistence of mucositis is an intricate physiological process involving cross-communication between the specific chemotherapeutic drug, the immune system, and gut microbes that results in a loss of mucosal integrity leading to gut-barrier dysfunction. Intestinal mucositis has a severe impact on a patient's quality of life and negatively influences the outcome of treatment. Most importantly, intestinal mucositis is a major contributor to the decreased survival rates and early onset of death associated with certain chemotherapy treatments. Understanding the pathophysiology and symptomology of intestinal mucositis is important in reducing the negative consequences of this condition. Prophylaxis, early diagnosis, and proper symptom management are essential to improved survival outcomes in cancer patients. This review focuses on the pathobiology of intestinal mucositis that accompanies chemotherapy treatments. In addition, we will discuss the therapeutic potential of select strategies that have shown promise in mitigating chemotherapies' off-target effects without hampering their anti-cancer efficacy.

Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

“…There is an unmet need to identify and develop efficient drug treatments for GI toxicities caused by chemotherapeutics (Stringer et al, 2009;Sougiannis et al, 2021). The overall aims of any intervention are to reduce the GI related symptoms experienced by cancer patients-this would relieve suffering, enable dose escalation, or avoid dose de-escalation.…”

“…Melatonin, a serotonin derivative, is a hormone that controls the sleep-wake cycle and is primarily released by the pineal gland at night (Auld et al, 2017). Melatonin is also synthesized and released by the enterochromaffin cells in the intestine, where it binds to the melatonin membrane receptors MT1 and MT2, and to the cytosolic MT3 receptor (Soták et al, 2006;Söderquist et al, 2015). It also scavenges free radicals (Hardeland and Pandi-Perumal, 2005).…”

“…Chemotherapy is in general associated with extensive anti-tumor effects, but also serious adverse effects and long-term safety issues for both cancer patients and healthcare providers (Sougiannis et al, 2021). One of the more common off-target toxicities is chemotherapeutics-induced intestinal mucositis (CIM), which is a complex gastrointestinal (GI) complication.…”

Beneficial Effects of Polysaccharides on the Epithelial Barrier Function in Intestinal Mucositis

“…Rodent models of intestinal mucositis have been essential to allow the dissection of the mechanisms involved in chemotherapy-induced toxicity (Bowen et al, 2011). The different treatment schemes, including dosing schedules, routes of administration, duration of treatments, and period of experimental follow-up, generally reflect the five-phase model of intestinal mucositis: initiation, messenger signaling, signal amplification, ulceration with inflammation, and healing (Sonis et al, 2004;Sougiannis et al, 2021). The main drugs used in rodent models of intestinal mucositis include 5fluorouracil (5-FU) and irinotecan; however, cyclophosphamide, cisplatin, and etoposide are also used (Ribeiro et al, 2016;Wardill et al, 2019).…”

“…Inflammation and oxidative stress account for as underlying mechanisms of the intestinal pathological changes caused by chemotherapy (Sougiannis et al, 2021). Chemotherapy triggers an initial tissue response in which DNA damage occurs, followed by an intense production of ROS, up-regulation of inflammatory genes, inflammasome activation and influx of activated immune cells.…”