Role of gut microbiota modulation in the control of cancer progression and associated cachexia
(2013)
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- Authors
- Supervisors
- Delzenne, Nathalie
- Abstract
- (en) Cancer is a leading cause of death worldwide (approximately 13 % of all deaths), accounting for 7.6 million deaths in 2008. Up to 50 % of cancer patients suffer from cachexia, defined as a progressive loss of adipose tissue and skeletal muscle atrophy. This results in reduced quality of life and shortened survival time. Nowadays, gut microbiota is proposed as a crucial regulator of host immunity and metabolism and is involved in the occurrence and/or evolution of several metabolic and inflammatory diseases, such as obesity, diabetes, inflammatory bowel diseases and allergies. These diseases have been associated in humans with intestinal dysbiosis. Intestinal dysbiosis is characterised by ‘‘alterations in the composition and/or activity of the gut microbiota in comparison to healthy individuals, which are associated to pathological features”. This PhD work was dedicated to the investigation of gut microbiota function in case of cancer and associated cachexia. The working hypothesis was that gut microbiota is altered in cancer cachexia and that gut microbiota modulation might influence cancer progression and associated disorders. Several mouse models of cachexia were compared. We chose the BaF3 model, a mouse model of cachexia which mimics an acute leukaemia. We showed that dysbiosis occurred in this model and, specifically, that the levels of gut lactobacilli were decreased. Actually, lactobacilli were also qualitatively modified: L. reuteri and L. johnsonii/gasseri were decreased, whereas L. murinus/animalis was not modified. The administration of a mixture of L. reuteri 100-23 and L. gasseri 311476 in the drinking water restored the levels of these lactobacilli and decreased systemic inflammation and muscle atrophy markers. Analysis of the gut microbiota composition in two other mouse models of cancer cachexia, B16 and C26 models, suggests that dysbiosis is not a hallmark of the BaF3 model. Prebiotics such as short-chain inulin-type fructans (ITF) have been shown to increase lactobacilli in vitro and in vivo in some conditions. ITF feeding in BaF3 mice neither restored gut lactobacilli nor decreased muscle atrophy markers. However, interestingly, prebiotics administration reduced the invasion of cancer cells in the liver. We postulated that a short-chain fatty acid produced by the bacterial fermentation of ITF – propionate – was responsible for the control of cancer cell proliferation in the liver tissue. The measurement of short-chain fatty acids in the portal serum revealed that propionate levels were increased upon prebiotics. Interestingly, serum levels of other short-chain fatty acids, such as acetate and butyrate, were not modified. This anti-proliferative action of propionate was established through several in vitro experiments. We investigated the potential implication of GPR43, a G-protein-coupled receptor which binds propionate and is regulated in response to gut microbiota modulation. Based on experimental evidence, we propose that the anti-proliferative action of propionate is partially cAMP-dependent, and that GPR43 is of therapeutic interest for the treatment of lymphomas. The last part of the thesis includes a study of the mechanisms underlying the modulation of GPR43 expression. Among others, we showed that GPR43 expression level is increased by a synthetic agonist of GPR43 through a STAT3-dependent mechanism, and that GPR43 transcript level is a marker, rather than a driver, of cell growth arrest. In conclusion, we show that gut microbiota composition is altered in cancer cachexia and that gut microbiota modulation, by prebiotic or probiotic approaches, can differentially impact on cancer progression and associated disorders, thereby highlighting the importance of research focusing on gut microbes-host interactions for managing systemic and severe diseases such as leukaemia.
- Affiliations
Citations
Bindels, L. (2013). Role of gut microbiota modulation in the control of cancer progression and associated cachexia. https://hdl.handle.net/2078.5/76155