Lactose maldigestion during methotrexate-induced gastrointestinal mucositis in a rat model

Abstract

Fijlstra M, Rings EH, Verkade HJ, van Dijk TH, Kamps WA, Tissing WJ. Lactose maldigestion during methotrexate-induced gastrointestinal mucositis in a rat model. Am J Physiol Gastrointest Liver Physiol 300: G283-G291, 2011. First published November 18, 2010 doi:10.1152/ajpgi.00462.2010.-Patients with chemotherapy-induced gastrointestinal mucositis suffer from anorexia, diarrhea, and stomach pain, often causing weight loss and malnutrition. When the intestinal function during mucositis would be known, a rational feeding strategy might improve the nutritional state, accelerate recuperation, and increase survival of mucositis patients. We developed a methotrexate (MTX)-induced mucositis rat model to study nutrient digestion and absorption. To determine lactose digestion and absorption of its derivative glucose during mucositis, we injected Wistar rats intravenously with MTX (60 mg/kg) or 0.9% NaCl (controls). Four days later, we orally administered trace amounts of [1-13 C]lactose and [U-13 C]glucose and quantified the appearance of labeled glucose in the blood for 3 h. Finally, we determined plasma citrulline level and harvested the small intestine to assess histology, myeloperoxidase level, glycohydrolase activity, immunohistochemical protein, and mRNA expression. MTX-treated rats showed profound villus atrophy and epithelial damage. During the experimental period, the absorption of lactose-derived [1-13 C]glucose was 4.2-fold decreased in MTXtreated rats compared with controls (P Ͻ 0.01). Lactose-derived [1-13 C]glucose absorption correlated strongly with villus length (rho ϭ 0.86, P Ͻ 0.001) and with plasma citrulline level (rho ϭ 0.81, P Ͻ 0.001). MTX treatment decreased jejunal lactase activity (19.5-fold, P Ͻ 0.01) and immunohistochemical protein and mRNA expression (39.7-fold, P Ͻ 0.01) compared with controls. Interestingly, MTX treatment did not affect the absorption of [U-13 C]glucose during the experimental period. We conclude that lactose digestion is severely decreased during mucositis while glucose absorption is still intact, when supplied in trace amounts. Plasma citrulline level might be a useful objective, noninvasive marker for lactose maldigestion during mucositis in clinic.

Garcinia buchananii bark extract is an effective anti-diarrheal remedy for lactose-induced diarrhea

“…The ingestion of a HLD resulted in the onset of diarrhea in less than 24 h. The signs of diarrhea and loss of body weight seen in this study correspond with findings from previous studies in which rats fed HLD had chronic diarrhea and became malnourished (Arciniegas et al, 2000;Bueno et al, 1994;Fijlstra et al, 2010;Lawrence et al, 1956;Liuzzi et al,1998;Norton et al, 2001). Few animals with delayed onset diarrhea consumed less food indicating a correlation of disease severity with the amount of diet consumed.…”

“…The considerable decrease in the weight of HLD rats indicates malnutrition (Bueno et al, 1994;Fijlstra et al, 2010;Liuzzi et al, 1998;Norton et al, 2001), which is a key symptom of lactoseinduced diarrhea in humans (Brown, 2003;Lomer et al, 2008;Moore et al, 2010;Nyeko et al, 2010). In most incidences of diarrhea, intestinal injury, altered mucosal function and loss of appetite results in poor nutritional status (Brown, 2003;Moore et al, 2010;Nyeko et al, 2010;Thapar and Sanderson, 2004;UNICEF/WHO, 2009).…”

“…A novel hypothesis suggests that diarrhea, flatulence, nausea, pain and other symptoms of lactose-intolerance arise from the effects of toxic bacterial metabolites such as alcohols, acids, ketones and methylgyoxal on gut effector tissues including the epithelium, muscle and nervous tissue (Campbell et al, 2010). It has been shown that a high-lactose diet induces severe and persistent diarrhea, intestinal damage and malnutrition in experimental animals (Arciniegas et al, 2000;Bueno et al, 1994;Fijlstra et al, 2010;Liuzzi et al, 1998;Norton et al, 2001). These effects of lactose-induced diarrhea are to some extent, similar to changes seen in children suffering from gastroenteritis or chronic diarrhea (Bueno et al, 1994).…”

Effect of a Fermented Brown Rice Extract on the Gastrointestinal Function in Methotrexate-Treated Rats

“…CON, control group of rats fed control diet; MTX, methotrexate-administration group of rats fed control diet; MTX-ERF, methotrexate-administration group of rats fed diet containing extract of fermented brown rice The mucosal weight was also significantly decreased, and pathological scores of the intestines were significantly increased by the administration of MTX, as shown in Table 4 and Table 6. Fijlstra et al 23) have suggested that the administration of MTX decreased the activity of glycohydrolases, crucial enzymes related to carbohydrate digestion and glucose absorption, resulting in diarrhea. These findings agree with our results, at least in part.…”

Biomarkers and non-invasive tests for gastrointestinal mucositis

“…In preclinical studies, it was shown that plasma citrulline correlates significantly with the villus length in a methotrexate-induced mucositis rat model [23]. Furthermore, preclinical studies showed that the use of plasma citrulline corresponded with radiation-induced mucositis in rats and mice [24, 25].…”