Increased gut permeability in cancer cachexia: mechanisms and clinical relevance

// Laure B. Bindels 1 , Audrey M. Neyrinck 1 , Audrey Loumaye 2 , Emilie Catry 1 , Hannah Walgrave 1 , Claire Cherbuy 3 , Sophie Leclercq 1, 4 , Matthias Van Hul 1, 5 , Hubert Plovier 1, 5 , Barbara Pachikian 1 , Luis G. Bermúdez-Humarán 3 , Philippe Langella 3 , Patrice D. Cani 1, 5 , Jean-Paul Thissen 2 and Nathalie M. Delzenne 1 1 Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium 2 Endocrinology, Diabetology and Nutrition Department, Institut de Recherches Expérimentales et Cliniques, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium 3 Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France 4 Pôle Clinique, Psychiatrie, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium 5 Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium Correspondence to: Laure B. Bindels, email: laure.bindels@uclouvain.be Nathalie M. Delzenne, email: nathalie.delzenne@uclouvain.be Keywords: cancer cachexia; gut barrier function; gut dysbiosis; lipopolysaccharide-binding protein; Enterobacteriaceae Received: December 15, 2017      Accepted: February 26, 2018      Published: April 06, 2018 ABSTRACT 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.