THEMES
Stress and the Gastrointestinal Tract
IV. Modulation of intestinal inflammation by stress: basic mechanisms and clinical relevance

Stephen M. Collins

McMaster University Medical Centre, Hamilton, Ontario L8N 3Z5, Canada


    ABSTRACT
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ABSTRACT
INTRODUCTION
CLINICAL OBSERVATIONS
CAN STRESS INDUCE INFLAMMATION...
STRESS-INDUCED REACTIVATION OF...
THE STRESS RESPONSE AND...
THE MODULATION OF INFLAMMATION...
CONCLUSIONS AND FUTURE...
REFERENCES

The stress response in a healthy organism is generally viewed as a warning and thus a protective reaction to a threat. However, the response may be deleterious if it is linked to an inflammatory stimulus or if it proceeds an inflammatory event. Prior stress enhances the response to an inflammatory stimulus by a mechanism that is independent of the release of hypothalamic corticotropin-releasing factor (CRF) or arginine vasopressin. Putative mechanisms include an increase in intestinal permeability as well as the release of the proinflammatory neuropeptide substance P. Stress may also reactivate previous inflammation when applied in conjunction with a small luminal stimulus. This reactivation involves increased permeability and requires the presence of T lymphocytes. Inflammatory mediators activate hypothalamic pathways, and a negative feedback loop, mediated by CRF release, has been proposed because animals with impaired hypothalamic CRF responses are more susceptible to inflammatory stimuli. Together, these experimental observations provide insights into the expression of inflammatory disorders in humans, including inflammatory bowel disease and postinfective irritable bowel syndrome.

corticotrophin-releasing factor; epithelial permeability; substance P; inflammatory bowel disease; irritable bowel syndrome; infection


    INTRODUCTION
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ABSTRACT
INTRODUCTION
CLINICAL OBSERVATIONS
CAN STRESS INDUCE INFLAMMATION...
STRESS-INDUCED REACTIVATION OF...
THE STRESS RESPONSE AND...
THE MODULATION OF INFLAMMATION...
CONCLUSIONS AND FUTURE...
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ALTHOUGH STRESS HAS LONG BEEN implicated in the pathogenesis of a variety of gastrointestinal conditions, with emphasis placed on functional bowel disorders, it is only recently that the role of stress in modulating intestinal inflammatory processes has received the attention of investigators. The feasibility of considering stress as a modulator of inflammatory processes in the gut arises from the following developments: 1) the understanding that corticosteroids elaborated through activation of the hypothalamic-pituitary-adrenal (HPA) axis by stress are anti-inflammatory and that attenuated HPA responses to stress may predispose to inflammation (22); 2) the recognition that many immune and inflammatory cells recognize and respond to neuropeptides (24); and 3) the knowledge that stress may render an organism susceptible to an inflammatory stimulus by altering intestinal physiology, such as the permeability of the epithelium (10).


    CLINICAL OBSERVATIONS
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CLINICAL OBSERVATIONS
CAN STRESS INDUCE INFLAMMATION...
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It is important to identify clinical observations that might help place this large body of literature in an appropriate disease context. Inflammatory bowel disease (IBD) in humans consists of Crohn's disease and ulcerative colitis. These are chronic idiopathic inflammatory diseases, conditions in which environmental factors and a genetic predisposition converge to express the disease. Initially, colitis was considered to have a major psychological component and was, in fact, listed among psychosomatic conditions. As our awareness of the role of the immune system in IBD has increased, less attention has been paid to the role of the nervous system and stress in the expression of these conditions, despite some florid demonstrations of a tangible modulatory role of the nervous system in precipitating relapse in humans (9). Initially, there was also a consideration that early life stresses may predispose a person to the development of IBD (18). Today, speculations about the role of stress in IBD are focussed on the precipitation of relapses and perhaps on a facilitative role in the initial presentation of the disease.

Irritable bowel syndrome (IBS) is a chronic functional disorder research about which is dominated by behavioral issues. Recent studies have identified bacterial gastroenteritis as the strongest risk factor for the development of IBS identified to date (6). Preliminary data suggest that there is evidence of immune activation and increased epithelial permeability in these IBS patients when examined several months after the infection (20). Interestingly, stressful life events before the infection increase the risk of postinfective IBS (8). Thus, as with IBD, it appears that stress may converge with environmental factors such as infection, and perhaps a genetically determined predisposition to inflammation (3), to precipitate this subset of IBS patients.


    CAN STRESS INDUCE INFLAMMATION OR IMMUNE ACTIVATION?
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In a recent study in healthy volunteers and patients with food allergy, a cold pressor test increased luminal release of mast cell mediators and jejunal water secretion in both groups (16). Although stress-induced release of tryptase and histamine was greater in food-allergic patients, the study does link stress and mast cell degranulation in the gut in the absence of other inflammatory or immunological stimuli. This is in keeping with the demonstration of Pavlovian conditioning of mast cell degranulation in the rat (11). Together, these findings indicate that neuroendocrine brain-gut circuitry can be activated to stimulate immune cells in the absence of preexisting disease. The clinical counterpart to these findings may lie more closely with immune- and non-immune-based food intolerances than with chronic inflammatory conditions.

Although it is well known that emotional stress can result in hyperemia or ulceration of the gut, there are no experimental data to support the notion that stress per se can induce inflammation. However, stress can augment the response of an inflammatory stimulus to the gut; experiments have shown that partial restraint stress, applied during 4 consecutive days before the induction of colitis by 2,4,6-trinitrobenzenesulfonic acid (TNB), enhanced the subsequent acute inflammatory response (7). Interestingly, the enhancement of colitis by stress could not be blocked by the antagonist alpha -helical corticotropin-releasing factor (CRF)-(9-41) or by arginine vasopressin antagonists administered centrally immediately before each stress period. Previous work has shown that these antagonists blocked colonic motor response to stress (2), indicating that the neuroendocrine response to stress involves several independent pathways.


    STRESS-INDUCED REACTIVATION OF INFLAMMATION
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A common clinical scenario is the apparent exacerbation of chronic inflammatory conditions by stress. Most clinical studies rely on symptom reports to temporally correlate disease "activity" with stressful life events. Thus a positive correlation may simply reflect stress-induced changes in gut physiology as a basis for symptom generation rather than an increase in the activity of the inflammatory condition. A previous study in rats showed that mild restraint stress rekindled the inflammatory process in rats recovered from TNB colitis 6 wk previously. This was reflected by an increase in colonic myeloperoxidase activity but without accompanying structural damage (5, 12). However, a subsequent study in mice fully recovered from hapten-induced colitis 8 wk previously showed that a combination of mild restraint plus acoustic stress, together with a subthreshold dose of the hapten delivered intrarectally, resulted in overt inflammation, with mucosal ulceration and a polymorphonuclear leukocyte infiltration (15). In that study, the susceptibility to stress-induced reactivation of colitis could be adoptively transferred by a CD4-enriched population of lymphocytes from spleen and mesenteric lymph nodes; naive mice did not develop colitis on receiving these cells, but colitis occurred following stress plus a subthreshold dose of hapten. The model based on these findings is illustrated in Fig. 1. This finding provides proof of the concept that stress can reactivate inflammation in the gut, provided that the appropriate immune cells are present. The clinical implication is that aggressive immunomodulatory therapy is likely to minimize stress-induced exacerbations of IBD. The study also found an increase in colonic permeability following stress and suggests that this may play a facilitatory role in allowing the entry of luminal antigen (to activate presensitized T cells). What remains to be determined in this model is the HPA mediators involved and the role of bacteria in the reactivation process.


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Fig. 1.   Mechanisms underlying stress-induced reactivation of colitis. This model is based on studies performed in mice with a histologically proven recovery from hapten-induced colitis 8 wk previously (15). Stress caused a reduction in mucous secretion and an increase in colonic permeability, causing reactivation of colitis. When stress was coupled with a subthreshold intrarectal dose of hapten, there was reactivation of colitis, which required the presence of CD4+ cells. The proposed mechanism of reactivation of colitis is a stress-induced reduction in mucin and an increase in permeability (10, 17), which facilitate the entry of hapten and other antigens from the lumen to stimulate presensitized T cells.


    THE STRESS RESPONSE AND SUSCEPTIBILITY TO INTESTINAL INFLAMMATION
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There is a robust literature linking impairment of HPA response to stress and susceptibility of peripheral organs to inflammatory stimuli. LEW/N rats have a markedly reduced CRF content of the hypothalamus and paraventricular nucleus compared with histocompatible Fischer (F344/N) rats (22). When stimulated by serotonin agonists, interleukin-1beta , or exogenous CRF, LEW/N rats exhibit markedly impaired plasma corticotropin and corticosterone responses. These rats are susceptible to experimental arthritis induced by streptococcal cell wall, whereas F344/N rats are relatively resistant to this form of arthritis. Moreover, transplantation of hypothalamic tissue from inflammation-resistant rats to LEW/N rats confers protection against inflammatory stimuli (21). Recently, this model was extended to involve gut inflammation.

Million et al. (13) examined TNB-induced colitis in LEW/N and F344/N rats. At 7 days after dinitrobenzene administration, a similar degree of inflammation was observed in both strains and was inhibited in each strain by intracerebroventricular administration of CRF (13). As expected, LEW/N rats had lower corticosterone levels than F334/N rats after dinitrobenzene or stress. Restraint stress or water avoidance stress for 6 days before TNB resulted in a greater degree of colitis in LEW/N rats, and colitis was further enhanced by intracerebroventricular administration of the CRF antagonist astressin. The model represented by the findings in these studies is illustrated in Fig. 2.


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Fig. 2.   The relationship of impaired stress response and susceptibility to inflammation. This model is based on studies in inflammation-prone Lewis rats (21). These rats have a defect in hypothalamic corticotropin-releasing factor (CRF) production and exhibit decreased corticosterone levels when challenged with a variety of stressors (22). The reduction in circulating corticosterone leaves organs, including the colon (13), more susceptible to an inflammatory stimulus. Conversely, Fischer rats with normal CRF responses are relatively resistant to inflammatory stimuli. IL, interleukin.

Thus genetic or pharmacological attenuation of the CRF-mediated response to stress results in a substantially greater colonic inflammatory response in rats. The applicability of this finding to IBD is, however, uncertain. The traditional view is that the susceptibility to IBD lies primarily in the domain of immune regulation or epithelial integrity. However, other loci of susceptibility may exist in some IBD patients, and although there are no published data on the HPA response to stress in IBD patients, such studies appear warranted on the basis of the animal work cited here.


    THE MODULATION OF INFLAMMATION BY STRESS: PERIPHERAL MECHANISMS
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STRESS-INDUCED REACTIVATION OF...
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From these studies, it is evident that stress augments or reactivates inflammatory responses in the gut in animals without HPA disturbances, prompting consideration of other mechanisms. The ability of stress to increase intestinal permeability is an attractive explanation for these observations. Studies in stress-prone Wistar-Kyoto rats have shown that acute restraint stress increases intestinal permeability via the activation of cholinergic nerves (17). Subsequent work by this group has shown that macromolecular transport across the epithelium of stressed rats occurs via atropine-sensitive transcellular and paracellular pathways (10). The extent to which this is a direct effect of cholinergic nerves on epithelial cells or an indirect effect involving other nerves and cell types remains to be determined. Studies in mice have indicated that substance P is involved in stress-mediated abortion (1); this neuropeptide possesses proinflammatory properties and has been shown to enhance experimental colitis in mice (23). This may have clinical relevance in light of the previously documented increases in substance P binding sites in IBD patients.

Stress has also been implicated in the development of IBS following acute bacterial gastroenteritis (8), and patients with this type of IBS have recently been shown to have increased intestinal permeability (20). It is possible that in these patients stress caused an increase in permeability, which then augmented the inflammatory and immune response to infection and amplified the disturbances in gut motor and sensory function that are known to accompany gut inflammation (4).


    CONCLUSIONS AND FUTURE DIRECTIONS
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It is evident from animal work that stress is a potent modulator of the inflammatory response. Future work needs to address this in the context of chronic rather than acute inflammation and to apply paradigms other than those of acute stress responses. In other systems, attention is being drawn to the long-term consequences of stress in early life, including prenatal stress, on responsiveness to immune and inflammatory stimuli (14, 19). It has been shown, for example, that mice subjected to prenatal stress exhibit enhanced allergen-induced airway inflammation when tested in adulthood (14). The potential impact of early life events on the later development of intestinal inflammatory responses needs to be examined, particularly in light of clinical suggestions that IBD may, in some cases, be associated with infection or other traumas in early life (18, 25).


    ACKNOWLEDGEMENTS

My work cited in this manuscript has been supported by grants from the Medical Research Council of Canada (Canadian Institutes for Health Research).


    FOOTNOTES

Address for reprint requests and other correspondence: S. M. Collins, Rm. 4W8, McMaster Univ. Medical Centre, Hamilton, ON L8N 3Z5, Canada (E-mail: scollins{at}fhs.mcmaster.ca).


    REFERENCES
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ABSTRACT
INTRODUCTION
CLINICAL OBSERVATIONS
CAN STRESS INDUCE INFLAMMATION...
STRESS-INDUCED REACTIVATION OF...
THE STRESS RESPONSE AND...
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REFERENCES

1.   Arck, PC, Merali F, Stanisz AM, Stead RH, Chaouat G, Manuel J, and Clark DA. Stress-induced murine abortion with substance P-dependent alteration in cytokines in maternal uterine decidua. Biol Reprod 53: 814-819, 1995[Abstract].

2.   Buéno, L, Gué M, and Delrio C. CNS vasopressin mediates emotional stress and CRH-induced colonic motor alterations in rats. Am J Physiol Gastrointest Liver Physiol 262: G427-G431, 1992[Abstract/Free Full Text].

3.   Cheng, J, Gonsalkorale M, Perrey C, Previca V, Hajeer A, and Whorwell PJ. IL-10 and TGF-beta genotype in irritable bowel syndrome: evidence to support an inflammatory component? (Abstract). Gastroenterology 118, Suppl1: A184, 2000.

4.   Collins, SM. The immunomodulation of enteric neuromuscular function: implications for motility and inflammatory disorders. Gastroenterology 111: 1683-1699, 1996[ISI][Medline].

5.   Collins, SM, McHugh K, Jacobson K, Khan I, Riddell R, Murase K, and Weingarten HP. Previous inflammation alters the response of the rat colon to stress. Gastroenterology 111: 1509-1515, 1996[ISI][Medline].

6.   Garcia Rodriguez, LA, Wallander MA, Johansson S, and Olbe L. Detection of colorectal tumor and inflammatory bowel disease during follow-up of patients with initial diagnosis of irritable bowel syndrome. Scand J Gastroenterol 35: 306-311, 2000[ISI][Medline].

7.   Gué, M, Bonbonne C, Fioramonti J, More J, Rio-Lacheze C, Comera C, and Buéno L. Stress-induced enhancement of colitis in rats: CRF and arginine vasopressin are not involved. Am J Physiol Gastrointest Liver Physiol 272: G84-G91, 1997[Abstract/Free Full Text].

8.   Gwee, KA, Graham JC, McKendrick MW, Collins SM, Marshall JS, and Read NW. Psychological scores and persistence of irritable bowel after infectious diarrhea. Lancet 347: 150-153, 1996[ISI][Medline].

9.   Kemler, MA, Barendse GA, and Van Kleef M. Relapsing ulcerative colitis associated with spinal cord stimulation. Gastroenterology 117: 215-217, 1999[ISI][Medline].

10.   Kilaan, AJ, Saunders PR, Bijlsma PB, Berin MC, Taminiau JA, Groot JA, and Perdue MH. Stress stimulates transepithelial macromolecular uptake in rat jejunum. Am J Physiol Gastrointest Liver Physiol 275: G1037-G1044, 1998[Abstract/Free Full Text].

11.   MacQueen, G, Marshall J, Perdue M, Siegel G, and Bienenstock J. Pavlovian conditioning of rat mucosal mast cells to secrete rat mast cell protease II. Science 243: 83-85, 1989[ISI][Medline].

12.   McHugh, K, Weingarten HP, Khan I, Riddell R, and Collins SM. Stress-induced exacerbation of experimental colitis in the rat (Abstract). Gastroenterology 104: A1051, 1993.

13.   Million, M, Taché Y, and Anton P. Susceptibility of Lewis and Fischer rats to stress-induced worsening of TNB-colitis: protective role of brain CRF. Am J Physiol Gastrointest Liver Physiol 276: G1027-G1036, 1999[Abstract/Free Full Text].

14.   Nogueira, PJ, Ferreira HH, Antunes E, and Teixeira NA. Chronic mild prenatal stress exacerbates the allergen-induced airway inflammation in rats. Mediators Inflamm 8: 119-122, 1999[ISI][Medline].

15.   Qiu, BS, Vallance BA, Blennerhassett PA, and Collins SM. The role of CD4+ lymphocytes in the susceptibility of mice to stress-induced reactivation of experimental colitis. Nat Med 5: 1178-1182, 1999[ISI][Medline].

16.   Santos, J, Saperas E, Nogueiras C, Mourelle M, Antolin M, Cadahia A, and Malagelada JR. Release of mast cell mediators into the jejunum by cold pain stress in humans. Gastroenterology 114: 640-648, 1998[ISI][Medline].

17.   Saunders, PR, Hanssen NP, and Perdue MH. Cholinergic nerves mediate stress-induced intestinal transport abnormalities in Wistar-Kyoto rats. Am J Physiol Gastrointest Liver Physiol 273: G486-G490, 1997[Abstract/Free Full Text].

18.   Schwartz, RA, and Schwartz IK. Psychiatric disorders associated with Crohn's disease. Int J Psychiatry Med 12: 67-73, 1982[ISI][Medline].

19.   Shanks, N, Windle RJ, Perks PA, Harbuz MS, Jessop DS, Ingram CD, and Lightman SL. Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation. Proc Natl Acad Sci USA 9: 5645-5650, 2000.

20.  Spiller RC, Jenkins D, Thornley JP, Hebden J, Wright T, Skinner M, and Neal KR. Increased rectal mucosal enteroendocrine cells, T lymphocytes and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. In press.

21.   Sternberg, EM. Neuroendocrine factors in susceptibility to inflammatory disease: focus on the hypothalamic-pituitary-adrenal axis. Horm Res 43: 159-161, 1995[ISI][Medline].

22.   Sternberg, EM, Young WS, 3rd, Bernardini R, Calogero AE, Chrousos GP, Gold PW, and Wilder RL. A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats. Proc Natl Acad Sci USA 86: 4771-4775, 1989[Abstract].

23.   Sturiale, S, Barbara G, Qiu B, Figini M, Geppetti P, Gerard N, Gerard C, Grady EF, Bunnett NW, and Collins SM. Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P. Proc Natl Acad Sci USA 96: 11653-11658, 1999[Abstract/Free Full Text].

24.   Van Hagen, PM, Hofland LJ, ten Bokum AM, Lichtenauer-Kaligis EG, Kwekkeboom DJ, Ferone D, and Lamberts SW. Neuropeptides and their receptors in the immune system. Ann Med 31 Suppl2: 15-22, 1999[ISI][Medline].

25.   Whorwell, PJ, Holdstock G, Whorwell GM, and Wright R. Bottle feeding, early gastroenteritis, and inflammatory bowel disease. Br Med J 1: 382, 1979[ISI][Medline].


Am J Physiol Gastrointest Liver Physiol 280(3):G315-G318
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