Gut barrier dysfunction in the Apc(Min/+) mouse model of colon cancer cachexia.

Background: The Apc(Min/+) mouse, an animal model of colorectal cancer and cachexia, has a heterologous mutation in the Apc tumor suppressor gene, predisposing the mouse to intestinal and colon tumor development. This mouse develops intestinal polyps by ~4 weeks of age, and loses body weight gradually between ~14 and ~20 weeks of age. The strengths of this cachexia model derive from several features that mimic human cancer, including a gradual increase in tumor burden, chronic inflammation, and anemia. Little is known about the role of gut barrier dysfunction and endotoxemia in the development of cancer cachexia. We sought to determine how gut permeability and resultant endotoxemia change with the progression of cachexia.

Methods: Intestinal gut barrier integrity was assessed by permeability to FITC-dextran (MW(av)=4000kDa; FD4). Plasma glucose and triglycerides were measured by enzymatic assays, IL-6 by enzyme-linked immunosorbent assay, and endotoxin by the limulus amoebocyte assay. Body temperature was measured using a rectal probe.

Results: Progression of cachexia was accompanied by development of gut barrier dysfunction (permeability to FD4), hypertrophy of mesenteric lymph nodes, and an increase in plasma endotoxin concentration. Changes in blood glucose and glucose tolerance, plasma IL-6, triglycerides, and body temperature were characteristic of endotoxemia.

Conclusion: We propose a role for gut barrier dysfunction (GBD) and subsequent endotoxemia in the development of inflammation and progression of cachexia in the Apc(Min/+) mouse.