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.

The Role of Gut Microbiome Perturbation in Fatigue Induced by Repeated Stress from Chemoradiotherapy: A Proof of Concept Study

“…A major gap in preventing and managing CRT-induced fatigue is that its biological mechanisms have not been identified. Nonetheless, renewed interest in the gut-brain-axis and the notable advances in high dimensional sequencing techniques/data have suggested a role of CRT-induced gut microbial perturbation/ dysbiosis in the pathobiology of CRT-related fatigue [4,5,8,9,14]; however, comprehensive microbiomics studies in this clinical population are scarce.…”

“…e etiology and associated mechanism of the cancer-related fatigue during CRT treatment remain elusive [3]. ere is some evidence, however, that suggests that cancer treatment-induced gut microbial perturbation/dysbiosis (an imbalance in the intestinal microbiota or microorganism that live in the gut) contributes to inflammation-enabling translocation of bacteria and microbially-mediated metabolites into systemic circulation and inducing aberrant activation of the immune system such as cytokine-induced (i.e., interleukin-6) inflammatory reaction, which can affect brain function and induce behavioral symptoms such as fatigue [4][5][6][7][8]. However, not enough microbiomic studies exist to identify associations between changes of the gut microbiota and fatigue severity during CRT for RC.…”

“…and an increase in Escherichia spp., as well as a decrease of goblet cell numbers or mucus secretion in the jejunum of rats [13]. e aforementioned evidence suggests that patients undergoing chemotherapy or RT may exhibit marked changes in their intestinal microbiota [4,5,9]. However, these studies focused on chemotherapy or RT, not both, had heterogeneous groups and small sample sizes suggesting that more research is needed regarding the disruption of the intestinal microbiata during CRT.…”

“…One small cohort study found that fatigue symptoms were positively correlated with the systemic markers of inflammation (haptoglobin), and the microbial diversity, richness, and the Firmicutes/Bacteroidetes ratio was significantly altered prior to pelvic RT in patients who later developed diarrhea with significant worsening in fatigue [14]. ere is an emerging interest in how CRT can play a part in decreased microbial diversity and increased bloom of pathobionts to influence systemic inflammatory responses with consequential behavioral effects [4,5,8,14]. is pilot study is aligned with that interest.…”

PDTC Alleviates Depressive Symptoms and Colon Tissue Injury via Inhibiting NO Overproduction in CUMS Rats

“…It is worth mentioning that the GI tract maintains an extensive intrinsic nervous system. The intrinsic enteric nervous system (ENS) can exert influences on the intestinal tract even when it is disconnected from the CNS (Bajic et al, 2018). The ENS is controlled by extrinsic innervation from the lower spinal cord, where sympathetic fibers suppress contraction of the colonic musculature, and parasympathetic fibers conversely facilitate colon motility, consequently affecting immune-, mucosa-, and microflora-related alterations (Camilleri and Ford, 1998;Mayer, 2011).…”