The Autonomic Nervous System in Functional Bowel Disorders

iv78 Gut 2000;(Suppl IV)47:iv78–iv80

The autonomic nervous system in functional Gut: first published as 10.1136/gut.47.suppl_4.iv78 on 1 December 2000. Downloaded from bowel disorders

G Tougas

Summary with increased motor activity.34Under certain Communications along the brain-gut axis conditions, altered autonomic balance (includ- involve neural pathways as well as immune and ing low vagal tone and increased sympathetic endocrine mechanisms. The two branches of activity) may also alter visceral perception. the autonomic nervous system are integrated Autonomic dysfunction could also represent anatomically and functionally with visceral the physiological pathway accounting for many sensory pathways, and are responsible for the of the extraintestinal symptoms seen in irrita- homeostatic regulation of gut function. The ble bowel syndrome (IBS) patients, and for autonomic nervous system is also a major some of the frequent gastrointestinal com- mediator of the visceral response to central plaints reported by patients with disorders such influences such as psychological stress and as chronic fatigue and fibromyalgia. other central factors. As presently defined, functional disorders Introduction represent a constellation of symptoms, some of In recent years, we have undergone a substan- which suggest the presence of altered percep- tial shift in our conceptual definitions of what tion while other symptoms point to disordered constitutes functional bowel disorders and gastrointestinal function as the cause of the IBS. In general, we now view these conditions symptoms. There have been a growing number as a group of disorders or clinical entities char- Digestive Diseases acterised by the presence of, to a varying Research Program, of reports demonstrating disordered auto- Division of nomic function in subgroups of functional degree, chronic pain, discomfort, and disor- Gastroenterology, bowel patients.1–3 While a number of diVerent dered gastrointestinal function. While this type McMaster University, methods were used to assess autonomic of clinical definition corresponds to how these 1200 Main St West, function, they generally point to decreased patients present, it has proved diYcult to apply Room 3N5D, in the search for the pathophysiological fac- vagal (parasympathetic) outflow or increased Hamilton, Ontario, tor(s) potentially involved in these conditions. sympathetic activity in conditions usually asso- Canada While much remains to be done in that regard, G Tougas ciated with slow or decreased gastrointestinal it is increasingly accepted that these conditions motility. Other studies found either increased Correspondence to: are multifactorial, and that the symptoms Dr G. Tougas. cholinergic activity or decreased sympathetic experienced by two individual patients, al- [email protected] activity in patients with symptoms compatible though somewhat similar, may in fact result http://gut.bmj.com/ from a number of diVerent aetiologies. Abnormalities of motor and secretory func- Stress tion as well as altered enteric neural function can be identified in many patients with functional disorders (fig 1). However, most patients have ANS imbalance no demonstrable motor dysfunction and the abnormalities that have been identified vary Increased from study to study, each of these abnormalities on September 27, 2021 by guest. Protected copyright. sensitivity being present in small and very specific groups ↓ Sensory inhibition of patients which do not represent the majority of those seen in clinical practice. The concept of these conditions being primarily motility or enteric nervous disorders is now also generally Increased ∴ ↑ Sensitivity viewed as failing to account for many of the afferent other characteristics that are present in these patients, in particular the discomfort and pain activity Low grade often reported in the presence of apparently inflammation ± Impaired motor activity normal gastrointestinal function. Hp infection In many patients with functional bowel disor- ders, the presence of altered visceral perception ↓ Accommodation to various visceral stimuli, such as distension, has been identified. This issue of altered visceral perception in IBS is extensively discussed elsewhere. It remains important to point out that while a primary disorder of visceral sensory per- Altered motor and sensory function ception provides a plausible explanation for many of the symptoms reported in functional bowel disorders, it remains a largely unproved Dyspepsia

Figure 1 Putative pathogenesis of dyspepsia. ANS, autonomic nervous system; HP, Abbreviations used in this paper: IBS, irritable Helicobacter pylori. bowel syndrome.

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concept at the clinical level. In specific situations disorders, it is essential to remember the Gut: first published as 10.1136/gut.47.suppl_4.iv78 on 1 December 2000. Downloaded from such as the development of chronic symptoms homeostatic nature of autonomic function. following an acute inflammatory or infectious While many local gastrointestinal stimuli will event (such as post-infectious irritable bowel elicit responses and reflexes whose involvement syndrome), altered function of the normal is essentially limited to the immediate region sensory mechanisms, either within the gut wall that was primarily stimulated, when more or along visceral aVerent pathways, are conceiv- intense or potentially noxious stimuli occur, ably possible, at least in the short term. It is more other systems, including the central nervous sys- diYcult at this point to implicate altered visceral tem, are also involved in addition to the gastro- sensory pathways in the pathogenesis of func- intestinal tract. Transmission of information to tional symptoms such as diarrhoea or bloating. the central nervous system allows for elaboration Such symptoms are present in many post- of an integrated homeostatic response that may infectious IBS patients, but also in patients include a behavioural as well as a physiological where there is no history of any acute inflamma- response. In this type of response, both visceral tory or infectious precipitant prior to the devel- and autonomic nervous pathways are essential. opment of symptoms. Similarly, the hypothesis Many of the systemic responses elicited by of altered visceral sensory perception as the only visceral stimuli are produced through auto- factor involved in functional disorders fails to nomic reflexes. These reflexes, which occur account for the very high association of stress, primarily through the brain stem, may not be psychologically traumatic experiences, and emo- associated with conscious perception of the tional distress with the development and persist- sensory stimulus. However, other visceral ence of functional bowel symptoms. Unless one sensory stimuli will be suYciently intense as to extends the concept of altered visceral sensory be felt and to elicit pain or discomfort. perception to include the cortical centres associ- The type and degree of the autonomic reflex ated with visceral perception, or a central response to a specified visceral stimulus depends nervous system modulation of the aVerent and on the location, type, and intensity of the stimu- spinal pathways involved with perception of vis- lus. If prior sensitisation of the visceral aVerent ceral stimuli, it is somewhat diYcult to build a pathways has resulted in a state of hyperalgesia conceptual framework capable of reconciling or allodynia, the reflex response may be cortical events such as emotions with the exaggerated, while a peripheral sensory neu- peripheral sensory pathways involved with vis- ropathy may be associated with a decreased ceral sensory function. If a pragmatic approach reflex response. Similarly, psychological factors is used to reconcile the various components such as increased vigilance, anxiety, and depres- identified in the clinical expression of functional sion are also likely to aVect autonomic reflexes.5 bowel disorders with an overall concept of the pathophysiological factors involved, several con- Assessing autonomic function ditions must be met. Firstly, the condition (IBS) A number of methods have been developed to involves central as well as peripheral sites: pain is

assess specific aspects of autonomic nervous http://gut.bmj.com/ ultimately a cortical event while events such as function. Some of the older approaches, which diarrhoea and mucus production imply that were very cumbersome and involved rather there is also dysfunction of the gut per se There- . complex measurements, have been largely aban- fore, functional disorders must to some extent doned. In recent years, the development of tech- involve the brain as well as the gut. Secondly, if niques based on the autonomic modulation of visceral factors such as an infectious event in the heart rate function have largely replaced other gut aVect the cortical response to visceral methods because of their simplicity and validity

stimuli, and if conversely, psychological events on September 27, 2021 by guest. Protected copyright. as markers of vagal as well as sympathetic func- can alter the function of the gut, gut-brain and tion.6 The use of techniques such as power brain-gut communication must be one of the spectral analysis of heart rate variability now important modulators involved. Therefore, it provide a simple and accurate measure of the seems logical that the autonomic nervous respective outflow of the vagal and sympathetic system, which is the primary pathway involved branches of the autonomic nervous system.4 As in brain-gut communication, plays an important role in functional bowel disorders (fig 2). The autonomic nervous system could be Higher brain centres simply a conduit through which the central nervous system controls visceral function or it may be that primary alterations in visceral Brain stem nuclei autonomic function are one of the pathophysi- ological factors involved in these conditions. In the following sections we will examine the pos- Visceral Parasympathetic Sympathetic sible role of the autonomic nervous system in afferents efferents efferents functional disorders and some of the therapeu- tic opportunities that modulation of autonomic function may provide in the management of Enteric nervous system functional disorders.

Functional bowel disorders: brain-gut, Sensory Motor Interneurones gut-brain, or both? neurones neurones In assessing the role of the autonomic nervous system in conditions such as functional bowel Figure 2 Autonomic nervous system alternate view.

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with non-cardiac chest pain, we have found the Gut: first published as 10.1136/gut.47.suppl_4.iv78 on 1 December 2000. Downloaded from 4 opposite; those patients with increased visceral sensitivity to oesophageal acid infusion had 1. Abnormal stimulation of normal higher resting sympathetic tone and decreased GI receptors vagal activity, suggesting that the abnormalities may diVer according to the gut region involved 1 2. Abnormal response of GI (foregut v hindgut). receptors to normal stimuli However, it is diYcult from these associa- 5 tions to ascribe a definite causative role to any 3. Abnormal intrinsic GI motility type of autonomic dysfunction in functional disorders until studies aimed at restoring a 4. Abnormal central perception of more normal basal autonomic balance are also shown to change the altered visceral perception normal GI afferent signals 2 1 and function that is present in these patients. Central and emotional factors, which are well 5. Abnormal central stimulation of 3 known to be associated with functional gut GI secretion/motility via efferent symptoms, are also capable of altering auto- pathways nomic balance. It would be naïve not to consider that in a large number of cases where Gut wall central as well as autonomic factors are involved it is the eVects of the former that may Figure 3 Functional bowel disease. lead to the occurrence of the latter and of the method requires only a surface electrocar- gastrointestinal symptoms (fig 3). diogram, it can be done in almost any setting.6

Autonomic function and bowel disorders Conclusions In recent years, there have been a number of There is increasing agreement that autonomic reports suggesting that functional bowel disor- abnormalities can often be associated with func- ders are associated with autonomic distur- tional disorders of the gut. We still have to gain a bance.7 However, none of these studies estab- better understanding of the mechanisms respon- lished more than an association, and should sible for the symptoms and of their fate with res- not at this point be interpreted to indicate that toration of autonomic function. Until then the altered autonomic function is causally related exact role of altered autonomic function in the to functional disorders. pathogenesis of functional disorders will remain In animals, surgical ablation of coeliac or as poorly defined as that of the other putative mesenteric ganglia has profound eVects on mechanisms involved in these disorders. Once gastrointestinal function.8 Furthermore, more, the urgent need for studies focusing on tumour invasion of the sympathetic ganglia can the mechanisms of disease rather than its clinical result in intestinal and/or colonic pseudo- manifestation, and on pathophysiology rather http://gut.bmj.com/ obstruction in patients with metastatic cancer.9 than symptomatology, is apparent. Conditions aVecting autonomic function, such as Parkinsonism and autonomic neuropathies, 1 Spaziani RM, Djuric V, Kamath MV, et al. A low resting also have profound eVects on gut function, as vagal tone predicts response to acid perfusion in patients with esophageal symptoms. Gastroenterology do the degenerative neuropathies associated 1996;110:A762. with diabetes and amyloidosis.10 However, 2 Jorgensen LS, Christiansen P, Raundahl U, et al. Autonomic nervous system function in patients with functional these alterations are clearly not the direct cause abdominal pain. Scand J Gastroenterol 1993;28:63–8. on September 27, 2021 by guest. Protected copyright. of symptoms in the majority of patients with 3 Aggarwal A, Cutts TF, Abell TL, et al. Predominant symp- toms in irritable bowel syndrome correlate with specific functional symptoms. autonomic nervous system abnormalities. Gastroenterology Altered autonomic function may also be 1994;106:945–50. 4 Kamath MV, Fallen EL. Power spectral analysis of heart rate involved in other gastrointestinal conditions, variability: a non-invasive signature of cardiac autonomic such as gastro-oesophageal reflux disease and function. Crit Rev Biomed Eng 1993;21:245–311. 5 Almy TP. The irritable bowel syndrome. Back to square neuropathic upper gastrointestinal motility dis- one. Dig Dis Sci 1980;25:401–3. orders.11 12 More interestingly, such vagal abnor- 6 Tougas G, Kamath M, Watteel G, et al. Modulation of neu- rocardiac function by oesophageal stimulation in humans. malities have also been identified in patients Clin Sci 1997;92:167–74. with functional gut disorders, including func- 7 Bharucha AE, Camilleri M, Low PA, et al. Autonomic dys- 13 14 function in gastrointestinal motility disorder. Gut 1993;34: tional dyspepsia and colonic inertia. 397–401. More recently, Aggarwal et al have shown 8 Popielski L. Zur physiologie des plexus coeliacus (experi- mentelle untersuchung). Arch Anat Physiol 1903:338–60. convincingly that a subgroup of patients with 9 Ogilvie H. Large intestine colic due to sympathetic invasion. IBS also showed various autonomic abnormali- BMJ 1948;2:671–3. 3 10 Camilleri M. Disorders of gastrointestinal motility in neuro- ties. However, the findings were varied and not logic diseases. Mayo Clin Proc 1990;65:825–6. present in all patients in their cohort. Patients 11 Chakraborty TK, Ogilvie AL, Heading RC, et al. Abnormal cardiovascular reflexes in patients with gastro-oesophageal with increased sympathetic activity and low reflux. Gut 1989;30:46–9. vagal tone tended to have constipation, whereas 12 Ogilive AL, James PD, Atkinson M. Impairment of vagal diarrhoea prone patients primarily showed function in reflux oesophagitis. QJMed1985;54;61–74. 13 Haug TT, Svebak S, Hausken T, et al. Low vagal activity as increased parasympathetic activity. Another mediating mechanism for the relationship between person- group has shown that functional abdominal pain ality factors and gastric symptoms in functional dyspepsia. Psychosom Med 1994;56:181–6. without any motility abnormalities was associ- 14 Latimer P, Sarna S, Campbell D, et al. Colonic motor and myoelectrical activity: a comparative study of normal ated with increased basal parasympathetic activ- subjects, psychoneurotic patients and patients with irritable 2 ity and lower sympathetic activity. In patients bowel syndrome. Gastroenterology 198l;80:893–900.

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