Investigation of the gut microbiota in patients with acute myeloid leukemia
Cancer cachexia is a complex multi-organ syndrome characterized by body weight loss, weakness, muscle atrophy and fat depletion. Clinically, cachexia results in increased morbidity and mortality rates as well as reduced tolerance to anti-cancer treatments and complicates patients’ management1, 2. Currently, only limited therapeutic options exist for this important medical challenge and new approaches to tackle this syndrome, including innovative and scientifically relevant nutritional tools, are needed3, 4 . In this context, targeting the gut microbiota represents an exciting opportunity for this public health issue5.
Gut microbiota is considered a crucial regulator of host immunity and metabolism6 and microbial dysbiosis has been associated with the occurrence and/or evolution of several metabolic and inflammatory diseases7. Gut microbiota composition and function can be modulated using specific nutrients called prebiotics8. Links between gut microbiota and cancer have been studied for years9, 10, but it is only recently that the existence of a crosstalk between gut microbiota and metabolic alterations occurring during cancer (cachexia) has been proposed mainly based on three observations. First, administration of lactobacilli counteracted muscle atrophy in a mouse model of leukemia and cachexia11, an effect also reported in 2016 in another model12. Second, a common microbial signature (e.g. increased Enterobacteriaceae) was found in models of cancer cachexia, some bacteria being related to the cachectic phenotype13, 14. Finally, nutritional interventions that target the microbiota (including prebiotics) decreased cancer progression, reduced morbidity and fat mass loss, and increased survival of cachectic mice with leukemia13, 14. Altogether, a previously unexpected link between cancer, cachexia and the gut microbiota emerges from these preclinical studies.
These studies raised several questions. Can these findings be translated to cachectic patients? How is the gut microbiota composition affected in cancer cachexia? To start answering these questions, we have initiated a cohort study to investigate the composition and activity of the gut microbiota of patients newly diagnosed for acute myeloid leukemia (AML), in relationship with their food habits and cachectic hallmarks. The recruitment for this study is currently ongoing with the help of clinicians, nurses and data managers at the Cliniques universitaires Saint-Luc, UZ Leuven (Campus Gasthuisberg) and UZ Gent.
- To assess the composition and activity of the gut microbiota in patients with acute myeloid leukemia (AML) compared to matched control subjects.
- To investigate correlations between the gut microbiota, cachectic hallmarks and gut microbiota-related markers in the blood (gut permeability markers, microbial compounds, microbial metabolites).
- To characterize the changes in the gut microbial ecosystem that are induced by chemotherapy and associated with colitis.
- To assess whether the composition of the gut microbiota can predict the severity of chemotherapy-related colitis.
This is an academic multi-centric prospective study. The study is composed of two cohorts (Fig. 1). In Cohort A, patients are included before any chemotherapy. Biological samples (urine, feces, blood) are collected, alongside information on nutritional habits, appetite and medical records. Muscle strength and body composition are also measured. Only patients receiving a standard chemotherapy are included in Cohort B. In Cohort B, biological samples are collected and body composition, muscle strength and appetite are evaluated at 2 different time points, at the end of the chemotherapy (T1) and at discharge (T4).
We estimated a sample size of 30 to 40 AML patients who will be recruited during 2 to 3 years. As controls, healthy subjects will be recruited. They will be matched to AML patients for sex, BMI and age. The whole study will be completed within 3 to 4 years.
Fig. 1: Design of the MicroAML study. Standard chemotherapy is defined as idarubicine 12mg/m², on days 1, 2, 3, and Ara-C (cytarabine) 200mg/m², from day 1 to 7. T0: before any chemotherapy and antibiotics; T1: first weekday after the end of the chemotherapy; T2: one week after the end of the chemotherapy; T3: two weeks after chemotherapy; T4: last weekday before discharge. CRF: Clinical Reporting Form.
Expected perspectives for the study
We expect that this study will establish correlations between alterations of the gut microbial ecosystem and cachectic hallmarks. If this is the case, it will provide a scientific rational for a future trial with nutritional intervention (e.g. prebiotics). Furthermore, the faecal samples collected at the baseline could be used to conventionalize germ-free mice (mice devoid of any microbes). This model of gnotobiotic humanized mice would allow us to assess the impact of several prebiotics on the gut microbiota of those patients, thereby leading to the selection of an appropriate candidate for this future interventional trial.
Subinvestigators Saint-Luc Brussels
Dr. Violaine Havelange
Prof. Jean-Baptiste Demoulin
Subinvestigators UZ Leuven, Campus Gasthuisberg
Prof. Johan Maertens
Dr. Hélène Schoemans
Subinvestigators UZ Gent
Dr. Ine Moore
Prof. Tessa Kerre
Subinvestigator for the volunteers
Dr. Florence Bindels
- von Haehling S, Anker MS, Anker SD. Prevalence and clinical impact of cachexia in chronic illness in Europe, USA, and Japan: facts and numbers update 2016. J Cachexia Sarcopenia Muscle 2016;7:507-509.
- Farkas J, von Haehling S, Kalantar-Zadeh K, et al. Cachexia as a major public health problem: frequent, costly, and deadly. J Cachexia Sarcopenia Muscle 2013;4:173-8.
- Argiles JM, Busquets S, Stemmler B, et al. Cancer cachexia: understanding the molecular basis. Nat. Rev. Cancer 2014;14:754-762.
- Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia. Nat. Rev. Clin. Oncol 2013;10:90-99.
- Ebner N, von Haehling S. Unlocking the wasting enigma: Highlights from the 8th Cachexia Conference. J Cachexia Sarcopenia Muscle 2016;7:90-4.
- Delzenne NM, Cani PD, Everard A, et al. Gut microorganisms as promising targets for the management of type 2 diabetes. Diabetologia 2015.
- Marchesi JR, Adams DH, Fava F, et al. The gut microbiota and host health: a new clinical frontier. Gut 2016;65:330-339.
- Bindels LB, Delzenne NM, Cani PD, et al. Towards a more comprehensive concept for prebiotics. Nat. Rev. Gastroenterol. Hepatol 2015;12:303-310.
- Schwabe RF, Jobin C. The microbiome and cancer. Nat. Rev. Cancer 2013;13:800-812.
- Garrett WS. Cancer and the microbiota. Science 2015;348:80-86.
- Bindels LB, Beck R, Schakman O, et al. Restoring Specific Lactobacilli Levels Decreases Inflammation and Muscle Atrophy Markers in an Acute Leukemia Mouse Model. PLoS. One 2012;7:e37971.
- Varian BJ, Goureshetti S, Poutahidis T, et al. Beneficial bacteria inhibit cachexia. Oncotarget 2016;7:11803-16.
- Bindels LB, Neyrinck AM, Claus SP, et al. Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia. ISME. J 2016;10:1456-1470.
- Bindels LB, Neyrinck AM, Salazar N, et al. Non Digestible Oligosaccharides Modulate the Gut Microbiota to Control the Development of Leukemia and Associated Cachexia in Mice. PLoS. One 2015;10:e0131009.
Sponsor: Université catholique de Louvain
Belgian Registration Number: B403201317128
This work is funded through an ESPEN Research Fellowship awarded to Laure Bindels.