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A case for an immunological basis for irritable bowel syndrome
2078
EDITORIALS
GASTROENTEROLOGY Vol. 122, No. 7
A Case for an Immunological Basis for Irritable Bowel Syndrome See article on page 1778.
rritable bowel syndrome (IBS) is a clinical descriptor rather than a diagnosis with an established underlying etiology. Definitions of IBS focus on the presence of pain and the multiplicity and chronicity of abdominal symptoms. The clinical heterogeneity of this condition has prompted its classification into symptomatically homogeneous subgroups.1,2 Congruency between these clinical subgroups and the underlying pathogeneses seems unlikely. Several pathogenetic processes have been postulated for IBS and among these is a growing body of evidence that inflammation and immune activation contribute to a least a subset of IBS patients. The article by Chadwick et al.3 is a significant contribution to this thesis. In this study, Chadwick et al.3 examine mucosa biopsies from 77 IBS patients who met Rome criteria. Of these patients, 55% were diarrhea-predominant, 31% alternated between diarrhea and constipation, and 14% were constipation-predominant. A sudden onset suggestive of an acute infective trigger was described in 36%, but the majority had an insidious onset. The mean duration of symptoms was 2.5 years with actual durations ranging from as low as 3 months to 29 years. The striking finding of this study was that almost 90% of the patients with IBS showed evidence of immune activation, regardless of the type of onset, the duration of illness, dominant symptom profile, or the presence or absence of increased cellularity of the mucosa on routine histological examination. More than half these patients had a normal mucosa biopsy appearance on routine examination and the remainder had increased cellularity of the mucosa and submucosa consistent with a diagnosis of microscopic colitis. The authors’ interpretation of their findings as evidence of immune activation arises from finding higher
I
numbers of CD25⫹ve cells in the IBS patient group. CD25 is a component of the IL-2 receptor and an expression of cell activation. CD25⫹ve cells are regulatory T cells that are considered important in the prevention of autoimmunity, as well in controlling inflammatory responses in the gut4,5; their absence in mice leads to spontaneous colitis.4 The increased presence of CD25⫹ve cells in IBS raises the possibility that there is auto- or exogenous antigen challenge in these patients, and that the CD25⫹ cells are preventing the progression to a more florid inflammatory response. One may speculate that in a subset of patients with IBS, inflammation is in check, and may, under certain conditions, progress to a clinically more relevant state of inflammation.6 The finding of increased intraepithelial lymphocytes (IELs), CD3⫹ve cells, natural killer (NK), and mast cells contributes to a growing body of literature demonstrating an increased inflammatory cell presence in the colonic mucosa of certain IBS patients. This is well documented in patients with postinfective IBS in which T cell subgroups remain increased for more than a year after infection, and may reflect activation by luminal antigen because intestinal permeability is increased in these patients.7 Other studies, cited by the authors, describe an increase in the number of mast cells and macrophages in IBS patients. Although each patient experienced abdominal pain and met an earlier version of the Rome criteria, several observations prompt reconsideration of the extent to which the findings can be extrapolated to the general IBS population. First, the sample of IBS patients in a tertiary care setting is clearly subject to a referral bias. Second, the distribution of symptoms among these patients is unusual in that the majority of cases are diarrhea predominant; this subgroup is often in the minority in other IBS populations. Third, the finding of lymphocytic colitis, a rare diagnosis by most standards, in 10% of the
June 2002
study group raises questions about the nature of population under study. Thus, caution is urged in extrapolating these results to the general IBS population. Two recent studies have shown that latent celiac disease may present with IBS-like symptoms.8,9 From a study of 300 consecutive Rome II positive IBS patients referred to a teaching hospital, 66 patients had positive celiac serology. Of these, 14 had celiac disease compared with 2 controls.9 The authors concluded that IBS is significantly associated with celiac disease (P ⫽ 0.004, odds ratio ⫽ 7.0 [95% CI, 1.7–28.0]). In another study, 70% of patients with diarrhea-predominant IBS-like symptoms had at least one marker of celiac disease, and 26 patients with these markers were fed a gluten-free diet for 6 months. Those patients stratified for the HLADQ2 genotype, or positive anti-gliadin or tissue transglutaminase antibodies in duodenal aspirate responded to the diet with a significant reduction in stool frequency. In contrast, those patients lacking these markers failed to respond.8 Although celiac disease is an unlikely explanation for the findings of Chadwick et al.,3 as a practical point, it should be remembered that increased lymphocytes are also present in colonic biopsies of patients with untreated celiac disease.10,11 There is evidence that patients with postinfective IBS have increased cellularity of the lamina propria,12 increased IELs, as well as T lymphocytes.7 In the study by Chadwick et al.,3 prominence of these cells might be expected in the patients with acute onset and short duration IBS. This was not the case. Indeed, evidence of immune activation, as reflected by CD25⫹ve staining, and the number of IELs were more prominent in patients with insidious onset and chronic IBS compared to those with abrupt onset and a shorter history. This finding is counterintuitive and suggests that inflammation or immune activation may extend beyond the postinfective subset of IBS patients. This is supported by the results of a preliminary report of increased lymphocytes in the mucosa and myenteric plexus of a group of patients who submitted themselves to a laparoscopic-assisted fullthickness intestinal biopsy.13 Similarly, reports of increased numbers of other inflammatory cell types in IBS have not been restricted to patients with an abrupt onset of symptoms suggestive of a postinfective IBS.14,15 There is an understandable tendency to segregate IBS as a top or centrally driven pathogenesis and a peripherally driven mechanism such as infection.16 This distinction, while pragmatic, may be somewhat artificial as centrally mediated mechanisms, such as stress, may alter susceptibility and responsiveness to inflammatory events in the gut. This is clearly evident from animal stud-
EDITORIALS
2079
ies,17–19 and may explain why stressful life events are an identified risk factor for the development of IBS postinfection in humans.12 Conversely, inflammation or immune activation in the gut may induce changes in brain activity20 and behavior.21 The integration of behavioral and intestinal processes, such as inflammation and immune activation, into a biopsychosocial model offers a more comprehensive approach to IBS.22 In this regard, the absence of psychosocial information in the article by Chadwick et al.3 may be viewed as a weakness. What mechanistic interpretation should be applied to the findings of Chadwick et al.3 and those of similar studies? It is unlikely that the presence of immune and inflammatory cells in the mucosa compartment directly influences function in the deeper neuromuscular tissues, which are generally presumed to be the main locus of perturbed gut function in IBS. It is more likely that their presence in the mucosa is a marker of a process that likely also affects the neuromuscular tissues in a more direct manner. Studies in animal models of superficial gut inflammation, in which the inflammatory stimulus is directed at the mucosa, reveal discrete inflammatory or immune cell presence in the neuromuscular layers23 where they are responsible for perturbations in local function.24,25 Moreover, this is supported by a preliminary report on full-thickness biopsies from severe IBS patients that show an increase in IELs in the mucosa compartment, and discrete infiltration by lymphocytes in the myenteric plexus, with evidence of axonal damage.13 The article by Chadwick et al.3 is an important contribution to our conceptualization of IBS, and promotes the hypothesis that in at least in a subset of patients, low-grade inflammation and immune activation plays a pathophysiological role. The study requires confirmation and extension before attempts are made to extrapolate these findings to the IBS patient population at large. If confirmed, careful comparison of the data is required to identify potential markers of this subgroup. This, along with parallel mechanistic studies in animal models, could provide a basis for developing new diagnostic and therapeutic approaches to this IBS subgroup. STEPHEN M. COLLINS Division of Gastroenterology McMaster University Medical Center Hamilton, Ontario, Canada
References 1. Drossman DA. The Rome criteria process: diagnosis and legitimization of irritable bowel syndrome. Am J Gastroenterol 1999; 94:2803–2807. 2. Drossman DA. The functional gastrointestinal disorders and the Rome II process. Gut 1999;45 Suppl 2:II1-II5.
2080
EDITORIALS
3. Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002;122:1778 –1783. 4. Singh B, Read S, Asseman C, Malmstrom V, Mottet C, Stephens LA, Roncarolo MG. Control of intestinal inflammation by regulatory T cells. Immunol Rev 2001;182:190 –200. 5. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Stepankova R, Tlaskalova H, Powrie F. A CD4⫹ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737–742. 6. Garcia Rodriguez LA, Ruigomez A, Wallander MA, Johansson S, 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 2000;35:306 – 311. 7. Spiller RC, Jenkins D, Thornley JP, Hebden J, Wright T, Skinner M, 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 2000;47:804 – 811. 8. Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology 2001;121:1329 –1338. 9. Sanders DS, Carter MJ, Hurlstone DP, Pearce A, Ward AM, McAlindon ME, Lobo AJ. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 2001;358: 1504 –1508. 10. Fine KD, Do K, Schulte K, Ogunji F, Guerra R, Osowski L, McCormack J. High prevalence of celiac sprue-like HLA-DQ genes and enteropathy in patients with the microscopic colitis syndrome. Am J Gastroenterol 2000;95:1974 –1982. 11. Fine KD, Lee EL, Meyer RL. Colonic histopathology in untreated celiac sprue or refractory sprue: is it lymphocytic colitis or colonic lymphocytosis? Hum Pathol 1998;29:1433–1440. 12. Gwee KA, Leong YL, Graham C, McKendrick MW, Collins SM, Walters SJ, Underwood JE, Read NW. The role of psychological and biological factors in post-infective gut dysfunction. Gut 1999; 44:400 – 406. 13. Tornblom H, Lindberg G, Nyberg B, Veress B. Histopathological findings in the jejunum of patients with severe irritable bowel syndrome (abstr). Gastroenterology 2000;118(Suppl 1);A140. 14. O’Sullivan M, Clayton N, Breslin NP, Harman I, Bountra C, McLaren A, O’Morain CA. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil 2000;12:449 – 457. 15. Weston AP, Biddle WL, Bhatia PS, Miner PB Jr. Terminal ileal
GASTROENTEROLOGY Vol. 122, No. 7
16. 17.
18.
19.
20.
21.
22. 23.
24.
25.
mucosal mast cells in irritable bowel syndrome. Dig Dis Sci 1993;38:1590 –1595. Mayer EA, Naliboff BD, Chang L. Basic pathophysiologic mechanisms in irritable bowel syndrome. Dig Dis 2001;19:212–218. Gue M, Bonbonne C, Fioramonti J, More J, Rio-Lacheze C, Comera C, Bueno L. Stress-induced enhancement of colitis in rats: CRF and arginine vasopressin are not involved. Am J Physiol 1997;272(1 Pt 1):G84 –G91. Million M, Tache Y, Anton P. Susceptibility of Lewis and Fischer rats to stress-induced worsening of TNB-colitis: protective role of brain CRF. Am J Physiol 1999;276(4 Pt 1):G1027–G1036. Qiu BS, Vallance BA, Blennerhassett PA, Collins SM. The role of CD4⫹ lymphocytes in the susceptibility of mice to stress-induced reactivation of experimental colitis. Nat Med 1999;5:1178–1182. Castex N, Fioramonti J, Fargeas MJ, Bueno L. c-fos expression in specific rat brain nuclei after intestinal anaphylaxis: involvement of 5-HT3 receptors and vagal afferent fibers. Brain Res 1995; 688:149 –160. McHugh KJ, Weingarten HP, Keenan C, Wallace JL, Collins SM. On the suppression of food intake in experimental models of colitis in the rat. Am J Physiol 1993;264:R871–R876. Ringel Y, Sperber AD, Drossman DA. Irritable bowel syndrome. Annu Rev Med 2001;52:319 –338. Berezin I, Huizinga JD, Collins SM. Structural relationships between immune cells and longitudinal muscle during a Trichinella spiralis infection in the rat intestine. Neurogastroenterol Motil 1999;11:179 –192. Galeazzi F, Haapala EM, van Rooijen N, Vallance BA, Collins SM. Inflammation-induced impairment of enteric nerve function in nematode-infected mice is macrophage dependent. Am J Physiol Gastrointest Liver Physiol 2000;278:G259 –G265. Vallance BA, Croitoru K, Collins SM. T lymphocyte-dependent and -independent intestinal smooth muscle dysfunction in the T. spiralis-infected mouse. Am J Physiol 1998;275(5 Pt 1):G1157– G1165.
Address requests for reprints to: Stephen M. Collins, MBBS, FRCP (UK), FRSCP, Division of Gastroenterology, McMaster University Medical Center, Room 4W8, 1200 Main Street West, Hamilton, Ontario L8N 3Z5 Canada. e-mail: [email protected]; fax: (905) 521-4958. The author is a consultant for Astra Zeneca, Solvay, and Glaxo Smith Kline. © 2002 by the American Gastroenterological Association 0016-5085/02/$35.00 doi:10.1053/gast.2002.34097
EDITORIALS
GASTROENTEROLOGY Vol. 122, No. 7
A Case for an Immunological Basis for Irritable Bowel Syndrome See article on page 1778.
rritable bowel syndrome (IBS) is a clinical descriptor rather than a diagnosis with an established underlying etiology. Definitions of IBS focus on the presence of pain and the multiplicity and chronicity of abdominal symptoms. The clinical heterogeneity of this condition has prompted its classification into symptomatically homogeneous subgroups.1,2 Congruency between these clinical subgroups and the underlying pathogeneses seems unlikely. Several pathogenetic processes have been postulated for IBS and among these is a growing body of evidence that inflammation and immune activation contribute to a least a subset of IBS patients. The article by Chadwick et al.3 is a significant contribution to this thesis. In this study, Chadwick et al.3 examine mucosa biopsies from 77 IBS patients who met Rome criteria. Of these patients, 55% were diarrhea-predominant, 31% alternated between diarrhea and constipation, and 14% were constipation-predominant. A sudden onset suggestive of an acute infective trigger was described in 36%, but the majority had an insidious onset. The mean duration of symptoms was 2.5 years with actual durations ranging from as low as 3 months to 29 years. The striking finding of this study was that almost 90% of the patients with IBS showed evidence of immune activation, regardless of the type of onset, the duration of illness, dominant symptom profile, or the presence or absence of increased cellularity of the mucosa on routine histological examination. More than half these patients had a normal mucosa biopsy appearance on routine examination and the remainder had increased cellularity of the mucosa and submucosa consistent with a diagnosis of microscopic colitis. The authors’ interpretation of their findings as evidence of immune activation arises from finding higher
I
numbers of CD25⫹ve cells in the IBS patient group. CD25 is a component of the IL-2 receptor and an expression of cell activation. CD25⫹ve cells are regulatory T cells that are considered important in the prevention of autoimmunity, as well in controlling inflammatory responses in the gut4,5; their absence in mice leads to spontaneous colitis.4 The increased presence of CD25⫹ve cells in IBS raises the possibility that there is auto- or exogenous antigen challenge in these patients, and that the CD25⫹ cells are preventing the progression to a more florid inflammatory response. One may speculate that in a subset of patients with IBS, inflammation is in check, and may, under certain conditions, progress to a clinically more relevant state of inflammation.6 The finding of increased intraepithelial lymphocytes (IELs), CD3⫹ve cells, natural killer (NK), and mast cells contributes to a growing body of literature demonstrating an increased inflammatory cell presence in the colonic mucosa of certain IBS patients. This is well documented in patients with postinfective IBS in which T cell subgroups remain increased for more than a year after infection, and may reflect activation by luminal antigen because intestinal permeability is increased in these patients.7 Other studies, cited by the authors, describe an increase in the number of mast cells and macrophages in IBS patients. Although each patient experienced abdominal pain and met an earlier version of the Rome criteria, several observations prompt reconsideration of the extent to which the findings can be extrapolated to the general IBS population. First, the sample of IBS patients in a tertiary care setting is clearly subject to a referral bias. Second, the distribution of symptoms among these patients is unusual in that the majority of cases are diarrhea predominant; this subgroup is often in the minority in other IBS populations. Third, the finding of lymphocytic colitis, a rare diagnosis by most standards, in 10% of the
June 2002
study group raises questions about the nature of population under study. Thus, caution is urged in extrapolating these results to the general IBS population. Two recent studies have shown that latent celiac disease may present with IBS-like symptoms.8,9 From a study of 300 consecutive Rome II positive IBS patients referred to a teaching hospital, 66 patients had positive celiac serology. Of these, 14 had celiac disease compared with 2 controls.9 The authors concluded that IBS is significantly associated with celiac disease (P ⫽ 0.004, odds ratio ⫽ 7.0 [95% CI, 1.7–28.0]). In another study, 70% of patients with diarrhea-predominant IBS-like symptoms had at least one marker of celiac disease, and 26 patients with these markers were fed a gluten-free diet for 6 months. Those patients stratified for the HLADQ2 genotype, or positive anti-gliadin or tissue transglutaminase antibodies in duodenal aspirate responded to the diet with a significant reduction in stool frequency. In contrast, those patients lacking these markers failed to respond.8 Although celiac disease is an unlikely explanation for the findings of Chadwick et al.,3 as a practical point, it should be remembered that increased lymphocytes are also present in colonic biopsies of patients with untreated celiac disease.10,11 There is evidence that patients with postinfective IBS have increased cellularity of the lamina propria,12 increased IELs, as well as T lymphocytes.7 In the study by Chadwick et al.,3 prominence of these cells might be expected in the patients with acute onset and short duration IBS. This was not the case. Indeed, evidence of immune activation, as reflected by CD25⫹ve staining, and the number of IELs were more prominent in patients with insidious onset and chronic IBS compared to those with abrupt onset and a shorter history. This finding is counterintuitive and suggests that inflammation or immune activation may extend beyond the postinfective subset of IBS patients. This is supported by the results of a preliminary report of increased lymphocytes in the mucosa and myenteric plexus of a group of patients who submitted themselves to a laparoscopic-assisted fullthickness intestinal biopsy.13 Similarly, reports of increased numbers of other inflammatory cell types in IBS have not been restricted to patients with an abrupt onset of symptoms suggestive of a postinfective IBS.14,15 There is an understandable tendency to segregate IBS as a top or centrally driven pathogenesis and a peripherally driven mechanism such as infection.16 This distinction, while pragmatic, may be somewhat artificial as centrally mediated mechanisms, such as stress, may alter susceptibility and responsiveness to inflammatory events in the gut. This is clearly evident from animal stud-
EDITORIALS
2079
ies,17–19 and may explain why stressful life events are an identified risk factor for the development of IBS postinfection in humans.12 Conversely, inflammation or immune activation in the gut may induce changes in brain activity20 and behavior.21 The integration of behavioral and intestinal processes, such as inflammation and immune activation, into a biopsychosocial model offers a more comprehensive approach to IBS.22 In this regard, the absence of psychosocial information in the article by Chadwick et al.3 may be viewed as a weakness. What mechanistic interpretation should be applied to the findings of Chadwick et al.3 and those of similar studies? It is unlikely that the presence of immune and inflammatory cells in the mucosa compartment directly influences function in the deeper neuromuscular tissues, which are generally presumed to be the main locus of perturbed gut function in IBS. It is more likely that their presence in the mucosa is a marker of a process that likely also affects the neuromuscular tissues in a more direct manner. Studies in animal models of superficial gut inflammation, in which the inflammatory stimulus is directed at the mucosa, reveal discrete inflammatory or immune cell presence in the neuromuscular layers23 where they are responsible for perturbations in local function.24,25 Moreover, this is supported by a preliminary report on full-thickness biopsies from severe IBS patients that show an increase in IELs in the mucosa compartment, and discrete infiltration by lymphocytes in the myenteric plexus, with evidence of axonal damage.13 The article by Chadwick et al.3 is an important contribution to our conceptualization of IBS, and promotes the hypothesis that in at least in a subset of patients, low-grade inflammation and immune activation plays a pathophysiological role. The study requires confirmation and extension before attempts are made to extrapolate these findings to the IBS patient population at large. If confirmed, careful comparison of the data is required to identify potential markers of this subgroup. This, along with parallel mechanistic studies in animal models, could provide a basis for developing new diagnostic and therapeutic approaches to this IBS subgroup. STEPHEN M. COLLINS Division of Gastroenterology McMaster University Medical Center Hamilton, Ontario, Canada
References 1. Drossman DA. The Rome criteria process: diagnosis and legitimization of irritable bowel syndrome. Am J Gastroenterol 1999; 94:2803–2807. 2. Drossman DA. The functional gastrointestinal disorders and the Rome II process. Gut 1999;45 Suppl 2:II1-II5.
2080
EDITORIALS
3. Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002;122:1778 –1783. 4. Singh B, Read S, Asseman C, Malmstrom V, Mottet C, Stephens LA, Roncarolo MG. Control of intestinal inflammation by regulatory T cells. Immunol Rev 2001;182:190 –200. 5. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Stepankova R, Tlaskalova H, Powrie F. A CD4⫹ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737–742. 6. Garcia Rodriguez LA, Ruigomez A, Wallander MA, Johansson S, 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 2000;35:306 – 311. 7. Spiller RC, Jenkins D, Thornley JP, Hebden J, Wright T, Skinner M, 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 2000;47:804 – 811. 8. Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology 2001;121:1329 –1338. 9. Sanders DS, Carter MJ, Hurlstone DP, Pearce A, Ward AM, McAlindon ME, Lobo AJ. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 2001;358: 1504 –1508. 10. Fine KD, Do K, Schulte K, Ogunji F, Guerra R, Osowski L, McCormack J. High prevalence of celiac sprue-like HLA-DQ genes and enteropathy in patients with the microscopic colitis syndrome. Am J Gastroenterol 2000;95:1974 –1982. 11. Fine KD, Lee EL, Meyer RL. Colonic histopathology in untreated celiac sprue or refractory sprue: is it lymphocytic colitis or colonic lymphocytosis? Hum Pathol 1998;29:1433–1440. 12. Gwee KA, Leong YL, Graham C, McKendrick MW, Collins SM, Walters SJ, Underwood JE, Read NW. The role of psychological and biological factors in post-infective gut dysfunction. Gut 1999; 44:400 – 406. 13. Tornblom H, Lindberg G, Nyberg B, Veress B. Histopathological findings in the jejunum of patients with severe irritable bowel syndrome (abstr). Gastroenterology 2000;118(Suppl 1);A140. 14. O’Sullivan M, Clayton N, Breslin NP, Harman I, Bountra C, McLaren A, O’Morain CA. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil 2000;12:449 – 457. 15. Weston AP, Biddle WL, Bhatia PS, Miner PB Jr. Terminal ileal
GASTROENTEROLOGY Vol. 122, No. 7
16. 17.
18.
19.
20.
21.
22. 23.
24.
25.
mucosal mast cells in irritable bowel syndrome. Dig Dis Sci 1993;38:1590 –1595. Mayer EA, Naliboff BD, Chang L. Basic pathophysiologic mechanisms in irritable bowel syndrome. Dig Dis 2001;19:212–218. Gue M, Bonbonne C, Fioramonti J, More J, Rio-Lacheze C, Comera C, Bueno L. Stress-induced enhancement of colitis in rats: CRF and arginine vasopressin are not involved. Am J Physiol 1997;272(1 Pt 1):G84 –G91. Million M, Tache Y, Anton P. Susceptibility of Lewis and Fischer rats to stress-induced worsening of TNB-colitis: protective role of brain CRF. Am J Physiol 1999;276(4 Pt 1):G1027–G1036. Qiu BS, Vallance BA, Blennerhassett PA, Collins SM. The role of CD4⫹ lymphocytes in the susceptibility of mice to stress-induced reactivation of experimental colitis. Nat Med 1999;5:1178–1182. Castex N, Fioramonti J, Fargeas MJ, Bueno L. c-fos expression in specific rat brain nuclei after intestinal anaphylaxis: involvement of 5-HT3 receptors and vagal afferent fibers. Brain Res 1995; 688:149 –160. McHugh KJ, Weingarten HP, Keenan C, Wallace JL, Collins SM. On the suppression of food intake in experimental models of colitis in the rat. Am J Physiol 1993;264:R871–R876. Ringel Y, Sperber AD, Drossman DA. Irritable bowel syndrome. Annu Rev Med 2001;52:319 –338. Berezin I, Huizinga JD, Collins SM. Structural relationships between immune cells and longitudinal muscle during a Trichinella spiralis infection in the rat intestine. Neurogastroenterol Motil 1999;11:179 –192. Galeazzi F, Haapala EM, van Rooijen N, Vallance BA, Collins SM. Inflammation-induced impairment of enteric nerve function in nematode-infected mice is macrophage dependent. Am J Physiol Gastrointest Liver Physiol 2000;278:G259 –G265. Vallance BA, Croitoru K, Collins SM. T lymphocyte-dependent and -independent intestinal smooth muscle dysfunction in the T. spiralis-infected mouse. Am J Physiol 1998;275(5 Pt 1):G1157– G1165.
Address requests for reprints to: Stephen M. Collins, MBBS, FRCP (UK), FRSCP, Division of Gastroenterology, McMaster University Medical Center, Room 4W8, 1200 Main Street West, Hamilton, Ontario L8N 3Z5 Canada. e-mail: [email protected]; fax: (905) 521-4958. The author is a consultant for Astra Zeneca, Solvay, and Glaxo Smith Kline. © 2002 by the American Gastroenterological Association 0016-5085/02/$35.00 doi:10.1053/gast.2002.34097