From the Bottom-Up: Chemotherapy and Gut-Brain Axis Dysregulation

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.

Keywords: chemotherapy-induced cognitive impairment; chemotherapy-induced gut toxicity; gut-brain axis; microbiota; mucositis.

Figure 1

The inflammatory reflex. (1) The inflamed zone represents tissue damage, infection and ischemia. (2) Increased expression of inflammatory mediators and cytokines, such as Il-1β and TNF-α are released by cells in the inflamed zone. (3) Cytokines activate primary afferent neurons within the vagal sensory ganglia. (4) Afferent visceral signals are relayed to nuclei in the dorsal vagal complex (DVC), such as the nucleus tractus solitarius. (5) Visceral information is further relayed from the DVC to higher order brain regions, such as the hypothalamus, hippocampus and forebrain. (6) Activation of efferent vagal motor activity inhibits cytokine synthesis. (7) Hypothalamus activation stimulates the release of adrenocorticotrophic hormone from the pituitary gland, initiating a humoral anti-inflammatory pathway. (8) Sympathetic outflow can increase localized adrenaline and noradrenaline expression further suppressing inflammation. IL-1β, interleukin-1 beta; TNF-α, tumor necrosis factor—alpha; DVC, dorsal vagal complex; NTS, nucleus tractus solitarius; HYP, hypothalamus; HIP, hippocampus; FB, forebrain; ACTH, adrenocorticotrophic hormone.

Figure 2

Adapted from Dodds et al. (2016). Neuroimmunological complications arising from cancer and chemotherapy treatment. (1) Cancer patients undergoing chemotherapy treatment express an altered immune profile with increases in proinflammatory cytokines. (2) Systemic proinflammatory cytokines and mediators, such as IL-1 and TNF released either from the malignancy or treatment-associated toxicities access the brain directly via leaky circumventricular organs or (3) indirectly via neural transmission. (4) Systemic or localized proinflammatory mediators and cytokines signal higher order brain regions and (5) activate microglia and astrocytes. Reactive glia undergo morphological changes and overproduce proinflammatory mediators whilst reducing anti-inflammatory output—resulting in neurotoxicity and neuroinflammation. (6) In particular brain regions primed glia and neuroinflammation influence behaviors involving cognition and contribute to various neurodegenerative diseases. (7) Centrally derived neurogenic inflammation and descending signaling in the spinal cord (8) contributes to the exacerbation of peripheral inflammatory conditions and exaggerated pain states. Therefore, peripheral-to-central innate immune signaling represents a plausible mechanism meditating chemotherapy-induced gut toxicity and neurological changes. FB, forebrain; HIP, hippocampus; IL-1, interleukin-1; TNF, tumor necrosis factor.

Figure 3

Schematic of a healthy gut-brain axis. The arrows highlight the bidirectional nature of the gut-brain axis; in a balanced system mechanisms from the bottom-up (and vice versa) exist in cohesion. In a healthy system, the gut-brain axis integrates information from many systems; the central nervous system (CNS), autonomic nervous system (ANS), enteric nervous system (ENS), neuroendocrine, enteroendochrine, neuroimmune, and hypothalamic-pituitary axis (HPA). The complex bidirectional communication pathways and systems shared between the gut and the brain maintain health and homeostasis in the CNS, GIT, and microbiota. Efferent signals from the brain involving neuro-endocrine, autonomic and HPA outputs influence motility, secretion, nutrient delivery and microbial balance in the GIT. Whilst afferent inputs from the GIT, such as intestinal hormones, cytokines and sensory perceptions influence neurotransmitter expression, stress, anxiety, mood and behavior. CNS, central nervous system; ANS, autonomic nervous system; ENS, enteric nervous system; HPA, hypothalamic-pituitary axis; GIT, gastrointestinal tract.

Figure 4

Chemotherapy disrupts several stages of the gut-brain axis. The arrows highlight the bidirectional nature of the gut-brain axis; in an unbalanced system mechanisms from the bottom-up (and vice versa) are disrupted. We suggest that chemotherapy-induced gut-brain axis dysregulation plays a major role in the intestinal, psychological and neurological complications experienced by many cancer patients. Chemotherapy exposure (1) often results in molecular and structural changes in the brain (2), e.g., hippocampal changes as identified in rodent models. Chemotherapy exposure causes cognitive and behavioral changes (2) to a subset of patients and these findings have been supported by some experimental models. The altered immune profile of chemotherapy recipients results in increased circulating pro-inflammatory cytokines (3) which have been reported to cause cytokine-induced sickness-like responses (4) which mimic chemotherapy-induced side-effects. Damage to peripheral nerves resulting in peripheral neuropathies (5) are experienced by some chemotherapy recipients. Chemotherapy targets the intestines and its microbial contents causing dysbiosis (6), impairing the nerves of the myenteric plexus (7), damaging intestinal wall parameters (8), and resulting in mucositis (9). Serotonin dysregulation under chemotherapy conditions (10) may play a role in chemotherapy-induced intestinal and neurological changes. Finally, both humoral and neural/vagal peripheral-to-central immune signaling pathways (11) may mediate chemotherapy-induced gut-brain axis dysregulation. Importantly, we acknowledge that the stress, anxiety and depression associated with cancer diagnosis and treatment (12) may contribute to both bottom-up and top-down pathways, having negative effects in the gut and the brain.