In the context of cancer cachexia

Bruxelles Woluwe

Our research team focusses on the development of new therapeutic pharmacological and nutritional tools based on the gut microbiota-host crosstalk in several pathological contexts. Our work highlights the importance of the gut and its microbes to target cancer cachexia, paving the way to new therapeutic opportunities (Genton et al, Front Cell Infect Microbiol 2019; Pötgens et al, Curr Opin Nutr Metab Care 2018). Our work has clearly led to a better consideration of the potential of the gut microbiota in cancer cachexia (Ebner et al, J Cach Sarc Muscle 2020; Argiles et al, Nat Rev Endocrinol 2018; Dzutsev et al, Annu Rev Immunol 2017).

Cancer cachexia is a complex multi-organ syndrome characterized by body weight loss, weakness, muscle atrophy and fat depletion (Fearon et al, Lancet Oncol 2011). Importantly, fat depletion may precede muscle wasting in cancer cachexia and preserving fat mass can spare muscle mass (Das et al, Science 2011). Paradoxically, accumulation of ectopic fat in the liver was found in rodent models of cancer cachexia and in cachectic patients (Berriel et al, Hepatology 2008). Clinically, cachexia results in increased morbidity and mortality rates as well as reduced tolerance to anti-cancer treatments (Farkas et al, J Cach Sarc Muscle 2013). Currently, limited therapeutic options exist for this important medical challenge and new approaches to tackle this syndrome, including innovative and scientifically relevant nutritional and pharmacological tools, are needed (Pötgens et al, Cur Opin Metab Care 2018). In this context, targeting the gut microbiota represents an exciting opportunity for this public health issue.

Links between gut microbiota and cancer have been studied for years (Schwabe & Jobin, Nat Rev Cancer 2013). Our research over the last ten years has evidenced the existence of a crosstalk between the gut, the microbes it 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 (Bindels et al, Plos ONE 2012).

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 (Bindels et al, Plos ONE 2015; Bindels et al, The ISME J 2016). This microbial signature was not due to the anorexia observed in the last stage of the disease (Bindels et al, Plos ONE 2011; Bindels et al, The ISME J 2016). More recently, we have highlighted that Klebsiella oxytoca was the Enterobacteriaceae species that was fostered in cancer cachexia. We evidenced a mechanism of emergence for this bacterium similar to the one described for the bloom of Enterobacteriaceae during antibiotics consumption. This framework includes a reduction in Treg cells in the intestine, together with a glycolytic switch and a host-derived production of nitrate (Pötgens et al, Sci Rep 2018).

Third, we found drastic changes in the gut permeability and intestinal morphology of 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). We also demonstrated that K. oxytoca behaves as a gut pathobiont contributing to intestinal dysfunction in cachectic mice (Pötgens et al, Sci Rep 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 (Bindels et al, the ISME J 2016; Bindels et al, Plos ONE 2015; Bindels et al, Br J Cancer 2013). 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 can control the proliferation of leukemic cells (Bindels et al, Br J Cancer 2013).

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 our team (Prof Bindels' team). To achieve such goal, her team is using targeted and untargeted metabolomics analyses (recent implementation of H1-NMR metabolomics) using the NEST and MASSMETplatforms. These data are integrated with targeted microbial metagenomics and transcriptomics to highlight new pathways involved in this crosstalk. Using such approach, we confirmed several hepatic metabolic alterations previously reported in the literature (such as a reduction in hepatic glycolysis) while revealing new pathways potentially involved in cachectic features.

Specifically, we highlight (i) an activation of the hexosamine pathway in the liver, likely as a consequence of an endoplasmic reticulum stress and an unfold protein response, that may impact the hepatic signaling through O-GlcNAcylation; (ii) a reduction in the carnitine levels and its biosynthesis, and in the phosphatidylinositol pathway as potential contributors to the hepatic steatosis found in these mice; (iii) a reduction in the transformation of carbohydrates and proteins by the gut bacteria, that associates to specific host genic modulations (metabolic and gut barrier functions) (Pötgens et al, J Cach Sarc Muscle 2021).

We further investigated the contribution of bile acids, one of the bacterial co-metabolites identified through this metabolomic study. This led us to highlight a cholestasis in cancer cachexia (2 mouse models and one cohort of 94 patients) and to unequivocally demonstrate that systemic inflammation strongly contributes to the impairment of the hepatobiliary transport system in cancer cachexia. Targeting the enterohepatic circulation, we showed that bile acids contribute to hepatic inflammation and disorders. Altogether, our work highlights a vicious circle between bile acids and inflammation and paves the way to new therapeutic strategies targeting bile acids to control hepatic inflammation and metabolic disturbances in cancer cachexia (Thibaut et al, J Cach Sarc Muscle 2021).