Increased gut permeability in cancer cachexia: mechanisms and clinical relevance
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Laure B. Bindels1, Audrey M. Neyrinck1, Audrey Loumaye2, Emilie Catry1, Hannah Walgrave1, Claire Cherbuy3, Sophie Leclercq1,4, Matthias Van Hul1,5, Hubert Plovier1,5, Barbara Pachikian1, Luis G. Bermúdez-Humarán3, Philippe Langella3, Patrice D. Cani1,5, Jean-Paul Thissen2 and Nathalie M. Delzenne1
1Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
2Endocrinology, Diabetology and Nutrition Department, Institut de Recherches Expérimentales et Cliniques, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
3Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
4Pôle Clinique, Psychiatrie, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium
5Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
Laure B. Bindels, email: [email protected]
Nathalie M. Delzenne, email: [email protected]
Keywords: cancer cachexia; gut barrier function; gut dysbiosis; lipopolysaccharide-binding protein; Enterobacteriaceae
Received: December 15, 2017 Accepted: February 26, 2018 Published: April 06, 2018
Intestinal disorders often occur in cancer patients, in association with body weight loss, and this alteration is commonly attributed to the chemotherapy. Here, using a mouse model of cancer cachexia induced by ectopic transplantation of C26 cancer cells, we discovered a profound alteration in the gut functions (gut permeability, epithelial turnover, gut immunity, microbial dysbiosis) independently of any chemotherapy. 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). The translational value of our findings was evaluated in 152 colorectal and lung cancer patients with or without cachexia. The serum level of the lipopolysaccharide-binding protein, often presented as a reflection of the bacterial antigen load, was not only increased in cachectic mice and cancer patients, but also strongly correlated with the serum IL-6 level and predictive of death and cachexia occurrence in these patients. Altogether, our data highlight profound alterations of the intestinal homeostasis in cancer cachexia occurring independently of any chemotherapy and food intake reduction, with potential relevance in humans. In addition, we point out the lipopolysaccharide-binding protein as a new biomarker of cancer cachexia related to gut dysbiosis.
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