Inhibitory effect of experimental colitis on fluid absorption in rat jejunum: role of the enteric nervous system, VIP, and nitric oxide

Abstract

Impairment of small intestinal absorption has been described in patients with ulcerative colitis and in animal models of experimental colitis. The pathophysiology of this dysfunction has not been elucidated. The aim of this study was to investigate the effect of chemical colitis on jejunal fluid absorption and determine the role of the enteric nervous system and some putative neurotransmitters. In a rat model of iodoacetamide-induced colitis, jejunal net fluid absorption was evaluated by the in vivo single-pass perfusion technique. The effects of 1) tetrodotoxin (TTX), 2) benzylalkonium chloride (BAC), 3) capsaicin, 4) vasoactive intestinal polypeptide (VIP) antagonism, 5) nitric oxide (NO) synthase (NOS) inhibition, and 6) 5-hydroxytryptamine type 3 and 4 (5-HT3 and 5-HT4) receptor antagonism on the changes in fluid movement were investigated. A significant decrease in jejunal net fluid absorption was found 2 and 4 days after colitis induction: 26 (SD 14) and 28 (SD 19) μl·min−1·g dry intestinal wt−1, respectively [P < 0.0002 compared with sham rats at 61 (SD 6.5) μl·min−1·g dry intestinal wt−1]. No histological changes were evident in jejunal sections. TTX and BAC reversed this decrease in fluid absorption: 54 (SD 13) and 44 (SD 14) μl·min−1·g dry intestinal wt−1 (P = 0.0005 and P = 0.019, respectively, compared with colitis). Ablation of capsaicin-sensitive primary afferent fibers had a partial effect: 45 (SD 5) μl·min−1·g dry intestinal wt−1 (P = 0.001 and P = 0.003 compared with colitis and sham, respectively). Constitutive and neuronal NOS inhibition and VIP antagonism returned jejunal net fluid absorption to normal values: 66 (SD 19), 61 (SD 5), and 56 (SD 14) μl·min−1·g dry intestinal wt−1, respectively. 5-HT3 and 5-HT4 receptor antagonism had no effect. Chemical colitis is associated with a significant decrease in jejunal net fluid absorption. This decrease is neurally mediated and involves VIP- and NO-related mechanisms. Ulcerative colitis (UC) is a well-known chronic relapsing inflammatory bowel disease (IBD); however, its etiology has not been totally elucidated. The pathogenesis presents a wide spectrum of interactions between genetic predisposition, exogenous and endogenous triggers, and modifying factors. These interactions lead to spontaneously relapsing and remitting inflammatory processes, resulting in tissue injury mediated by the immune system (51). Accumulation of different types of immune cells (e.g., neutrophils and macrophages), in addition to increased levels of interleukins 1, 2, 6, and 8 and their mRNA, correlates with an increase in TNF-α and arachidonic acid metabolite levels in the colon (2, 51, 53). In addition, the hypothesis of neural involvement in IBD is illustrated by colonic neuronal damage and loss of mucosal neuropeptidic innervation (10, 26). Although UC is confined to the colon, many studies have shown some functional abnormalities in the small intestine of patients with UC. These abnormalities are manifested by a decrease in intestinal water, d-xylose, amino acid, and fat absorption (1, 4, 8, 11, 49). The pathophysiology of this decrease in water and nutrient absorption has not been studied. Although some investigators have found some pathological changes in the jejunum of patients with UC (11, 49), these findings have not been universally reproducible (47, 52), and the contribution of these changes to small intestinal dysfunction is not clear. In addition, clinical observations show that IBD patients have a low body weight, which could be attributed to one or a combination of the following factors: decrease in food intake, decrease in intestinal absorption of nutrients, and/or highly extensive catabolic state secondary to the chronicity of the inflammatory process. In an animal model of iodoacetamide-induced colitis, we previously showed a significant reduction in alanine absorption from the jejunum (4).