Post-infectious irritable bowel syndrome: The past, the present and the future

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1 doi: /j x GASTROENTEROLOGY _ Post-infectious irritable bowel syndrome: The past, the present and the future Uday C Ghoshal and Prabhat Ranjan Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Key words chronic diarrhea, dysentery, functional bowel disease, gastroenteritis, tropical sprue. Accepted for publication 24 January Correspondence Uday C Ghoshal, Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow , India. udayghoshal@gmail.com Conflict of interest No potential conflict of interest to disclose. Abstract Background: Irritable bowel syndrome (IBS), once thought to be a psychosomatic disease, is being considered to be more organic. Post-infectious IBS (PI-IBS), defined as acute onset IBS (by Rome criteria) after gastrointestinal infection in an individual without prior IBS with two or more of the followings: fever, vomiting, diarrhea, a positive stool culture. The recent and old literature of PI-IBS will be reviewed. Future directions for research will be presented. Methods: Literature on PI-IBS was reviewed by electronic search and cross references of these papers. Results: Interest in studies on PI-IBS, which was described five to six decades ago, re-surfaced recently. 3.6 to 32% patients with acute gastroenteritis develop PI-IBS during 3 12 month follow-up. PI-IBS is commonly diarrhea predominant. Factors implicated in development include nature of pathogens, duration and severity of diarrhea, younger age, female gender and psychological co-morbidities like anxiety and depression. The pathogenesis of PI-IBS is largely related to continuing gut inflammation due to inability of the host to contain the inflammatory reaction, altered gut microbiota, increased intestinal permeability, muscle hyper-contractility and visceral hypersensitivity. There could be an overlap between PI-IBS and post-infectious malabsorption syndrome (PI-MAS), popularly known as tropical sprue. Conclusions: Development of IBS in a subset of patients with acute gastroenteritis is uncontested. This is expected to open a paradigm shift in understanding the pathogenesis of IBS. Future studies should address the issue of overlap of PI-IBS and PI-MAS. Exploring the molecular mechanisms of pathogenesis of PI-IBS may help to design preventive and therapeutic strategies. Introduction Irritable bowel syndrome (IBS) is a common gastrointestinal disorder affecting 4 22% of population. 1 Till date, the exact etiology of IBS remains somewhat enigmatic. In the recent years, however, IBS has been described following acute gastrointestinal infection in a subset of patients. 2 Furthermore, quantitative and qualitative alteration of gut flora has been shown to be important in pathogenesis of IBS. 2,3 Therapeutic manipulation of gut flora using either antibiotics or probiotics has been used in management of IBS. 2,3 Based on these evidence, many experts believe that a subset of patients with IBS might has a more organic disease like low-grade inflammatory bowel disease resulting from exaggerated immunological response to a normal or abnormal gut flora. 4 6 Literature on epidemiological, clinical and pathophysiological issues of post-infectious IBS (PI-IBS) will be reviewed here including the studies published in the past and the present. The future direction for research on this disease will also be presented. Post-infectious IBS: the past In 1950, Stewart et al. described PI-IBS. 7 Subsequently, in a study published in 1962, Chaudhary and Truelove reported 130 patients with IBS of whom 34 (26%) reported that their symptoms began following an episode of bacillary or amoebic dysentery. 8 They coined the term post-dysenteric IBS to describe these patients. 8 They also noted that prognosis of patients with post-dysenteric IBS was better than other subtypes of disease. In 1960 s, studies from southern India showed that about 10% subjects in a rural community experiencing an attack of acute gastroenteritis continued to have increased frequency and liquidity of the stool. 9 This was described as epidemic tropical sprue or post-infective malabsorption syndrome However, to diagnose tropical sprue, one needs to show biochemical evidence of malabsorption of two unrelated substances such as that of carbohydrate, fat and vitamin B Tests for malabsorption were, however, performed in a subset of the patients only in the southern Indian study. 9 Therefore, some of these patients might be suffering from PI-IBS described recently. All 94 Journal of Gastroenterology and Hepatology 26 (2011) Suppl. 3;

2 UC Ghoshal and P Ranjan Post-infectious irritable bowel syndrome these studies document that PI-IBS was described long ago but did not receive much attention until recently. PI-IBS: the current literature Definition and epidemiology of PI-IBS PI-IBS has been defined as acute onset IBS symptoms (by Rome criteria) that develop after the individual, who has not previously met the Rome criteria, experiences a gastrointestinal infection with two or more of the following characteristics: fever, vomiting, diarrhea, or a stool culture positive for an infectious agent. 2 Interest on PI-IBS re-surfaced after a study by Gwee et. al. from Sheffield, England in This study showed that of 75 patients suffering from an attack of acute gastroenteritis, 20 (26.6%) had persistent bowel-related symptoms that fulfilled criteria for diagnosis of IBS even 6 months after the episode of diarrheal disease. Subsequently, several studies (Table 1) from United Kingdom, 13 16,20,21 US, 23 Canada 19,28 and Asia 22,24 reported that in 6 to 17% patients with IBS, symptoms began after acute infective gastroenteritis. Table 1 shows frequency of PI-IBS in various studies to 31.6% patients with acute gastroenteritis developed PI-IBS during 3 12 month follow-up period; in contrast, 0.3% to 10.2% controls developed IBS during the same follow-up period. Recently, two meta-analyses on PI-IBS have been reported. 35,36 All the studies qualified enough to be included in the metaanalysis showed a risk estimate (odds ration) greater than one. 36 Median prevalence of IBS after gastroenteritis was 9.8% (interquartile range, IQR ), in control 1.2% (IQR , P = 0.01) during a median follow-up duration of 9-mo (interquartile range mo). 36 An attack of acute gastroenteritis is associated with 7-fold increase in risk of PI-IBS. 36 Difference in frequency of PI-IBS reported in different studies might be related to variable presence of other risk factors influencing susceptibility to PI-IBS development. Risk factors for development of PI-IBS Several factors have been implicated to increase the risk of development of IBS following acute gastroenteritis. These include agent factors such as the nature of pathogen and host related factors like genetic and psychological state, and host agent interaction (Fig. 1). Bacterial pathogens are more commonly associated with PI-IBS; the bacteria implicated include Campylobacter, Escherichia coli, Salmonella and Shigella. 35,36 Severity of acute gastroenteritis as reflected by duration and severity of diarrhea might predispose to development of PI-IBS. 35,36 Recently, two studies showed that patients with Giardiasis may develop IBS symptoms during follow-up. 33,37 However, in another study, patients with giardiasis (82 had IBS by Rome criteria) were randomized in four groups, two of which (A and B, 41 patients each) included patients with giardiasis and IBS and the remaining two (C and D, 9 patients each), included patients with giardiasis only. 38 The groups A and C were treated with metronidazole, whereas groups B and D were treated with drugs commonly used for IBS. 38 Treatment with metronidazole was ineffective in the groups with giardiasis and IBS. 38 Instead, the treatment for IBS ameliorated the symptoms in these patients. 38 On the contrary, the groups without IBS improved only with metronidazole. 38 This study suggests that Giardiasis may not be etiologically related to IBS. 38 In two other studies from India, 39,40 amoebiasis was not found to be a cause of IBS. Viral diarrhea has been recently shown to be a cause of IBS from Canada, 31 though it was found that the duration of IBS following viral diarrhea was shorter. Host factors include younger age, 21,41 female gender 21,32,41,42 and psychological co-morbidities like anxiety and depression. 13,16,35,36 Influence of gender, however, was not found important in development of PI-IBS in many studies including those from Asia. 22,24 A study revealed that rectal mucosa had less mast cell and lymphocytes in older subjects, which might result in lesser inflammation in response to infection reducing the risk of IBS in older subjects. 20 Sykes et al. 43 observed that the people with anxiety disorders were at higher risk of PI-IBS after acute gastroenteritis. In a recent study on Walkerton cohort, 44 prospectively followedup, of 1368 subjects exposed to acute gastroenteritis in May 2000, 417 developed PI-IBS during long-term follow-up. On multivariate analysis, female gender, diarrheal illness lasting more than 7 days, peak frequency of seven or more loose stools per day, abdominal cramps, and weight loss of at least 10 pounds were independent predictors for development of PI-IBS. In a mataanalysis, young age, prolonged fever, anxiety and depression were risk factors for PI-IBS. 35 Studies on PI-IBS in Asia Though acute gastroenteritis is common in several developing countries of Asia, the data on PI-IBS from these regions are scanty. PI-IBS has been reported only from Korea and China. 22 In the study from Beijing and Guangzhou cities from China, 22,45,46 of 293 patients with acute bacillary dysentery, 8% developed IBS by Rome II criteria during month follow-up in contrast to 0.8% of 243 controls. Longer duration of diarrhea (> 7 days) was associated with a higher risk, a finding similar to the studies from the West. However, unlike the studies from UK, where 77% of women developed IBS compared to only 36% of men, similar risks were observed for men and women in China. In a Korean study 24 on 101 patients affected in an outbreak of bacillary dysentery in 2001 and 102 controls followed-up for 12-months, 15 (15%) patients and 6 (6%) controls developed IBS (odds ratio for developing IBS 2.9), which was similar to the Chinese study. Longer duration of diarrhea during the attack of gastroenteritis was an independent risk factor for development of IBS and gender did not influence its development. Lack of influence of gender on development of PI-IBS is in accordance with epidemiology of IBS from Asian countries where female preponderance of IBS is not observed, in contrast to that in the West. 1 The Korean group followed-up these patients for 5-year and found that half of PI-IBS and previous IBS patients with or without infection recovered over 5 years. 26 In another Korean study, 47 colonic biopsies from 42 IBS patients showed mucosal hyperplasia, lymphocyte aggregation and eosinophilia, findings that are suggestive of low-grade inflammation compared with asymptomatic subjects. This study also suggested that IBS may be considered as lowgrade inflammatory bowel disease. Journal of Gastroenterology and Hepatology 26 (2011) Suppl. 3;

3 Post-infectious irritable bowel syndrome UC Ghoshal and P Ranjan Table 1 Summary of studies on post-infective irritable bowel syndrome (IBS) Author Year Country Controls Type of exposure Follow-up (mo) Criteria for diagnosis of IBS Frequency of PI-IBS in exposed cohort Frequency of IBS development in control group Reference McKendrick 1994 UK None Salmonella 12 Rome I 31.6% NA 14 Gwee 1996 UK None Shigella, Campylobacter, Salmonella 12 Rome I 20.2% NA 13 Neal 1997 UK None Bacterial gastroenteritis 6 Modified Rome I 6.3% NA 15 Gwee 1999 UK None Gastroenteritis 6 Clinical assessment 10.5% NA 16 Rodriguez 1999 UK Uninfected general population Mearin 2001 Spain Uninfected general population Bacterial gastroenteritis 12 Physician diagnosis 4.4% 0.3% 17 Salmonella 12 Rome II 13.2% 1.5% 18 Ilnyckyj 2003 Canada Uninfected travelers Traveler s diarrhea 3 Rome I 4.2% 1.6% 19 Dunlop 2003 UK None Campylobactor 3 Rome I 13.8% NA 20 Parry 2003 UK Community subjects Campylobacter, Salmonella 6 Rome II 14.1% 1.9% 21 Wang 2004 China Uninfected family Shigella 24 Rome II 8.1% 0.8% 22 Okhuysen 2004 US None Traveler s diarrhea 6 Rome II 3.6% NA 23 Ji 2005 South Korea Healthy Shigella 12 Modified Rome I&II 10.5% 5.8% 24 Kim 2006 Korea Uninfected healthy subjects Shigella 36 Modified Rome I&II 14.9% 4.5% 25 Jung 2009 Korea Uninfected volunteers Shigella 60 Modified Rome I&II 5% 5% 26 Marshal 2006 Canada Uninfected local residents E.coli, Campylobacter 36 Rome I 30.5% 10.2% 27 Borgaonkar 2006 Canada None Bacterial pathogen 3 Manning & Rome I 3.7% NA 28 Moss-morris 2006 New Zealand Mononucleosis Campylobacter 6 Rome I&II 11.0% 8% 29 Stermer 2006 Israel Uninfected travelers Traveler s diarrhea 6 Rome II 11.0% 2.4% 30 Marshall 2007 Canada Uninfected volunteers Viral 3,6,12,24 Rome I 16.3% 3.4% 31 Spence 2007 New Zealand None Campylobacter 3,6 Rome I&II 10.2% NA 32 Hanevik 2009 Norway None Giardia Rome II 80.5% NA 33 IBS, irritable bowel syndrome; NA: not applicable. 96 Journal of Gastroenterology and Hepatology 26 (2011) Suppl. 3;

4 UC Ghoshal and P Ranjan Post-infectious irritable bowel syndrome Subjects with acute gastroenteritis Bacteria, virus,?giardia Subjects without acute gastroenteritis Genetic susceptibility, intestinal inflammation, permeability, altered sensory motor function, organism responsible and severity of gastroenteritis, psychological and psychiatric disturbances, host factors (genetic make-up, young age, female gender) Figure 1 Outline of outcome of acute gastroenteritis and risk-factors for post-infectious irritable bowel syndrome (abbreviation used: IBS, irritable bowel syndrome). Postinfectious IBS Post-infectious malabsorption No gastrointestinal sequel Special issues on post-infectious IBS in Asia Paradox of frequent gastrointestinal infection but infrequent IBS in the tropics Frequency of acute gastroenteritis is common in tropical countries with poor hygiene. Frequency of IBS, however, was lower in population studies from most of these countries (4.2% in India, % in Thailand, % in Bangladesh, % in Pakistan 51 ). In contrast, frequency of IBS in population of developed countries was higher in spite of low frequency of acute gastroenteritis. 1 It is difficult to explain this paradoxical phenomenon. Suggested hypothesis could be related to modulation of immune system to Th2 type by other infection such as that with helminthes, higher degree of tolerance of the host due to exposure to these infections from early childhood and host genetic factors. 52 More studies are needed on these issues. Special issues on diagnosis of PI-IBS in areas endemic for tropical malabsorption In 1962, epidemics of malabsorption syndrome following acute gastroenteritis, also called epidemic tropical sprue or postinfective tropical malabsorption was described from southern Indian villages. 9,53,54 Similar epidemics were also reported in other tropical regions such as Philippines 55 and Bangladesh. 56 Tropical malabsorption is often accompanied by colonization and overgrowth of bacteria in the small bowel, 57,58 as has been recently reported in association with IBS. 59,60 Both tropical malabsorption and PI-IBS are associated with prolonged diarrhea. 57,61 Chronic functional diarrhea and diarrheapredominant IBS are more often associated with small intestinal bacterial overgrowth (SIBO) than other types of IBS. 62 Tropical malabsorption is also associated with SIBO frequently. 57 Abnormal small intestinal permeability, which is a feature of malabsorption syndrome including tropical malabsorption, has been described in patients with diarrhea-predominant and PI-IBS. 63,64 Since IBS is a symptom-based diagnosis, a patient with mild malabsorption syndrome can be mis-diagnosed as IBS, particularly of diarrhea-predominant type, unless malabsorption is carefully excluded by appropriate investigations. In fact, after successful treatment of patients with tropical malabsorption, those who continued to have abnormal small intestinal permeability had more frequent stools than those in whom permeability normalized. 64 Without appropriate investigations, these patients may be diagnosed as IBS. In most studies on PI-IBS, post-infective malabsorption syndrome has not been carefully excluded using tests for mucosal malabsorption like D-xylose excretion or fecal fat estimation and duodenal biopsy. Hence, there may be some overlap between PI-IBS and post-infective malabsorption syndrome (PI-MAS). In future, this issue needs to be studied carefully. Pathophysiological mechanisms of PI-IBS Change in gut flora PI-IBS may result from protracted low-grade inflammation of the gut following an acute inflammatory reaction in response to an inciting pathogen. Acute diarrheal illness can also change the gut flora. 65 Altered gut flora is known to be associated with IBS. In a study on 27 patients with IBS and 22 controls, fecal microbiota was found to be different in two groups using real time polymerase chain reaction (PCR). 66 Moreover, diarrheal IBS had different microbiota compared to constipated IBS. 66 In another study, 67 patients with diarrheal IBS had more Proteobacteria and Firmicutes, but less Actinobacteria and Bacteroidetes compared to control. In another recent study, 68 symptom pattern was found to be related to type and quantities of certain microbes. Pimentel et al. fed rats with Campylobacter jejuni that colonized its gut as documented using real-time PCR. 69 Campylobacter jejuni altered Journal of Gastroenterology and Hepatology 26 (2011) Suppl. 3;

5 Post-infectious irritable bowel syndrome UC Ghoshal and P Ranjan the stool frequency, consistency and gut lymphocytosis consistent with findings in IBS patients. 69 This animal model of PI-IBS showed that colonizing gut with pathogenic microbes can cause PI-IBS like symptoms. 69 Volume and composition of gas is largely dependent on the type of gut flora. Excessive methane production can cause constipation due to slowing of gut motility. 70 Patients with IBS are less often methane producer than healthy subjects with consequent higher volume of gas in their gut, which may cause abdominal bloating. 71 Higher amount of breath hydrogen is excreted by patients with IBS both in fasting state and after ingestion of substrates for bacterial fermentation such as glucose. 62,72 Placing IBS patients on a carbohydrate-restricted diet reduces gas production and symptoms, suggesting a possible pathogenic role for bacterial fermentation. 76 Manipulation of gut flora using probiotics and antibiotics also relieve symptoms of IBS. 2 These data suggest that gut flora of patients with IBS is likely to be different than healthy subjects. 2 The mechanisms by which altered fecal flora induce disease are poorly understood. Altered colonic short chain fatty acids, which are important in maintenance of colonic epithelium and motility may cause disease. 77 Abnormalities in short chain fatty acids are known in patients with diarrhea-predominant IBS. 78 Altered small intestinal permeability, sensory-motor function, muscle hyper-contractility Small intestinal permeability is frequently abnormal in patients with PI-IBS. 63 In a study, patients with acute gastroenteritis due to Campylobacter infection underwent serial rectal biopsies and tests for intestinal permeability using lactulose/mannitol ratio. 12 asymptomatic controls were also studied. Number of enteroendocrine cells, CD3, CD4, and CD8 lymphocyte counts in lamina propria and intraepithelial lymphocytes and small intestinal permeability increased in patients with PI-IBS as compared with controls. 79 In another study 80 on 132 patients with PI-IBS and 86 controls enrolled in a community clinic, small intestinal permeability was more frequently abnormal in IBS than controls. Interestingly, IBS patients with increased intestinal permeability were more likely to report increased stool frequency. 80 PI-IBS may be related to continuing low-grade gut inflammation following an episode of infective diarrhea. 81 Persistently increased number of inflammatory cells in the rectal mucosa even 3 months after an acute infective diarrhea has been demonstrated. 81 In this study, 81 PI-IBS patients (n = 8) exhibited significantly greater expression of IL-1b mrna in rectal biopsies by reverse transcriptase-polymerase chain reaction during and 3 months after acute gastroenteritis than patients who had acute gastroenteritis but no IBS subsequently (n = 7) or the healthy subjects (n = 18). 81 On the other hand, IL-1ra mrna expressions were similar among the three groups. 81 Since gut inflammation is an important determinant of its sensorimotor functions and development of functional bowel disease, this study may suggest that immune system plays important role in development of IBS following acute gastroenteritis. 81 Digestive product of fat and fat itself reduces the motility of proximal small intestine. 82 Colonic flora of the infective gut produces short chain fatty acid, reflux of which into the ileum liberates peptide YY, neurotensin and glucagon-like peptide These are known to inhibit proximal gut motility. 82 Short chain fatty acid produced by gut flora influences serotonin, motilin and somatostatin containing enteroendocrine cells in the colon and ileum and these are the key mediators of gut motility. In this ways neuroendocrine factors play a very crucial role in sensory motor function. 83 In another study on experimental model, NIH Swiss mice were infected with Trichinella spiralis; the mice developed persistent gut hyper-contractility. 84 During acute infection, the expression of IL-4, IL-13, transforming growth factor (TGF)-b1, and cyclooxygenase (COX)-2 were found increased in intestinal smooth muscle. 84 Incubation of tissue with IL-4, IL-13, TGF-b1, or PGE2 increased carbachol-induced muscle contractility. 84 COX-2 inhibitor attenuated TGF-b1-induced hyper-contractility of the muscles. 84 Another study showed that infection of the intestinal mucosa released pro-inflammatory cytokines that led to their expression in neuromuscular layers. 81 In another study, expression of Th2 cytokines IL-4 and IL-13 in the muscularis externa induced the changes in neuromuscular function. 85 All these findings illustrate the role of inflammation induced by infection on gut motility, which is important in development of PI-IBS. Inflammatory cells release mediators (eg, histamine, proteases, and cytokines) and enterochromaffin cells release serotonin (5-HT). 86 These mediators affect the enteric nervous system and smooth muscle activity, which lead to intestinal motor dysfunction. 86 Interaction of these mediators with sensory afferents evokes increased sensory perception. 86 As a result, PI-IBS is linked to the persistence of mucosal abnormalities, enterochromaffin cell hyperplasia, and increased mucosal permeability including lowgrade intestinal inflammation. 86 Increased permeability allows antigens to easily enter through gut mucosa, which results in inflammatory cascade characterized by increase of various immune cells. 86 Genetic factors in PI-IBS The genes which show polymorphism in patients with PI-IBS are TLR9 (for innate immunity), IL6, and CDH1. Villani et al. 87 studied 79 functional variants of genes involved in serotoninergic pathways, intestinal epithelial barrier function, and innate immunity on members of Walkerton cohort developing PI-IBS (n = 228) and compared the data with residents with gastroenteritis who did not develop PI-IBS (n = 581). 87 They found that four variants were associated with PI-IBS, although the association was not significant after correction for the total number of single nucleotide polymorphisms. 87 Two were located in TLR9, which encodes a pattern recognition receptor (rs352139, P545P; P = and rs , -T1237C; P = ; r(2) < 0.14), one was in CDH1, which encodes a tight junction protein (rs16260, -C160A; P = ), and one was in IL6, which encodes a cytokine (rs , -G174C; P = ). Denser mapping of these three regions revealed one novel association in IL6 (rs ; P = ) and 14 associations that could be accounted for by linkage disequilibrium with the four original variants. 87 These genes play important roles in bacterial recognition, inflammatory response and epithelial integrity and provide considerable support for the hypothesis that links IBS onset to disturbances in the microbiota and the host response. 98 Journal of Gastroenterology and Hepatology 26 (2011) Suppl. 3;

6 UC Ghoshal and P Ranjan Post-infectious irritable bowel syndrome The future Development of IBS following acute gastroenteritis is uncontested. This is expected to open a paradigm shift in understanding the pathogenesis of a disease hitherto considered to be enigmatic. Future studies should also address the issue of possible overlap of post-infective malabsorption syndrome and PI-IBS. Exploring the possible molecular mechanisms involved in the pathogenesis of PI-IBS may help design therapeutic strategies to prevent and treat this disease. Manipulation of gut flora qualitatively using probiotics and quantitatively using antibiotics to treat IBS in general and infection-associated IBS in particular, is being understood more and more. Peptic ulcer disease, once thought to be a psychosomatic disease, is now considered to be due to Helicobacter pylori infection, which bagged Warren and Marshall the Nobel Prize in Medicine. Similarly, would understanding the pathogenesis of IBS and its treatment change with time targeting gut microbiota and its manipulation? We have to work for it and wait for the future to see this change! References 1 Gwee KA, Lu CL, Ghoshal UC. Epidemiology of irritable bowel syndrome in Asia: something old, something new, something borrowed. J. Gastroenterol. Hepatol. 2009; 24: Ghoshal UC, Park H, Gwee KA. Bugs and irritable bowel syndrome: the good, the bad and the ugly. J. Gastroenterol. Hepatol. 2010; 25: Collins S, Verdu E, Denou E, Bercik P. The role of pathogenic microbes and commensal bacteria in irritable bowel syndrome. Dig. Dis. 2009; 27 (Suppl. 1): Cuomo R, Savarese MF, Gargano R. Almost all irritable bowel syndromes are post-infectious and respond to probiotics: consensus issues. Dig. Dis. 2007; 25: Spiller RC. Infection, immune function, and functional gut disorders. Clin. Gastroenterol. Hepatol. 2004; 2: Spiller RC. 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