The chemo-gut study: investigating the long-term effects of chemotherapy on gut microbiota, metabolic, immune, psychological and cognitive parameters in young adult Cancer survivors; study protocol

Julie M Deleemans, Faye Chleilat, Raylene A Reimer, Jan-Willem Henning, Mohamad Baydoun, Katherine-Ann Piedalue, Andrew McLennan, Linda E Carlson, Julie M Deleemans, Faye Chleilat, Raylene A Reimer, Jan-Willem Henning, Mohamad Baydoun, Katherine-Ann Piedalue, Andrew McLennan, Linda E Carlson

Abstract

Background: The gut microbiota is an important modulator of immune, metabolic, psychological and cognitive mechanisms. Chemotherapy adversely affects the gut microbiota, inducing acute dysbiosis, and alters physiological and psychological function. Cancer among young adults has risen 38% in recent decades. Understanding chemotherapy's long-term effects on gut microbiota and psycho-physiological function is critical to improve survivors' physical and mental health, but remains unexamined. Restoration of the gut microbiota via targeted therapies (e.g. probiotics) could potentially prevent or reverse the psycho-physiological deficits often found in young survivors following chemotherapy, ultimately leading to reduced symptom burden and improved health.

Methods: This longitudinal study investigates chemotherapy induced long-term gut dysbiosis, and associations between gut microbiota, and immune, metabolic, cognitive and psychological parameters using data collected at < 2 month (T1), 3-4 months (T2), and 5-6 months (T3) post-chemotherapy. Participants will be 18-39 year old blood or solid tumor cancer survivors (n = 50), and a healthy sibling, partner or friend as a control (n = 50). Gut microbiota composition will be measured from fecal samples using 16 s RNA sequencing. Psychological and cognitive patient reported outcome measures will include depression, anxiety, post-traumatic stress disorder symptoms, pain, fatigue, and social and cognitive function. Dual-energy X-ray Absorptiometry (DXA) will be used to measure fat and lean mass, and bone mineral concentration. Pro-inflammatory cytokines, C-reactive protein (CRP), lipopolysaccharide (LPS), serotonin, and brain derived neurotrophic factor (BDNF) will be measured in serum, and long-term cortisol will be assayed from hair. Regression and linear mixed model (LMM) analyses will examine associations across time points (T1 - T3), between groups, and covariates with gut microbiota, cognitive, psychological, and physiological parameters.

Conclusion: Knowing what bacterial species are depleted after chemotherapy, how long these effects last, and the physiological mechanisms that may drive psychological and cognitive issues among survivors will allow for targeted, integrative interventions to be developed, helping to prevent or reverse some of the late-effects of treatment that many young cancer survivors face. This protocol has been approved by the Health Research Ethics Board of Alberta Cancer Committee (ID: HREBA.CC-19-0018).

Keywords: Cancer; Chemotherapy; Cortisol; Cytokines; Gut microbiota; Psycho-oncology; Young adult.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Chemotherapy Driven Dysbiosis of the Microbiota-Gut-Brain Axis. The Chemotherapy Driven Dysbiosis of the Microbiota-Gut-Brain Axis model posits that chemotherapy given to young cancer patients induces long-term gut dysbiosis, increasing intestinal permeability (i.e. “leaky gut”), which allows bacterial toxins, such as lipopolysaccharide (LPS), to enter the blood stream. This subsequently leads to systemic inflammation via increases in pro-inflammatory cytokines, especially IL-6, IL-1b, and TNF-a, and C-reactive protein, as well as dysregulation of the HPA-axis. This creates a feedback loop in which inflammatory mechanisms trigger the stress response to increase systemic cortisol, feeding back into the immune system to exacerbate levels of inflammation. Gut microbiota dysbiosis and dysregulation of the immune system and HPA-axis attenuate levels of serotonin (5-HT) and brain derived neurotrophic factor (BDNF), which then work in tandem to induce changes in psychological and cognitive function, including increased symptoms of anxiety and depression (i.e. “sickness behaviours”), pain, fatigue, and social and cognitive deficits. Finally, gut dysbiosis, immune, and HPA-axis dysregulation may also augment patients’ vulnerability to increased adipose tissue, and subsequent overweight and obesity, further compromising their health

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