Innervation of the Gastrointestinal Tract PDF

Preface

Eating is an extremely hazardous way to make a living, biologically speaking. The strategy of ingesting foreign organisms, breaking them down and reusing the spare parts is fraught with risks. For one thing, the organism concerned is likely to resist being broken down for scrap and may, in fact, have designs on the body parts of the diner. For another, the chemicals required to digest food are equally capable of breaking down the structure of the gut wall and the rest of the consumer's body as well. It seems that minimising these risks, while meeting the imperative to absorb nutrients, has influenced many of the design principles of the gastrointestinal tract.

This long tube is composed of a variety of tissue types and is the largest internal organ of the body. Its main function is to digest food and absorb the released nutrients. It is subdivided into functionally distinct regions, so that ingested material is processed serially in a way that serves to minimise the risks of self-digestion and attack by ingested pathogens. After rapid propulsion through the thorax via the oesophagus, food is subjected to mechanical and chemical breakdown in the harshly acidic environment of the stomach. This tends to reduce the viability of (inadvertently) swallowed micro-organisms. If toxic material is detected, propulsion can be reversed and the ingested material can be rapidly expelled by vomiting. During its sojourn in the stomach, sphincteric muscles at either end of the organ prevent spillage of the corrosive acidic content into the susceptible neighbouring regions of the duodenum and oesophagus. Gastric contents are then gradually aliquoted into the duodenum at a carefully controlled rate, adapted to the calorific and nutrient content of the meal. In the duodenum, the acidity of the contents is neutralised and they are mixed with digestive enzymes, bile and watery secretions, to allow the complex chemistry of digestion to get to work. The resulting chyme is mixed, moved to and fro and gradually propelled along the small intestine, at a rate adapted to the requirements for absorption of nutrients.

A few hours after the meal, the small intestine is basically empty, the residual matter having been expelled into the colon. Here it may reside for several days, as water and ions are reabsorbed, playing a potentially vital role in the water balance of the organism. Eventually, the near-solid material is expelled from the body. In mechanical terms, this is a decidedly non-trivial event. The prolonged retention of contents in the colon makes it inevitable that large numbers of bacteria will be present, posing an enormous potential danger to the organism. If large numbers of micro-organisms colonise the small intestine, the barrier between the vasculature and the outside world is rapidly compromised and massive septicaemia results. Parasites in food may survive the digestive process and then attack the wall of the gut. The consuming organism defends itself against these perils with specialised motor patterns, which are triggered to remove such noxious threats with great rapidity from the body.

The multiplicity of functions required of the digestive tract makes it a fascinating subject for biological research by a range of disciplines, including immunology, microbiology, biochemistry, oncology etc. However it provides an especially appealing subject for neuroscientists. Neuronal circuitry is intimately involved in controlling many of the functions of the gut. It controls the activity of the smooth muscle in the gut wall, which mixes and propels the contents. Between meals, specialised patterns of motor activity periodically empty sloughed-off epithelial cells and accumulated mucous, thus preventing the build-up of a culture medium for the ever-threatening bacteria. Other highly propulsive motor patterns can be triggered by toxic chemicals, bacterial infection, parasitic infestation or identified allergens. While we consider the symptoms associated with these motor patterns (diarrhoea and pain) to be unpleasant, there is little doubt that these specialised mechanisms are of profound adaptive significance to our survival.

The feature of the innervation of the gastrointestinal tract that is most appealing to neuroscientists is the presence of extensive networks of neural circuits embedded in its walls – the enteric nervous system. Containing approximately the same number of nerve cells as the spinal cord, it is connected with the central nervous system via visceral afferents and sympathetic and parasympathetic efferents of the autonomic nervous system. The presence of an entire, specialised nervous system within this peripheral organ system provides an opportunity for detailed study, without having to contend with the central nervous system. Since the studies of Bayliss and Starling (1899), Langley and Magnus (1905) and Trendelenburg (1917), it has been apparent that the enteric nervous system is capable of displaying a great deal of autonomy in controlling gastrointestinal function. Thus the enteric nervous system is studied by gastroenterologists seeking to understand how gut function is controlled, and also by neuroscientists endeavouring to understand how a relatively simple, autonomous mammalian neural circuit is organised. Obviously these two motivations are not mutually exclusive and many students of the enteric nervous system have foot in both camps.

The complexity of the enteric nervous system began to be recognised with the discovery of the two major neural plexuses, the submucous plexus by Meissner (1857) and the myenteric plexus by Auerbach (1862). Langley (1921) placed the intrinsic enteric innervation in a class of its own after he recognised that many of the neural functions depend on the circuits entirely intrinsic to the digestive tract, rather than being solely determined by extrinsic neural inputs. Despite this early insight, it took many more years before the enteric nervous system was recognised by gastroenterologists as a relatively independent component of the autonomic nervous system. Combined studies by neuroanatomists, pharmacologists and physiologists eventually demonstrated that the study of the enteric nervous system was not only relevant to gastroenterology, but essential for its progress.

During much of the twentieth century, the rate of progress was relatively slow in this field, which seemed to have fallen into a gap between neuroscience and gastroenterology. During this period, much emphasis was placed on the myogenic control of gastrointestinal motility, with little direct investigation of the roles of enteric neurons. It is only recently that the cellular basis of the spontaneous electrical activity of gut smooth muscle has begun to be understood in detail. It has been discovered that the mysterious cells, first described by Cajal as "interstitial cells" are involved both in generating myogenic activity and in mediating the input of enteric motor neurons to the smooth muscle (Sander, 1996; Huizinga et al., 1997). This breakthrough promises eventually to bridge the historical divide between the two schools of thought (myogenic versus neurogenic) about the control of gut motility.

In this volume of the series on the autonomic nervous system, the innervation of the gut by the enteric nervous system, and its interface with the extrinsic innervation, is examined from a number of different perspectives. It will become apparent that all of these different aspects of nervous control can be related directly to how gut function is adapted to minimise risk, while maximising digestive efficiency.

For example, the detailed analysis of enteric neural circuits controlling reflex motor activity of the intestine is elegantly summarised in the chapter by Joel Bornstein and colleagues. They provide an insightful synthesis of data gathered over many years by their own laboratory and by others around the world, as to how simple circuits may propel the gut contents, preventing excessive distension and perhaps contribute to the expulsion of pathogens. As described above, the stomach plays a very different role in the process of dealing with food, as it is not involved in digestion or absorption but is rather adapted for storage, mechanical breakdown and aliquoting of contents. Not surprisingly, the neuronal control of gastric motility has many different features from those of the small intestine. This is summarised in the extensive review of David Grundy and Michael Schemann who have contributed widely to the study of both the extrinsic and intrinsic innervation of the stomach. A particularly important role for extrinsic sensory nerves in protecting the stomach from a range of damaging agents has been identified in the last decade. Peter Holzer has been at the centre of this field and has written an authoritative review, summarising the role and mechanisms of action of these nerves in gastric protection.

At the other end of the gastrointestinal tract, the colon also plays a significant role as an organ of storage, but it has to deal with very different material. In particular, much of the activity of the colon is modulated by extrinsic neuronal inputs from both the sympathetic and parasympathetic divisions of the autonomic nervous system. For many years the contributions of the extrinsic innervation have been rather over-simplified. This is corrected in the chapter of Kalina Venkova, Beverely Greenwood-Van Meerveld and the late Jack Krier, who carried out so many foundation studies on the extrinsic innervation of the distal gut. The last specialised region to receive attention in this volume is the gallbladder and sphincter of Oddi. Gary Mawe's group have established themselves as leading investigators of this often overlooked accessory to the gut. Given the amount of trouble that it causes clinically, the biliary system and its motility are medically important subjects for study. The major differences between the organisation of the enteric nervous system of the gallbladder and sphincter of Oddi and that of the extensively studied small intestine are highlighted in this chapter.

Since the pioneering study of Paton (1955), the small intestine, particularly of the guinea-pig, has been a favoured preparation for pharmacologists around the world. A vast literature has developed about the effects of drugs acting on a huge range of receptors found in the enteric nervous system and smooth muscle of this preparation. Marcello Tonini and his colleagues have summarised an enormous body of work to provide an accessible, yet comprehensive summary of this field. It should be pointed out that the future ability of gastroenterologists to provide treatment for disorders of the gut will rely on the development of new drugs. Understanding the pharmacology of the enteric nervous system is a crucial step in this undertaking. This analysis is greatly extended by the review of Charles Hoyle, Pam Milner and Geoffrey Burnstock on the nature of neuroeffector transmission in the gut. A wide-ranging summary of the transmitters, receptors and pharmacology of neuromuscular transmission is provided in their contribution. Frequently, enteric neurobiologists forget about the secretory and absorptive functions of the gastrointestinal tract, which are so central to its role in digestion. Charles Hoyle and colleagues also give us a wonderful account of the major pathways, largely arising from the submucous plexus, which control epithelial function. Of course, the secretory and absorptive capability of the epithelium is closely coupled with maintenance of an adequate blood supply, as are the requirements for mucosal protection described in Peter Holzer's review. Neela Kotecha's chapter summarises what is known about the enteric and extrinsic control of the gut vasculature, providing a valuable foundation for appreciating how different aspects of neuronal control are integrated.

Lay people and funding agencies are often particularly interested in what scientists can tell them about the nature of medical disorders. This is as true for the innervation of the gut as it is for any other organ system. Many of the disorders of the gastrointestinal tract are related to the interactions between the immune system and the nerve cells and fibres in the gut wall. Jackie Wood and his many colleagues, over a long period, have been pioneers in this field. In his chapter, Professor Wood provides a compelling account of the central role of mast cells and mediators from leukocytes in modifying and sometimes determining the motor patterns and secretion of the small and large intestine during pathogen challenge.

In the chapter by Simon Brookes and Marcello Costa, the cellular organisation of the enteric nervous system and some of the changes associated with gut disorders have been summarised. This raises the question of how the enteric nervous system develops to the normal adult form. This field has made enormous progress in the last decade and at the forefront of the advance has been the New York-based group of Michael Gershon. In a scholarly review, Professor Gershon describes some of the major influences on the colonisation and phenotypic development of enteric neurones. He discusses evidence for the involvement of a number of powerful growth factors and their receptors. In addition, he examines how defects in them may contribute to the aganglionosis of the distal colon, which is one of the most common developmental disorders of the enteric nervous system.

The investigations summarised in this volume are beginning to reveal a large repertoire of neural mechanisms present in the digestive tract. It is not possible for a single book to encompass all knowledge about such a large and rapidly growing field. However, the chapters presented here give a good indication of the state of current knowledge. By reading between the lines, the astute reader will also be able to identify some of the current gaps in our knowledge. For example, it should not be surprising that there have been only few attempts to link cellular mechanisms to the functions of the entire organ, either in vitro or in vivo. In only a few cases have investigators been able to establish the circumstances under which a particular neural mechanism actually operates in normal living conditions. The gap between cellular physiology and organ physiology is still very wide. It should be clear from the reviews presented here that we now know a lot about what the neural system in the gut can do, but we know much less about how it actually operates under normal conditions. We know even less about how it changes, at the cellular level, to deal with different diets, with pathogens and in disease states. This represents a major challenge for the next generation of investigators. It can be expected that addressing these questions will be invaluable in the rational design of new therapies for disorders of the gastrointestinal tract.