Rotavirus is the major cause of acute gastroenteritis in young children. The mechanism underlying the intestinal fluid loss in this disease is yet unknown. Recent studies in humans and animals have, however, suggested that rotavirus evokes fluid and electrolyte secretion by activation of the enteric nervous system (ENS). The involvement of ENS in rotavirus diarrhoea indicates novel sites of action for drug treatment of this disease.
Acute diarrhoeal diseases are still a major health problem throughout the world, causing 25-30% of all deaths among children younger than 5 years of age in developing countries. Diarrhoeal diseases are also of public health importance in developed countries and are associated with considerable morbidity and a substantial number of hospitalizations among children and the elderly. Acute diarrhoea can be caused by many different agents including parasites, bacteria and virus the latter of which have been given significant attention in recent years. Rotavirus was discovered in early 1970s and is now established as the most common cause of acute gastroenteritis in children throughout the world resulting in more than 700,000 deaths every year. The discovery changed our view on the aetiology of acute gastroenteritis. Rotavirus is transmitted by fecal-oral inoculation and in exceptional cases from aerosol. The typical target for symptomatic rotavirus infection is young children. The clinical picture of the disease includes vomiting, watery diarrhoea and fever. The incubation time is 1-3 days and the symptoms usually remain for 5-8 days.
The nervous system of the small intestine
The intestinal mucosa consist of villi and crypts. Crypt cells are immature cells, which secrete fluid and electrolytes. As they move up to the villous they differentiate into absorptive cells. The gastrointestinal channel is innervated by the autonomous nervous system (ANS) composed of an extrinsic innervation (sympathetic and parasympathetic) and an intrinsic innervation (enteric nervous system) . There are almost as many neurons in the gastrointestinal channel as in the spinal cord. The enteric nervous system (ENS) is sometimes called "the little brain" because it can function independently from the central nervous system or other parts of the ANS. ENS is composed of two major nerve plexuses, the myenteric and the submucosal. The myenteric plexus is mainly involved in the control of the intestinal motility, while the submucous plexus regulates mucosal functions. The ENS is also involved in mucosal immunology.
Diarrhoea and the enteric nervous system
The pathophysiological mechanisms underlying the fluid losses seen in different types of diarrhoea have been debated for decades. The dominating hypothesis up to the 1970s was that most diarrhoea, including the infectious, were caused by motility disturbances. However, during the last three decades it has been become increasingly evident that disturbances in the epithelial transport are often one of the major causes of intestinal fluid loss, although motility may contribute, at least in some types of diarrhoea.
The demonstration that cholera toxin evoked an increase in intracellular cAMP concentration represented a major breakthrough at that time. Subsequently, it was shown that increasing the intracellular concentrations of several second messengers such as cAMP, cGMP and calcium ions also caused fluid losses from the intestine. It was believed that the secretory agent interacted with the secreting crypts to evoke a fluid secretion via one of the second messengers. This view is too simplistic since most luminal secretagogues, including rotavirus, do not reach the crypts in vivo.
Rotavirus infections are characterized by nausea and vomiting. However, it is still not known what produces these symptoms. The fact that drugs that inhibit the neurotransmitter serotonin (5-HT) also inhibit nausea and vomiting indicate that the nervous system may participate in these two disease symptoms. These observations led us to hypothesise a role of the ENS in rotavirus-induced fluid secretion. Studies on conscious neonatal mice with rotavirus diarrhoea showed that nerve blockers decreased diarrhoea. Subsequent studies in vitro using perfusion and "Ussing" chambers confirmed that neurotransmitter blockers inhibit fluid secretion in the intestine . Opiates have been known to inhibit intestinal fluid and electrolyte secretion as well as gut motility. The endogenous opiates, enkephalins, are found in enteric nerves as neutransmitters. Indirect experimental evidence for a nervous point of action for enkephalins was provided by Eklund et al. . They demonstrated that methionine-enkephalin given into the superior mesenteric artery caused a parallel reduction in cholera toxin-induced net fluid secretion and VIP release into the intestinal venous effluent in cats. Inhibitors of the enzymes degrading the enkephalins, the enkephalinases, can enhance this nervous action of enkephalins. In line with this the enkephalinase inbibitor acetorphan has been shown to attenuate acute diarrhoea in children and adults [4-6]. Finally, Salazar-Lindo et al.  have recently shown in a clinical trail that acetorphan (Racecadotril) markedly inhibited stool output in young Peruvian children with rotavirus diarrhoea.
As with many other infectious diseases, rotavirus infection affects children in the developing world most, with high mortality rates. In industrialized countries, morbidity is the major problem and involves considerable social costs. In Sweden, 1500-1700 children are estimated to be hospitalized annually due to diarrhoea caused by rotavirus.
The current treatment for rotavirus diarrhoea and all non-bacterial gastroenteritis are symptomatic, for example by rehydration solutions that optimize water absorption. However, there is currently no treatment to prevent the massive intestinal fluid secretion. Ongoing studies in our group aim to investigate which neurotransmitters are involved in rotavirus disease in order to develop possible future therapies. Granisetron is a specific serotonin receptor antagonist, which is clinically used for attenuating nausea. Preliminary results from our laboratory show that this drug reduces fluid secretion mice. This discovery indicates new therapeutical strategies for microbial gastroenteritis.
This work was supported by The Swedish Research Council (K2002-16X-10392-10A)
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