Abstract
The central nervous system and gastrointestinal tract form the primary targets of chemotherapy-induced toxicities. Symptoms associated with damage to these regions have been clinically termed chemotherapy-induced cognitive impairment and mucositis. Whilst extensive literature outlines the complex etiology of each pathology, to date neither chemotherapy-induced side-effect has considered the potential impact of one on the pathogenesis of the other disorder. This is surprising considering the close bidirectional relationship shared between each organ; the gut-brain axis. There are complex multiple pathways linking the gut to the brain and vice versa in both normal physiological function and disease. For instance, psychological and social factors influence motility and digestive function, symptom perception, and behaviors associated with illness and pathological outcomes. On the other hand, visceral pain affects central nociception pathways, mood and behavior. Recent interest highlights the influence of functional gut disorders, such as inflammatory bowel diseases and irritable bowel syndrome in the development of central comorbidities. Gut-brain axis dysfunction and microbiota dysbiosis have served as key portals in understanding the potential mechanisms associated with these functional gut disorders and their effects on cognition. In this review we will present the role gut-brain axis dysregulation plays in the chemotherapy setting, highlighting peripheral-to-central immune signaling mechanisms and their contribution to neuroimmunological changes associated with chemotherapy exposure. Here, we hypothesize that dysregulation of the gut-brain axis plays a major role in the intestinal, psychological and neurological complications following chemotherapy. We pay particular attention to evidence surrounding microbiota dysbiosis, the role of intestinal permeability, damage to nerves of the enteric and peripheral nervous systems and vagal and humoral mediated changes.
Highlights
The chemotherapy experience is associated with powerful psychological, neurological and somatic side-effects
We suggest that the gut-brain axis is an important mediator of a diverse range of cognitive and emotional disorders similar to those experienced by cancer survivors
The peripheral nervous system (PNS) is vulnerable to the cytotoxic nature of different chemotherapy drug classes, including platinum analogs, antitubulins, proteasome inhibitors, immunomodulatory agents and some newer biologics, such as brentuximab (Cavaletti and Marmiroli, 2015)
Summary
The chemotherapy experience is associated with powerful psychological, neurological and somatic side-effects. Due to the non-selective and systemic nature of most chemotherapy drugs, Chemotherapy and Gut-Brain Axis Dysregulation they target healthy, rapidly-dividing non-malignant cells. The regions of the body most susceptible to the unwanted toxicities of chemotherapy exposure are the gastrointestinal tract (GIT) and the central nervous system (CNS)—the gut and brain. Many chemotherapy drugs are small enough to readily cross the blood-brain barrier and result in molecular, structural and functional changes within the CNS, manifesting as cognitive changes in a subset of patients (Wigmore, 2012). Outside of the CNS, the cells of the GIT are vulnerable to damage following chemotherapy exposure. Epithelial cells within the mucosal layer lining the alimentary tract form prime targets due to chemotherapy drugs targeting proliferating enterocytes (Sonis, 2004). The complex network of pathways linking the gut to the brain will be discussed in more detail below as we present mechanisms by which chemotherapy results in gut-brain axis dysregulation
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