Amino acids in the rat intestinal lumen regulate their own absorption from a distant intestinal site

Abstract

Intestinal nutrient transport is altered in response to changes in dietary conditions and luminal substrate level. It is not clear, however, whether an amino acid in the intestinal lumen can acutely affect its own absorption from a distant site. Our aim is to study the effect of an amino acid present in rat small intestinal segment on its own absorption from a proximal or distal site and elucidate the underlying mechanisms. The effect of instillation of alanine (Ala) in either jejunum or ileum on its own absorption at ileal or jejunal level was examined in vivo. The modulation of this intestinal regulatory loop by the following interventions was studied: tetrodotoxin (TTX) added to Ala, subdiaphragmatic vagotomy, chemical ablation of capsaicin-sensitive primary afferent (CSPA) fibers, and IV administration of calcitonin gene-related peptide (CGRP) antagonist. In addition, the kinetics of jejunal Ala absorption and the importance of Na+-dependent transport were studied in vitro after instilling Ala in the ileum. Basal jejunal Ala absorption [0.198 ± 0.018 μmol·cm−1·20 min−1 (means ± SD)] was significantly decreased with the instillation of 20 mM Ala in the ileum or in an adjacent distal jejunal segment (0.12 ± 0.015; P < 0.0001 and 0.138 ± 0.014; P < 0.002, respectively). Comparable inhibition was observed in the presence of proline in the ileum. Moreover, basal Ala absorption from the ileum (0.169 ± 0.025) was significantly decreased by the presence of 20 mM Ala in the jejunum (0.103 ± 0.027; P < 0.01). The inhibitory effect on jejunal Ala absorption was abolished by TTX, subdiaphragmatic vagotomy, neonatal capsaicin treatment, and CGRP antagonism. In vitro studies showed that Ala in the ileum affects Na+-mediated transport and increases Km without affecting Vmax. Intraluminal amino acids control their own absorption from a distant part of the intestine, by affecting the affinity of the Na+-mediated Ala transporter, through a neuronal mechanism that involves CSPA and CGRP. the presence of nutrients in the lumen of the gastrointestinal tract (GI) triggers reflexes that optimize their processing by coordinating and controlling GI motility, blood flow, secretion, and absorption. Feedback inhibition of gastric secretory and motor function together with stimulation of pancreatic secretion, gallbladder contraction, and relaxation of the sphincter of Oddi are examples of these control mechanisms observed during the intestinal phase of a meal. The signals that elicit reflexes in response to the passage of nutrients in the lumen are not entirely known, but the existence of reflexes implies the activation of "sensors" or special cells that can detect the presence of nutrients (21, 45). It has been demonstrated that these sensors not only are located in the gut wall but may also exist in extraintestinal sites (21, 45). For example, glucose ingestion stimulates CCK release from the proximal small intestine (27), which may lead to a decrease in hexose absorption and thus reduces excessive increase in plasma glucose concentration during a meal (28). On the other hand, the presence of glucose or maltose in the ileum induces an increase in jejunal glucose absorption (16). Similarly, it has been shown that intestinal transport of amino acids and peptides is upregulated by their presence at high concentrations in the intestinal lumen (51). In addition, protein deprivation or semistarvation induces an increase in nutrient transport (36). On the other hand, prolonged total starvation leads to a reduction in nutrient transport as a result of decreased intestinal mass (2, 36). These adaptive changes usually take place over days (18, 20). The end products of protein digestion are absorbed at different rates along the jejunoileal axis, with small peptides being absorbed mostly in the jejunum and free amino acids mostly in the terminal ileum (22) ...