Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Respiratory Microbiota | Study protocol

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

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

Published in: BMC Cancer | Issue 1/2019

Login to get access

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).
Literature
1.
Petra AI, Panagiotidou S, Hatziagelaki E, Stewart JM, Conti P, Theoharides TC. Gut-microbiota-brain Axis and its effect on neuropsychiatric disorders with suspected immune Dysregulation. Clin Ther. 2015;37(5):984–95.PubMedPubMedCentralCrossRef
2.
Foster JA, Neufeld KM. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305–12.PubMedCrossRef
3.
Maes M, Kubera M, Leunis JC, Berk M, Geffard M, Bosmans E. In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand. 2013;127(5):344–54.PubMedCrossRef
4.
Dinan TG, Cryan JF. The microbiome-gut-brain Axis in health and disease. Gastroenterol Clin N Am. 2017;46(1):77–89.CrossRef
5.
Forsythe P, Bienenstock J, Kunze WA. Vagal pathways for microbiome-brain-gut axis communication. Adv Exp Med Biol. 2014;817:115–33.PubMedCrossRef
6.
Bai J, Behera M, Bruner DW. The gut microbiome, symptoms, and targeted interventions in children with cancer: a systematic review. Support Care Cancer. 2018;26(2):427–39.PubMedCrossRef
7.
Jordan KR, Loman BR, Bailey MT, Pyter LM. Gut microbiota-immune-brain interactions in chemotherapy-associated behavioral comorbidities. Cancer. 2018;124(20):3990–9.PubMedCrossRef
8.
Jacola LM, Edelstein K, Liu W, Pui CH, Hayashi R, Kadan-Lottick NS, Srivastava D, Henderson T, Leisenring W, Robison LL, et al. Cognitive, behaviour, and academic functioning in adolescent and young adult survivors of childhood acute lymphoblastic leukaemia: a report from the childhood Cancer survivor study. Lancet Psychiatry. 2016;3(10):965–72.PubMedPubMedCentralCrossRef
9.
Schulte F, Brinkman TM, Li C, Fay-McClymont T, Srivastava DK, Ness KK, Howell RM, Mueller S, Wells E, Strother D, et al. Social adjustment in adolescent survivors of pediatric central nervous system tumors: a report from the childhood Cancer survivor study. Cancer. 2018;124(17):3596–608.PubMedCrossRef
10.
11.
Borre YE, O'Keeffe GW, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med. 2014;20(9):509–18.PubMedCrossRef
12.
Cancer CPA. Adolescents and young adults with Cancer: system performance report. In. Toronto, Canada; 2017.
13.
Barr RD, Ferrari A, Ries L, Whelan J, Bleyer WA. Cancer in adolescents and young adults: a narrative review of the current status and a view of the future. JAMA Pediatr. 2016;170(5):495–501.PubMedCrossRef
14.
Asher A. Cognitive dysfunction among cancer survivors. Am J Phys Med Rehabil. 2011;90(5 Suppl 1):S16–26.PubMedCrossRef
15.
Seitz DC, Besier T, Debatin KM, Grabow D, Dieluweit U, Hinz A, Kaatsch P, Goldbeck L. Posttraumatic stress, depression and anxiety among adult long-term survivors of cancer in adolescence. Eur J Cancer. 2010;46(9):1596–606.PubMedCrossRef
16.
17.
Huang Y, Yang W, Liu H, Duan J, Zhang Y, Liu M, Li H, Hou Z, Wu KK. Effect of high-dose methotrexate chemotherapy on intestinal Bifidobacteria, Lactobacillus and Escherichia coli in children with acute lymphoblastic leukemia. Exp Biol Med (Maywood). 2012;237(3):305–11.CrossRef
18.
Montassier E, Gastinne T, Vangay P, Al-Ghalith GA, Bruley des Varannes S, Massart S, Moreau P, Potel G, de La Cochetiere MF, Batard E, et al. Chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment Pharmacol Ther. 2015;42(5):515–28.PubMedCrossRef
19.
Scully C, Epstein J, Sonis S. Oral mucositis: a challenging complication of radiotherapy, chemotherapy, and radiochemotherapy: part 1, pathogenesis and prophylaxis of mucositis. Head Neck. 2003;25(12):1057–70.PubMedCrossRef
20.
Dash S, Clarke G, Berk M, Jacka FN. The gut microbiome and diet in psychiatry: focus on depression. Curr Opin Psychiatry. 2015;28(1):1–6.PubMedCrossRef
21.
Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007;21(2):153–60.PubMedCrossRef
22.
Berk M, Williams LJ, Jacka FN, O'Neil A, Pasco JA, Moylan S, Allen NB, Stuart AL, Hayley AC, Byrne ML, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013;11:200.PubMedPubMedCentralCrossRef
23.
Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, Miller AH. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26(5):643–52.PubMedCrossRef
24.
O'Mahony SM, Hyland NP, Dinan TG, Cryan JF. Maternal separation as a model of brain-gut axis dysfunction. Psychopharmacology. 2011;214(1):71–88.PubMedCrossRef
25.
Beishuizen A, Thijs LG. Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis. J Endotoxin Res. 2003;9(1):3–24.PubMed
26.
27.
Schurman JV, Singh M, Singh V, Neilan N, Friesen CA. Symptoms and subtypes in pediatric functional dyspepsia: relation to mucosal inflammation and psychological functioning. J Pediatr Gastroenterol Nutr. 2010;51(3):298–303.PubMed
28.
Hilimire MR, DeVylder JE, Forestell CA. Fermented foods, neuroticism, and social anxiety: an interaction model. Psychiatry Res. 2015;228(2):203–8.PubMedCrossRef
29.
Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015;48:258–64.PubMedCrossRef
30.
31.
Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience. 2010;170(4):1179–88.PubMedCrossRef
32.
Anderson SC, Cryan JF, Dinan T. The Psychobiotic revolution: mood, food, and the new science of the gut-brain connection. Washington, DC: National Geographic Partners, LLC; 2017.
33.
Janssen DG, Caniato RN, Verster JC, Baune BT. A psychoneuroimmunological review on cytokines involved in antidepressant treatment response. Hum Psychopharmacol. 2010;25(3):201–15.PubMedCrossRef
34.
Sarkar A, Harty S, Lehto SM, Moeller AH, Dinan TG, Dunbar RIM, Cryan JF, Burnet PWJ. The microbiome in psychology and cognitive neuroscience. Trends Cogn Sci. 2018;22(7):611–36.PubMedCrossRef
35.
Vazquez E, Barranco A, Ramirez M, Gruart A, Delgado-Garcia JM, Martinez-Lara E, Blanco S, Martin MJ, Castanys E, Buck R, et al. Effects of a human milk oligosaccharide, 2′-fucosyllactose, on hippocampal long-term potentiation and learning capabilities in rodents. J Nutr Biochem. 2015;26(5):455–65.PubMedCrossRef
36.
Prehn-Kristensen A, Zimmermann A, Tittmann L, Lieb W, Schreiber S, Baving L, Fischer A. Reduced microbiome alpha diversity in young patients with ADHD. PLoS One. 2018;13(7):e0200728.PubMedPubMedCentralCrossRef
37.
Naseribafrouei A, Hestad K, Avershina E, Sekelja M, Linlokken A, Wilson R, Rudi K. Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil. 2014;26(8):1155–62.PubMedCrossRef
38.
Prasad PK, Hardy KK, Zhang N, Edelstein K, Srivastava D, Zeltzer L, Stovall M, Seibel NL, Leisenring W, Armstrong GT, et al. Psychosocial and neurocognitive outcomes in adult survivors of adolescent and early young adult Cancer: a report from the childhood Cancer survivor study. J Clin Oncol. 2015;33(23):2545–52.PubMedPubMedCentralCrossRef
39.
Deleemans JM, Reynolds K, Schulte F. Associations among health behaviours and psychosocial outcomes in adolescent and young adult (AYA) cancer survivors. Toronto, Ontario, Canada: Canadian Association of Psychosocial Oncology; 2018.
40.
Tai E, Buchanan N, Townsend J, Fairley T, Moore A, Richardson LC. Health status of adolescent and young adult cancer survivors. Cancer. 2012;118(19):4884–91.PubMedCrossRef
41.
Bervoets L, Van Hoorenbeeck K, Kortleven I, Van Noten C, Hens N, Vael C, Goossens H, Desager KN, Vankerckhoven V. Differences in gut microbiota composition between obese and lean children: a cross-sectional study. Gut Pathog. 2013;5(1):10.PubMedPubMedCentralCrossRef
42.
Bomhof MR, Paul HA, Geuking MB, Eller LK, Reimer RA. Improvement in adiposity with oligofructose is modified by antibiotics in obese rats. FASEB J. 2016;30(8):2720–32.PubMedCrossRef
43.
Dudek-Wicher RK, Junka A, Bartoszewicz M. The influence of antibiotics and dietary components on gut microbiota. Prz Gastroenterol. 2018;13(2):85–92.PubMedPubMedCentral
44.
Mahana D, Trent CM, Kurtz ZD, Bokulich NA, Battaglia T, Chung J, Muller CL, Li H, Bonneau RA, Blaser MJ. Antibiotic perturbation of the murine gut microbiome enhances the adiposity, insulin resistance, and liver disease associated with high-fat diet. Genome Med. 2016;8(1):48.PubMedPubMedCentralCrossRef
45.
46.
47.
Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C. Metagenomic biomarker discovery and explanation. Genome Biol. 2011;12(6):R60.PubMedPubMedCentralCrossRef
48.
Nicolucci AC, Hume MP, Martinez I, Mayengbam S, Walter J, Reimer RA. Prebiotics reduce body fat and Alter intestinal microbiota in children who are overweight or with obesity. Gastroenterology. 2017;153(3):711–22.PubMedCrossRef
49.
Berruti A, Dogliotti L, Terrone C, Cerutti S, Isaia G, Tarabuzzi R, Reimondo G, Mari M, Ardissone P, De Luca S, et al. Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. J Urol. 2002;167(6):2361–7 discussion 2367.PubMedCrossRef
50.
Sandberg E. Meso scale discovery training report. In: The University of Calgary; 2018.
51.
52.
Steudte S, Kirschbaum C, Gao W, Alexander N, Schonfeld S, Hoyer J, Stalder T. Hair cortisol as a biomarker of traumatization in healthy individuals and posttraumatic stress disorder patients. Biol Psychiatry. 2013;74(9):639–46.PubMedCrossRef
53.
Steudte-Schmiedgen S, Kirschbaum C, Alexander N, Stalder T. An integrative model linking traumatization, cortisol dysregulation and posttraumatic stress disorder: insight from recent hair cortisol findings. Neurosci Biobehav Rev. 2016;69:124–35.PubMedCrossRef
54.
Cessna JM, Jim HS, Sutton SK, Asvat Y, Small BJ, Salsman JM, Zachariah B, Fishman M, Field T, Fernandez H, et al. Evaluation of the psychometric properties of the PROMIS Cancer fatigue short form with cancer patients. J Psychosom Res. 2016;81:9–13.PubMedCrossRef
55.
Allan Cheyne J, Solman GJ, Carriere JS, Smilek D. Anatomy of an error: a bidirectional state model of task engagement/disengagement and attention-related errors. Cognition. 2009;111(1):98–113.PubMedCrossRef
56.
Chen W, Liu F, Ling Z, Tong X, Xiang C. Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PLoS One. 2012;7(6):e39743.PubMedPubMedCentralCrossRef
57.
Metadata
Title
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
Authors
Julie M. Deleemans
Faye Chleilat
Raylene A. Reimer
Jan-Willem Henning
Mohamad Baydoun
Katherine-Ann Piedalue
Andrew McLennan
Linda E. Carlson
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-6473-8

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue

Research article

LAPTM4B is a novel diagnostic and prognostic marker for lung adenocarcinoma and associated with mutant EGFR

Research article

Alterations in the glycome after HDAC inhibition impact oncogenic potential in epigenetically plastic SW13 cells

Research article

Reduction of metastatic potential by inhibiting EGFR/Akt/p38/ERK signaling pathway and epithelial-mesenchymal transition after carbon ion exposure is potentiated by PARP-1 inhibition in non-small-cell lung cancer

Research article

It’s never too late - balance and endurance training improves functional performance, quality of life, and alleviates neuropathic symptoms in cancer survivors suffering from chemotherapy-induced peripheral neuropathy: results of a randomized controlled trial

Research article

MUC16 impacts tumor proliferation and migration through cytoplasmic translocation of P120-catenin in epithelial ovarian cancer cells: an original research

Research article

A pan-cancer perspective of matrix metalloproteases (MMP) gene expression profile and their diagnostic/prognostic potential
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits