Lysine as a serotonin receptor antagonist: Using the diet to modulate gut function

It is well established that gut motor function is influenced by different components of the diet. Modifying the physical consistency of meals by changing fiber content alters the propulsive characteristics of the colon in animal models (Br J Nutr 1980;43:155–162). Eating elicits a range of motor phenomena including the small bowel–fed pattern and the gastrocolonic response. Consumption of an amino acid solution blunts the gastrocolonic response, whereas fats increase contractile activity, showing selective actions of different nutrient classes (Dig Dis Sci 1980;25:647–652). Intravenous amino acids have similar inhibitory effects on colonic motility, suggesting activation of systemic neurohumoral pathways that modify motor function (Dig Dis Sci 1985;30:33–39). Amino acid solutions given enterally or intravenously also prolong small intestinal transit and induce gastric relaxation (Gut 1999;44:240–245, Dig Dis Sci 2001;46:38–45). In general, the modulatory effects of nutrients are not felt to be mediated by receptors selective for given agents. One exception seems to be the amino acid tryptophan, which delays gastric emptying by action on specific tryptophan receptors (Am J Physiol 1976;231:848–853).

Serotonin mediates several motor and sensory activities in the gut. Mucosal stroking or luminal distention activates local peristalsis, which is mediated by serotonin receptor subtypes that vary depending on the species. In humans and rats, 5-HT₄ receptors participate in both the contractile response orad to the stimulus and the relaxant response caudad to the stimulus, whereas 5-HT₃ receptors are additionally involved in guinea pigs (Gastroenterology 1996;111:1281–1290, Am J Physiol 1996;270:G778–G782, Br J Pharmacol 1997;122:1174–1178). Binding experiments show prominent 5-HT₄ receptor densities in myenteric plexus throughout the gut (Life Sci 1996;59:2129–2137). 5-HT₄ receptor agonists stimulate colonic peristalsis and induce diarrhea in animal models (Auton Neurosci 2002;99:62–65, Eur J Pharmacol 1996;308:181–186). 5-HT₄ receptor–mediated stimulation of propulsion results in part from activation of cholinergic pathways (Naunyn Schmied Arch Pharmacol 1992;345:270–275, Neurogastroenterol Motil 2001;13:543–553). These physiologic mechanisms are the target of pharmaceutical intervention in functional bowel disorders. The recently released 5-HT₄ agonist tegaserod stimulates small bowel and proximal colon transit in patients with constipation-predominant irritable bowel syndrome (IBS) (Gastroenterology 2000;118:463–468). Placebo-controlled studies show improvements in stool frequency and other bowel parameters in constipated IBS patients (Aliment Pharmacol Ther 2001;15:1655–1666, Clin Ther 2003;25:1952–1974). Recent investigations report that 5-HT₄ receptor antagonists tend to prolong colonic transit in healthy volunteers and may delay orocecal transit in diarrhea-predominant IBS patients (Aliment Pharmacol Ther 1999;13:1437–1444, Gut 2000;47:667–674). Future investigations will determine if these drugs provide therapeutic benefit in IBS patients with diarrhea.

The nutrient composition of the diet exerts modulatory effects on circulating and tissue levels of serotonin. Diets devoid of amino acids or rich in carbohydrates increase serotonin content in the hypothalamus, whereas protein-rich diets decrease serotonin levels (Nutr Neurosci 2003;6:291–299, Nutr Neurosci 2003;6:117–124). Conversely, diets rich in tryptophan increase serotonin levels in the brainstem while tryptophan depletion decreases plasma and cerebrospinal fluid levels of the serotonin metabolite 5-hydroxyindoleacetic acid (J Neural Trans 1990;79:25–34, J Neurochem 1999;72:1641–1647). Tryptophan depletion also has been suggested to up-regulate serotonin 5-HT_2A and 5-HT_2C receptors (Neuropsychopharmacol 1997;17:342–350).

Stressful events and the life history of stress contribute to symptom severity in functional bowel disorders (J Behav Med 1997;20:177–193). In animal models, experimental stress markedly accelerates colonic transit (Gut 1989;30:455–459). In the central nervous system, corticotrophin releasing factor plays a crucial role as a mediator of stress effects on the gut (Dig Dis 2001;19:201–211). The peripheral transmitters involved in the disruption of motor function by stress are less well understood. However, it seems that 5-HT₄ receptor pathways are important in some models of stress-induced diarrhea. In rats exposed to restraint stress similar to that in the present investigation, a 5-HT₄ receptor antagonist reduced the increase in stool output elicited by the stressful stimulus without affecting basal colonic function in the absence of stress (Br J Pharmacol 2000;130:706–712).

The present study by Smriga and Torii is significant because it represents the first demonstration that a dietary constituent serves as a receptor antagonist to modulate gut motor function. Compelling evidence is provided to suggest that the essential amino acid L-lysine acts as a 5-HT₄ receptor antagonist to blunt serotonin-evoked contractile activity. The investigators further show in rats that L-lysine reduces the diarrheal response to a serotonin-mediated stressful stimulus at doses that are reasonably achieved in a normal diet (Comp Biochem Phyiol 1995;110:633–639). In general, the studies are well executed. However, the binding studies are inadequate to assess if L-lysine antagonism of the 5-HT₄ receptor subtype is competitive or complete in nature.

The current study also reports impressive effects of L-lysine to reduce anxiety elicited by a serotonin-associated maze locomotion model in experimental animals. This finding also is important because emotional disturbances are prominent in individuals with chronic gastrointestinal symptoms. In the general population, anxiety disorders are associated with heartburn, diarrhea, and constipation (Scand J Gastroenterol 2002;37:294–298). Degrees of anxiety measured by validated rating scales are higher in IBS patients than healthy volunteers or patients with inflammatory bowel disease (Behav Res Ther 1990;28:401–405).

The diet also plays a modulatory role in emotional conditions. Dietary tryptophan enrichment decreases depression during stress, whereas tryptophan depletion elicits temporary depressive symptoms (Am J Clin Nutr 2000;71:1536–1544, Lancet 1997;349:915–919, Psychoneuroendocrinol 1999;24:99–113). The investigators of the current study previously showed that dietary L-lysine deficiency increases footshock stress-induced anxiety in rats, whereas a diet fortified with lysine and arginine reduces the anxiogenic response to stress in pigs (J Nutr 2002;132:3744–3746, Nutr Neurosci 2003;6:283–289). There is evidence for 5-HT₄ receptor involvement in anxiety behavior. 5-HT₄ receptor antagonists exhibit anxiolytic capabilities in maze models similar to those in the present study (Neuropharmacology 1997;36:707–721). Coupled with these observations, the findings of the present study suggest but do not prove that the effects of L-lysine on anxiety behavior are mediated by its actions as a 5-HT₄ antagonist.

In its actions to decrease anxiety, L-lysine may be affecting other central nervous system pathways not explored in the present investigation. Lysine is catabolized into glutamate and may theoretically modulate neurotransmission via glutamate receptors (Curr Opinion Plant Biol 2001;4:261–266). Lysine also modulates central nervous system benzodiazepine receptors (Neurochem Res 1995;20:931–937). Furthermore, the lysine metabolite L-pipecolic acid may serve as a neuromodulator of brain γ-aminobutyric acid receptors (Brain Res 1986;372:176–179).

Despite these concerns, the findings of the study by Smriga and Torii provide evidence that dietary L-lysine may modulate gut motor function by action as a 5-HT₄ receptor antagonist. L-lysine contents are higher in meat proteins compared to plant proteins (Am J Clin Nutr 1985;41[Suppl 5]:1077–1090). Furthermore, lysine supplements are available as nonprescription oral supplements (J Am Coll Nutr 1997;16:7–21). Future investigations will determine if altering intake of L-lysine or other dietary amino acids can modify gut function in human models of functional bowel disease.