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

Abstract

BackgroundThe 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.MethodsThis 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.ConclusionKnowing 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).

Distal Gastrectomy with Billroth II Reconstruction is Associated with Oralization of Gut Microbiome and Intestinal Inflammation: A Proof-of-Concept Study

“… 56 , 57 However, there is a lack of data supporting whether dysbiosis persists in the long term, while this is still under investigation in an ongoing study. 58 Chemotherapy may have some long-lasting slight impact on the gut microbiome composition, potentially similar to long-lasting imprint described in healthy adults after exposure to short-term broad-spectrum antibiotics. 59 Therefore, in our present study, we could not rule out history of chemotherapy as a potential cofounder affecting microbiome, and excluded patients who received chemotherapy within the past 12 months.…”

Exploring the Potential Role of the Gut Microbiome in Chemotherapy-Induced Neurocognitive Disorders and Cardiovascular Toxicity

“…Currently, several ongoing large-scale clinical studies on young adult cancer survivors after chemotherapeutic treatment [ 136 ] and pediatric patients with solid tumors [ 137 ] aim to determine the role of the gut microbiome in treatment-induced short-term and long-term side effects.…”

The Butyrogenic and Lactic Bacteria of the Gut Microbiota Determine the Outcome of Allogenic Hematopoietic Cell Transplant

“…Radiotherapy and antibiotic/chemotherapy treatments that are practiced to kill fast dividing cancer cells and as treatment of complications of allo-HCT are known to induce oxidative stress, where high levels of reactive oxygen species (ROS) and reactive nitrogen species (NOS) are generated. The free oxygen radicals hydroxyl radical (OH), superoxide anion (O 2 −), hydrogen peroxide (H 2 O 2 ) trigger the up-regulation of cyclooxygenases (COX), nitric oxide synthase, lipoxygenases, and nicotinamide adenine dinucleotide phosphate oxidase, leading to DNA damage, inflammation (radiation-induced enteritis/radiation-induced bowel injury), cell apoptosis, and also modify the microbiota homeostasis ( Saha et al, 2017 ; Deleemans et al, 2019 ; Severyn et al, 2019 ). In a non-human primate model, ionizing radiations were also reported to induce up-regulation of tumor necrosis factor alpha (TNFα) and metalloprotease MMP7 ( Zheng et al, 2015 ), likely affecting the intestinal epithelium barrier integrity and bacterial infiltration.…”