The autonomic nervous system in functional bowel disordersLe système nerveux autonome et les troubles intestinaux fonctionnels RÉSUMÉ:Lescommunicationslelongdel’axecerveau-intestinmettent

The autonomic nervous systemin functional bowel disorders

Gervais Tougas MD CM FRCPC

In recent years, there has been a substantial shift in theconceptual definitions of what constitutes functional

bowel disorders and the irritable bowel syndrome (IBS). Ingeneral, these conditions are viewed as a group of disordersor clinical entities characterized by the presence, to a varyingdegree, of chronic pain, discomfort and disordered function.

While this type of clinical definition corresponds to how pa-tients present to physicians, it has proved difficult to apply inthe search for the pathophysiological factor(s) potentiallyinvolved in these conditions. While much remains to bedone in that regard, it is increasingly accepted that theseconditions are multifactorial and that the symptoms experi-

Can J Gastroenterol Vol 13 Suppl A March 1999 15A

G Tougas. The autonomic nervous system in functional boweldisorders. Can J Gastroenterol 1999;13(Suppl A):15A-17A.Communications along the brain-gut axis involve neural path-ways as well as immune and endocrine mechanisms. The twobranches of the autonomic nervous system are integrated anatom-ically and functionally with visceral sensory pathways, and are re-sponsible for the homeostatic regulation of gut function. Theautonomic nervous system is also a major mediator of the visceralresponse to central influences such as psychological stress. As de-fined, functional disorders comprise a constellation of symptoms,some of which suggest the presence of altered perception, whileother symptoms point to disordered gastrointestinal function asthe cause of the symptoms. A growing number of reports havedemonstrated disordered autonomic function in subgroups offunctional bowel patients. While a number of different methodswere used to assess autonomic function, the reports point to a gen-erally decreased vagal (parasympathetic) outflow or increasedsympathetic activity in conditions usually associated with slow ordecreased gastrointestinal motility, while other studies found ei-ther an increased cholinergic activity or a decreased sympatheticactivity in patients with symptoms compatible with an increasedmotor activity. Under certain conditions, altered autonomic bal-ance (including low vagal tone and increased sympathetic activ-ity) may alter visceral perception. Autonomic dysfunction mayalso represent the physiological pathway accounting for many ofthe extraintestinal symptoms seen in irritable bowel syndrome pa-tients and some of the frequent gastrointestinal complaints re-ported by patients with disorders such as chronic fatigue andfibromyalgia.

Key Words: Functional gut disorders, Gastrointestinal motility, Irri-

table bowel syndrome

Le système nerveux autonome et les troublesintestinaux fonctionnelsRÉSUMÉ : Les communications le long de l’axe cerveau-intestin mettenten jeu les voies neurales aussi bien que les mécanismes immunitaires et en-docriniens. Les deux branches du système nerveux autonome sont inté-grées sur le plan anatomique et fonctionnel aux voies sensorielles viscéraleset sont responsables de la régulation homéostatique de la fonction intesti-nale. Le système nerveux autonome est également un important médiateurde la réponse viscérale aux stimuli centraux, comme le stress psycholo-gique. Selon la définition, les troubles fonctionnels englobent toute unegamme de symptômes dont certains suggèrent la présence d’une perceptionaltérée, alors que d’autres semblent le reflet d’une fonction gas-tro-intestinale perturbée, responsable des symptômes. Un nombre crois-sant de rapports ont fait état d’une fonction autonome perturbée danscertains sous-groupes de patients atteints de troubles intestinaux fonction-nels. Alors qu’un nombre de méthodes différentes ont été utilisées pourmesurer la fonction autonome, les rapports indiquent une diminution gé-nérale du débit vagal (parasympathique) ou une activité sympathiqueaccrue dans des conditions habituellement associées à un ralentissementde la motilité gastro-intestinale. Tandis que d’autres études ont découvertsoit une activité cholinergique accrue ou une activité sympathique ralentiechez les patients dont les symptômes sont compatibles avec une activitémotrice accrue. Dans certaines conditions, la perturbation de l’équilibreautonome (y compris le faible tonus vagal et une activité sympathiqueaccrue) peut influer sur la perception viscérale. La dysfonction autonomepeut également représenter la voie physiologique responsable de nombreuxsymptômes extra-intestinaux observés chez des patients atteints d’un syn-drome du côlon irritable et de certains des symptômes gastro-intestinauxfréquemment signalés par des patients atteints de troubles comme la fa-tigue chronique et la fibromyalgie.

Digestive Diseases Research Program, Division of Gastroenterology, McMaster University, Hamilton, OntarioCorrespondence and reprints: Dr G Tougas, Digestive Diseases Research Program, Division of Gastroenterology, McMaster University Medical

Centre, 1200 Main Street West, Room 3N5C, Hamilton, Ontario L8N 3Z5. Telephone 905-521-2100 ext 3884, fax 905-522-3454,e-mail [email protected]

GUT DYSFUNCTION IN IBS

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enced by two individual patients, although somewhat simi-lar, may result from a number of different etiologies.

While motility abnormalities are identified in many pa-tients with functional disorders, the majority of patientshave no demonstrable motility dysfunction, and the motorabnormalities that have been identified vary from study tostudy; each abnormality is present in a small and very spe-cific group of patients who do not represent the majority ofthose seen in clinical practice. The concept that these con-ditions are primarily motility disorders is also generallyviewed as failing to account for many of the other character-istics that are present in these patients, in particular the dis-comfort and pain often reported in the presence of anapparently normal gastrointestinal motility.

In many patients with functional disorders, the presenceof an altered visceral perception to various stimuli, such asdistention, has been identified. This issue of altered visceralperception in IBS is discussed extensively elsewhere, but it isimportant to point out that, while a primary disorder of vis-ceral sensory perception provides a plausible explanation formany of the symptoms reported in functional bowel disor-ders, it remains a largely unproved concept at the clinicallevel. In specific situations, such as the development ofchronic symptoms following an acute inflammatory or infec-tious event (such as postinfectious IBS), altered function ofthe normal sensory mechanisms, either within the gut wallor along visceral afferent pathways, is conceivable, at least inthe short term. It is more difficult at this point to implicatealtered visceral sensory pathways in the pathogenesis offunctional symptoms such as diarrhea or increased gas thatare present in many postinfectious IBS patients but also inpatients in whom there is no history of any acute inflamma-tory or infectious precipitant before the development ofsymptoms. Similarly, the hypothesis of an altered visceralsensory perception as the only factor involved in functionaldisorders fails to account for the very high association ofstress, psychologically traumatic experiences and emotionaldistress with the development and persistence of functionalbowel symptoms. Unless the concept of altered visceral sen-sory perception is extended to include the cortical centresassociated with visceral perception or implicate some sort ofcentral nervous system modulation of the afferent and spinalpathways involved with perception of visceral stimuli, it issomewhat difficult to build a conceptual framework capableof reconciling cortical events such as emotions with the pe-ripheral sensory pathways involved with visceral sensoryfunction.

If a pragmatic approach is used to reconcile the variouscomponents identified in the clinical expression of func-tional bowel disorders with an overall concept of thepathophysiological factors involved, several conditions mustbe met. First, the condition involves central as well as pe-ripheral sites; pain is ultimately a cortical event, whileevents such as diarrhea and mucus production imply thatthere is also a dysfunction of the gut per se. Therefore, func-tional disorders must to some extent involve the brain aswell as the gut. Second, if visceral factors such as an infec-

tious event in the gut affect the cortical response to a visceralstimuli, and if, conversely, psychological events can alter thefunction of the gut, then gut-brain and brain-gut communi-cation must be one of the important modulators involved.Therefore, it seems logical that the autonomic nervous sys-tem, which is the primary pathway involved in brain-gutcommunication, may play an important role in functionalbowel disorders.

The autonomic nervous system may simply be a conduitthrough which the central nervous system controls visceralfunction, or primary alterations in visceral autonomic func-tion may be one of the pathophysiological factors involvedin these conditions. In the following sections, the possiblerole of the autonomic nervous system in functional disordersand some of the therapeutic opportunities that modulationof autonomic function may provide in the management offunctional disorders are examined.

FUNCTIONAL BOWEL DISORDERS:BRAIN-GUT, GUT-BRAIN OR BOTH?

When assessing the role of the autonomic nervous system inconditions such as functional bowel disorders, it is essentialto remember the homeostatic nature of autonomic function.While many local gastrointestinal stimuli elicit responsesand reflexes whose involvement is essentially limited to theimmediate region that was primarily stimulated, when moreintense or potentially noxious stimuli occur, other systemsincluding the central nervous system, in addition to the gas-trointestinal tract, are involved. The transmission of the in-formation to the central nervous system allows for theelaboration of an integrated homeostatic response that mayinclude a behavioural as well as a physiological response. Inthis type of response, both visceral and autonomic nervouspathways are essential.

Many of the systemic responses elicited by visceral stimuliare produced through autonomic reflexes. These reflexes,which occur primarily through the brainstem, may not be as-sociated with a conscious perception of the sensory stimulus.However, other visceral sensory stimuli are sufficiently in-tense to be felt as well.

The type and degree of the autonomic reflex response to aspecified visceral stimulus depend on the location, type andintensity of the stimulus. If prior sensitization of the visceralafferent pathways has resulted in a state of hyperalgesia orallodynia, the reflex response may be exaggerated, while aperipheral sensory neuropathy may be associated with a de-creased reflex response. Similarly, psychological factors suchas increased vigilance, anxiety and depression are also likelyto affect autonomic reflexes (1).

ASSESSING AUTONOMIC FUNCTIONA number of methods have been developed to assess specificaspects of autonomic nervous function. Some of the olderapproaches, which were very cumbersome and involvedrather complex measurements, have been largely aban-doned. In recent years, the development of techniques basedon the autonomic modulation of heart rate function have

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largely replaced other methods because of their simplicityand validity as markers of vagal as well as sympathetic func-tion. The use of techniques such as power spectral analysis ofheart rate variability provides a simple and very accuratemeasure of the respective outflow of the vagal and sympa-thetic branches of the autonomic nervous system (2). Be-cause the method requires only a surface electrocardiogram,it can be done in almost any setting.

AUTONOMIC FUNCTIONAND BOWEL DISORDERS

In recent years, there have been a number of reports suggest-ing that functional bowel disorders are associated with auto-nomic disturbances (3). However, none of these studiesestablishes anything more than an association, and their re-sults should not be interpreted to indicate that altered auto-nomic function is causally related with functional disorders.

In animals, surgical ablation of celiac or mesenteric gan-glia has profound effects on gastrointestinal function (4).Furthermore, tumour invasion of the sympathetic gangliacan result in intestinal and colonic pseudo-obstruction inpatients with metastatic cancer (5). Conditions affecting au-tonomic function, such as Parkinson’s disease and auto-nomic neuropathies, also have a profound effect on gutfunction as do the degenerative neuropathies associatedwith diabetes and amyloidosis (6). However, these alter-ations are clearly not the direct cause of symptoms in the ma-jority of patients with functional symptoms.

Altered autonomic function may also be involved in con-ditions such as gastroesophageal reflux disease and neuro-pathic upper gastrointestinal motility disorders (7,8). Moreinterestingly, such vagal abnormalities have also been iden-tified in patients with functional gut disorders includingfunctional dyspepsia and colonic inertia (9,10).

Recently Aggarwal et al (11) convincingly showed that asubgroup of patients with IBS had various autonomic abnor-malities. However, the findings were varied and certainlywere not present in all patients from their cohort. Patientswith vagal dysfunction tended to have constipation, whereasdiarrhea-prone patients primarily had increased sympatheticactivity. Another group has shown that functional abdomi-nal pain without any motility abnormalities was associatedwith an increased basal parasympathetic activity and a lowersympathetic activity (12). In a patient with noncardiac chestpain, the opposite effect was found; patients with increasedvisceral sensitivity to esophageal acid infusion had a higherresting sympathetic tone and a decreased vagal activity, sug-gesting that the abnormalities may differ according to thegut region involved (foregut versus hindgut) (13).

However, it is difficult from these associations to ascribe adefinite causative role to any type of autonomic dysfunctionin functional disorders until studies aimed at restoring amore normal basal autonomic balance are shown to changethe altered visceral perception and function that is present

in these patients. Central neural and emotional factors,which are well known to be associated with functional gutsymptoms, are also capable of altering autonomic balance. Itwould be naive not to consider that, in a large number ofcases where central neural as well as autonomic factors areinvolved, the effects of the former lead to the occurrence ofthe latter and of gastrointestinal symptoms.

CONCLUSIONSWhile there is increasing agreement that autonomic abnor-malities are often associated with functional disorders of thegut, until we gain a better understanding of the mechanismsresponsible for the symptoms, and of their fate with restora-tion of autonomic function, the exact role of altered auto-nomic function in the pathogenesis of functional disorderswill remain as poorly defined as that of the other putativemechanisms involved in these disorders. Once more, theneed for studies focusing on the mechanisms of disease ratherthan its clinical manifestation, and on pathophysiologyrather than symptomatology, is apparent.

ACKNOWLEDGEMENTS: The financial support of the MedicalResearch Council of Canada and of the DeGroote Foundation isgratefully acknowledged.

REFERENCES1. Almy TP. The irritable bowel syndrome. Back to square one. Dig Dis

Sci 1980;25:401-3.2. Kamath MV, Fallen EL. Power spectral analysis of heart rate

variability: a non-invasive signature of cardiac autonomic function.Crit Rev Biomed Eng 1993;21:245-311.

3. Bharucha AE, Camilleri M, Low PA, Zinsmeister AR. Autonomicdysfunction in gastrointestinal motility disorders. Gut1993;34:397-401.

4. Popielski L. Zur physiologie des plexus coeliacus (experimentelleuntersuchung). Arch Anat Physiol 1903;17:338-60.

5. Ogilvie H. Large intestine colic due to sympathetic invasion. Br Med J1948;ii:671-3.

6. Camilleri M. Disorders of gastrointestinal motility in neurologicdiseases. Mayo Clin Proc 1990;65:825-6.

7. Chakraborty TK, Ogilvie AL, Heading RC, Ewing DJ. Abnormalcardiovascular reflexes in patients with gastro-oesophageal reflux.Gut 1989;30:46-9.

8. Ogilive AL, James PD, Atkinson M. Impairment of vagal function inreflux oesophagitis. Q J Med 1985;54:61-74.

9. Haug TT, Svebak S, Hausken T, Wilhelmsen I, Berstad A, Ursin H.Low vagal activity as mediating mechanism for the relationshipbetween personality factors and gastric symptoms in functionaldyspepsia. Psychosom Med 1994;56:181-6.

10. Latimer P, Sarna S, Campbell D, Latimer M, Waterfall W, Daniel EE.Colonic motor and myoelectrical activity: a comparative study ofnormal subjects, psychoneurotic patients and patients with irritablebowel syndrome. Gastroenterology 1981;80:893-900.

11. Aggarwal A, Cutts TF, Abell TL, et al. Predominant symptoms inirritable bowel syndrome correlate with specific autonomic nervoussystem abnormalities. Gastroenterology 1994;106:945-50.

12. Jorgensen LS, Christiansen P, Raundahl U, et al. Autonomic nervoussystem function in patients with functional abdominal pain. Scand JGastroenterol 1993;28:63-8.

13. Spaziani RM, Djuric V, Kamath MV, et al. A low resting vagal tonepredicts response to acid perfusion in patients with esophagealsymptoms. Gastroenterology 1996;110:A762. (Abst)

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The autonomic nervous system in functional bowel disordersLe système nerveux autonome et les troubles intestinaux fonctionnels RÉSUMÉ:Lescommunicationslelongdel’axecerveau-intestinmettent