Increased gut permeability in cancer cachexia: mechanisms and clinical relevance

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.

Energy metabolism in cachexia

“…Arguing against this and supporting a systemic effect also in gastrointestinal cancer, increased gut leakage is also apparent in an additional mouse model where colon cancer cells are injected subcutaneously, excluding a direct mechanical effect of the primary tumor. In the latter study, gut integrity is restored by treatment with an anti‐IL‐6 antibody, demonstrating the involvement of the inflammatory system in intestinal dysfunction in cachexia . Inflammation therefore seems to be both cause and consequence of gut dysfunction, at least in rodent models.…”

Melatonin: Roles in influenza, Covid‐19, and other viral infections

“…include cardiovascular and lung disorders, diabetes, and cancer. 65 Many of the specific medical conditions that are included within these groups of disorders are linked to an elevation in gut dysbiosis/ permeability, 66,67 mitochondrial dysfunction, 68 and circadian dysregulation, 69,70 with melatonin showing utility in their management. 71,72 Ageing, the main risk factor for death from influenza and covid-19, is highly associated with these pathophysiological changes, [73][74][75][76] with melatonin, partly via sirtuin induction as well as circadian and mitochondria regulation, attenuating ageing-associated processes.…”

The Microbiota and Cancer Cachexia

“…Bindels et al further evaluated the interactions between cancer cachexia, gut barrier dysfunction and the microbiome through both human and animal studies [38]. Their mouse model for cancer cachexia was generated by the ectopic transplantation of C26 colon carcinoma cells.…”

“…Additional multivariate analysis revealed that increased LBP was significantly predictive of poor outcome in cancer patients. It was proposed that in the future LBP might be utilized as a biomarker in cancer cachexia [38]. Given this data, it is conceivable that the immune dysfunction may be both a cause and an effect of intestinal dysfunction and subsequent bacterial translocation.…”