“The mechanisms underpinning these chemobrain symptoms are poorly understood, posing a serious impediment to their clinical management”
Cancer is the second-leading cause of death in Europe and imposes significant human and economic costs. Research in recent decades has primarily focused on reducing mortality and relapse rates, leading to considerable improvements to established treatment regimens as well as the advent of new therapies, specifically the development of immunotherapies and more targeted anti-cancer agents. These advancements in treatment options have dramatically improved patient care and survival for several cancers and have also exposed a number of issues around the long-term side effects of cancer therapies that impact quality of life.
What is chemobrain?
A large subset of cancer patients and survivors frequently report neuropsychiatric symptoms and impairments during and following cancer treatment, including impaired cognition, increased incidence of mood and anxiety disorders, and increased pain and fatigue which collectively resembles “brain fog” and has been termed “chemobrain”. These impairments are most frequent during and immediately following therapy, although some cancer survivors experience these symptoms for decades after the resolution of their cancer, interfering with their well-being and return to normal life. These neuropsychiatric impairments are often difficult to quantify: while patients’ subjective reports indicate sluggish thinking and poorer cognitive performance following therapy, these are often not well captured by standard neuropsychological testing utilised in the majority of studies to date. This is most likely because standard neuropsychological tests were originally designed for diagnosis of focal lesions of the central and peripheral nervous systems, rather than diffuse damage throughout the brain. Approaches using methods from cognitive psychology, which are designed to assess cognitive performance within healthy populations, have identified that cancer patients and survivors suffer from difficulties with concentration and attention, short-term memory and executive function.
What the Research Tells us
While most research so far has shown that these neuropsychiatric symptoms and impairments are associated with traditional cytotoxic chemotherapy regimens in cancer patients and survivors, there is emerging evidence that newer immunotherapies 1 and targeted cancer therapies 2 may have similar impacts on brain health and function. The mechanisms underpinning these chemobrain symptoms are poorly understood, posing a serious impediment to their clinical management. Similarly to cancer patients and survivors, in vivo experiments with chemotherapeutic agents induce impairments in cognition and increased anxiety-like and pain behaviours. These experiments have shown that chemotherapeutic agents increase neuroinflammation, reduce neurogenesis and neurotransmitter availability, and alter neuronal morphology throughout the central and peripheral nervous systems when administered in both healthy animals and those with cancerous tumours.
The gut microbiota, cancer and chemobrain
The human gastrointestinal tract is populated by an ecosystem of bacteria and other micro-organisms, collectively known as the gut microbiota, that have co-evolved alongside humans to produce a complex symbiotic relationship. The gut microbiota supports host physiology through improved energy harvest, strengthened gut integrity and barrier function, protection from infection, immune modulation 3 , and brain health and function. 4 A healthy gut microbiota is thought to reduce the risk of cancer development, while altered gut microbiota community as well as specific gut microbes can increase the likelihood of developing gastrointestinal cancers 5 (for example, Helicobacter pylori causes stomach ulcers and increases the prevalence of stomach and small intestine cancers while Fusobacterium nucleatum promotes colorectal cancer development). Furthermore, the gut microbiota can modulate cancer therapy effectiveness through direct and indirect interactions with cancer drugs: chemotherapies can transiently shift gut microbiota composition and microbial metabolite production, and baseline microbiota composition and exposure to antibiotics influences patient responses to immunotherapy.
“Understanding the mechanisms at play can help find some muchneeded solutions to this problem and deliver potential interventions for these behavioural impairments”
The gut microbiota also appears to be involved in cancer therapy side effects involving the gut (diarrhoea and nausea), infection risk as well as changes in the central and peripheral nervous systems. A recent systematic review assessing the role of the microbiota in side effects reported by cancer patients concluded that microbiota composition was associated with fatigue, anxiety, depression, sleep quality, cognitive impairment and peripheral neuropathy in patients undergoing chemotherapy. 7 These results are in line with emerging evidence from experiments in vivo where chemotherapy-related fatigue 8 and peripheral neuropathy 9 are related to microbiota composition and can be modified through interventions targeting the microbiota. So far, only a few drugs and neuropsychological symptoms have been examined and several experts in the field have identified the microbiota as a potential site for intervention in chemobrain.
What is the role of drug-microbiota and brain-microbiota interactions in chemobrain?
Professors Gerard Clarke, John Cryan, and I at APC Microbiome Ireland, a Science Foundation Ireland funded research centre dedicated to the study of host-microbe interactions, are combining behavioural neuroscience and neuropharmacology approaches to address how traditional and novel cancer drugs may induce chemobrain through modulation of the gut microbiota, in collaboration with a multidisciplinary team spanning pharmacy, pharmacomicrobiomics (the study of drugmicrobiota interactions), microbiology and oncology. Our current project is grounded in the hypothesis that host-microbiota and drug-microbiota interactions underlie cancer-therapy associated behavioural impairment. Specifically, we propose that different cancer therapies will present unique drug-microbiota interactions that will modify host-microbiota interactions and subsequently behaviour.
The lived experience of cancer treatment means people often take longer than they anticipated to get back on their feet and fully engaged in life, and this is often due in part to chemobrain. Understanding the mechanisms at play can help find some much-needed solutions to this problem and deliver potential interventions for these behavioural impairments. The study of how microbiota-drug interactions alter drug benefits and side effects is a relatively new avenue of research with substantial scope to yield impactful new discoveries. The development of microbiota-targeted therapies holds promise for the management of these troublesome side effects that cloud quality of life for cancer patient and survivor.
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References:
1. Joly F, Castel H, Tron L, Lange M, Vardy J. Potential Effect of Immunotherapy Agents on Cognitive Function in Cancer Patients. J Natl Cancer Inst. 2020;112(2):123-127. doi:10.1093/jnci/djz168
2. Abdel-Aziz AK, Mantawy EM, Said RS, Helwa R. The tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in vivo via dysregulating VEGFR signaling, apoptotic and autophagic machineries. Exp Neurol. 2016 Sep;283(Pt A):129-41. doi: 10.1016/j. expneurol.2016.06.004.
3. Sekirov I, Russell SL, Antunes LCM et al. Gut Microbiota in Health and Disease. Physiological Reviews. 2010;90(3):859-904. doi: 10.1152/physrev.00045.2009.
4. Cryan, J., Dinan, T. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012 13, 701–712. https://doi. org/10.1038/nrn3346
5. Helmink, B.A., Khan, M.A.W., Hermann, A. et al. The microbiome, cancer, and cancer therapy. Nat Med 25, 377–388 (2019). https:// doi.org/10.1038/s41591-019-0377-7
6. Leigh SJ, Lynch CMK, Bird BRH, et al. Gut microbiota-drug interactions in cancer pharmacotherapies: implications for efficacy and adverse effects. Expert Opin Drug Metab Toxicol. 2022 Jan;18(1):5-26. doi: 10.1080/17425255.2022.2043849.
7. Song BC, Bai J. Microbiome-gut-brain axis in cancer treatment-related psychoneurological toxicities and symptoms: a systematic review. Support Care Cancer. 2021 Feb;29(2):605-617. doi: 10.1007/s00520-020- 05739-9.
8. Grant CV, Loman BR, Bailey MT, Pyter LM. Manipulations of the gut microbiome alter chemotherapy-induced inflammation and behavioral side effects in female mice. Brain Behav Immun. 2021 Jul;95:401-412. doi: 10.1016/j.bbi.2021.04.014.
9. Ramakrishna, C., Corleto, J., Ruegger, P.M. et al. Dominant Role of the Gut Microbiota in Chemotherapy Induced Neuropathic Pain. Sci Rep 9, 20324 (2019). https://doi. org/10.1038/s41598-019-56832-x
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