In the context of cancer cachexia

Bruxelles Woluwe

Our research team focusses on the development of new therapeutic nutritional tools based on the gut microbiota-host crosstalk in several pathological contexts. Such work highlights the importance of the gut and its microbes to target cancer cachexia, paving the way to new therapeutic opportunities (1-4).

Cancer cachexia is a complex multi-organ syndrome characterized by body weight loss, weakness, muscle atrophy and fat depletion. Mortality is predominantly due to muscle loss (5,6). Importantly, fat depletion may precedes muscle wasting in cancer cachexia and preserving fat mass can spare muscle mass (7,8). Paradoxically, accumulation of ectopic fat in the liver was found in rodent models of cancer cachexia and in cachectic patients (9-11). Clinically, cachexia results in increased morbidity and mortality rates as well as reduced tolerance to anti-cancer treatments (12,13). Currently, limited therapeutic options exist for this important medical challenge and new approaches to tackle this syndrome, including innovative and scientifically relevant nutritional tools, are needed (14,15). In this context, targeting the gut microbiota represents an exciting opportunity for this public health issue (1,16).

Links between gut microbiota and cancer have been studied for years (17,18). Our research over the last ten years has evidenced the existence of a crosstalk between the gut, the microbes its harbors and metabolic alterations occurring during cancer.

First, we showed in 2012 that restoring the lactobacilli levels through the administration of lactobacilli counteracted muscle atrophy and decreased systemic inflammation in a mouse model of leukemia and cachexia (3). This decrease in muscle atrophy upon lactobacilli administration was confirmed in 2016 in another model (19).

Second, we highlighted a common microbial signature (characterized mainly by an increase in Enterobacteriaceae) in preclinical models of cancer cachexia, in strong association with some cachectic features (2,4). This microbial signature was not due to the anorexia observed in the last stage of the disease (2,3).

Third, we found deep changes in the gut permeability and intestinal morphology in cachectic mice. Such changes were strongly correlated with the cachectic features. These alterations occurred independently of anorexia and were driven by interleukin 6. Gut dysfunction was found to be resistant to treatments with an anti-inflammatory bacterium (Faecalibacterium prausnitzii) or with gut peptides involved in intestinal cell renewal (teduglutide, a glucagon-like peptide 2 analogue) (Bindels et al, Oncotarget 2018).

Last but not least, we reported several times that nutritional interventions targeting the microbiota, such as prebiotics or probiotics, decreased cancer progression, reduced morbidity and fat mass loss, and/or increased survival of cachectic mice with leukemia (2,4,20). Our data highlight propionate, a short-chain fatty acid produced through the fermentation of prebiotics, as a potential mediator of this anti-cancer effect observed in leukemic mice with cachexia. Indeed, administration of inulin-type fructans (a well-known prebiotic) increased portal levels of propionate which is able to control the proliferation of leukemic cells (20). We investigated in this context the potential implication of FFAR2, a G-protein-coupled receptor which binds propionate and whose activation reduces cancer cell proliferation (20,21). Among others, our work indicates that a modulation of Ffar2 expression through nutritional microbiota-targeting tools may constitute an attractive therapeutic approach to tackle leukaemia progression in humans (22).

To evaluate the translational value of our experimental work, we have recently launched the MicroAML study. The MicroAML study aims to evaluate the composition and activity of the gut microbiota in patients with acute myeloid leukemia. Information related to appetite, food habits, body composition and muscle strength as well as biological samples are collected before any chemotherapy (additional details available online here). First results are expected for 2019.

Altogether, our studies reveal a previously unexpected link between cancer, cachexia and the gut microbiota. However, the exact mechanisms underlying this crosstalk remain elusive and constitute the topic of research of the newly established team of Prof Bindels.

References

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  3. Bindels LB, Beck R, Schakman O, et al. PLoS. One 2012.
  4. Bindels LB, Neyrinck AM, Salazar N, et al. PLoS. One 2015.
  5. Fearon K, Strasser F, Anker SD, et al. Lancet Oncol 2011.
  6. Zhou X, Wang JL, Lu J, et al. Cell 2010.
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  18. Garrett WS. Science 2015.
  19. Varian BJ, Goureshetti S, Poutahidis T, et al. Oncotarget 2016.
  20. Bindels LB, Porporato P, Dewulf EM, et al. Br. J. Cancer 2012.
  21. Bindels LB, Dewulf EM, Delzenne NM. Trends Pharmacol. Sci 2013.
  22. Bindels LB, Porporato PE, Ducastel S, et al. Br J Cancer 2017.