Gastrointestinal Permeability - a Parameter of Possible Prognostic Importance in Metastatic Colorectal Carcinoma

Abstract

Recently, we have observed in patients with ovarian carcinoma an association between intestinal permeability and prognosis and a correlation between urinary neopterin and parameters of intestinal permeability. In order to examine prognostic significance of intestinal permeability in a different group of patients, we have retrospectively analyzed pretreatment parameters of gastrointestinal permeability and urinary neopterin in 21 consecutive patients with metastatic colorectal carcinoma treated with the combination of cetuximab, irinotecan, leucovorin and 5-fluorouracil. Neopterin was determined by high-performance liquid chromatography, and gastrointestinal permeability was assessed by measuring, using capillary gas chromatography, urinary sucrose, lactulose, xylose, mannitol and sucralose after oral challenge. Pretreatment sucrose/mannitol ratio equal or above 0.04 (median survival 10.6 vs. 18.4 months; p = 0.03), sucrose/xylose equal or above 0.02 (12.1 vs. 19 months; p = 0.04) and urinary neopterin equal or above 220 µmol/mol creatinine (10.6 vs. 18.4 months; p = 0.02) were indicative of poor survival. A significant correlation was observed between urinary neopterin and sucrose/xylose ratio (rs = 0.57, p = 0.007), while correlation between urinary neopterin and sucrose/mannitol ratio (rs = 0.38, p = 0.096) was of borderline significance. In conclusion, present data demonstrate that gastrointestinal permeability is associated with systemic immune activation and may be of prognostic significance in patients with metastatic colorectal carcinoma.

The significance of altered gastrointestinal permeability in cancer patients

“…villus atrophy), increase in intestinal permeability (e.g. Increased disaccharide/monosaccharide ratio has been correlated with the presence of systemic immune activation reflected by increased concentrations of neopterin, a marker of macrophage activation [32,33,34 ], indicating activation of inflammatory and immune response associated with altered gut barrier function. This situation is hardly surprising if we consider the association of increased intestinal permeability with malnutrition [19] and the frequency of malnutrition in patients with advanced tumors.…”

“…an increase of disaccharide/monosaccharide ratio), decrease in xylose absorption as well as clinical signs of malabsorption are present even before the start of chemotherapy [20,30,31]. Some data even indicate that high baseline disaccharide/monosaccharide ratio may be predictive of poor prognosis in patients with advanced cancer [33]. Increased disaccharide/monosaccharide ratio has been correlated with the presence of systemic immune activation reflected by increased concentrations of neopterin, a marker of macrophage activation [32,33,34 ], indicating activation of inflammatory and immune response associated with altered gut barrier function.…”

In Vitro Rumen Fermentation Characteristics of Some Naturally Occurring and Synthetic Sugars

“…Besides their role as nutrients, combinations of monosaccharides (mannitol or Dxylose) and disaccharides (lactulose or cellobiose) resistant to mammalian digestive enzymes have been used in humans (Cox et al, 1999;Dastych et al, 2008) and laboratory animals (Hall, 1999) as markers to assess intestinal permeability. Sucralose has been recently proposed as an alternative to lactulose and cellobiose (Melichar et al, 2008) for the same purpose. In adult ruminants, their use may be compromised by the hydrolytic activity of the rumen microflora, but in the literature no data are available on the rumen fermentability of lactulose, mannitol and sucralose.…”

Intestinal permeability, vitamin A absorption, alpha-tocopherol, and neopterin in patients with rectal carcinoma treated with chemoradiation

“…Human monocytes/macrophages produce significant quantities of neopterin when stimulated with interferon-c, and increased concentrations of neopterin in serum or urine are considered to be an indicator of systemic immune activation [34]. Increased urinary and serum neopterin concentrations have been reported in patients with different primary tumors, including metastatic colorectal carcinoma, and high neopterin concentrations are indicative of poor prognosis in this tumor [12,35]. Increased neopterin concentrations were also described in patients with atherosclerosis [36][37][38].…”

“…An increase of intestinal permeability in cancer patients also correlates with increased concentrations of neopterin, an indicator of systemic immune response [11,12]. Neopterin may play an important role in antioxidant balance, and changes in neopterin concentrations may be associated with changes of other antioxidants, including alpha-tocopherol [13].…”