|Year : 2014 | Volume
| Issue : 1 | Page : 11-18
Role of gut pathogens in development of irritable bowel syndrome
Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
|Date of Submission||26-Mar-2013|
|Date of Web Publication||6-Mar-2014|
Assistant Professor, Division of Gastroenterology & Hepatology Mayo Clinic, 200 First Street SW, Rochester, MN 55905
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Acute infectious gastroenteritis is one of the most commonly identifiable risk factors for the development of irritable bowel syndrome (IBS). A number of bacterial, viral and parasitic pathogens have been found to be associated with the development of IBS and other functional gastrointestinal (GI) disorders. Epidemiological studies have identified demographic and acute enteritis-related risk factors for the development of post-infectious-IBS (PI-IBS). Immune dysregulation, alterations in barrier function, serotonergic and mast cell activation have been identified as potential pathophysiological mechanisms. Additionally, variations in host genes involved in barrier function, antigen presentation and cytokine response have been associated with PI-IBS development. However, it is unknown whether specific pathogens have unique effects on long-term alterations in gut physiology or different pathogens converge to cause common alterations resulting in similar phenotype. The role of microbial virulence and pathogenicity factors in development of PI-IBS is also largely unknown. Additionally, alterations in host gut sensation, motility, secretion, and barrier function in PI-IBS need to be elucidated. Finally, both GI infections and antibiotics used to treat these infections can cause long-term alterations in host commensal microbiota. It is plausible that alteration in the commensal microbiome persists in a subset of patients predisposing them to develop PI-IBS.
Keywords: Campylobacter jejuni - functional GI disorders - infectious gastroenteritis - irritable bowel syndrome - post-infectious irritable bowel syndrome
|How to cite this article:|
Grover M. Role of gut pathogens in development of irritable bowel syndrome
. Indian J Med Res 2014;139:11-8
| Introduction|| |
Gastrointestinal (GI) infections are globally prevalent and cause significant morbidity and mortality. Chronic GI disorders including celiac disease  , inflammatory bowel disease (IBD)  and irritable bowel syndrome (IBS)  have been causally associated with infectious gastroenteritis (IGE). Since the first description of post-infectious IBS (PI-IBS) provided by Chaudhary and Truelove in 1962 among patients with proven or presumptive episode of bacterial or amoebic dysentery  , numerous epidemiological studies have confirmed the association between acute IGE with different pathogens and development of IBS and other functional GI disorders (FGIDs)  . In addition to outbreaks in community or hospitalized settings, acute IGE sustained during a travel  or military recruitment  has also been associated with development of PI-IBS. Studies in different settings and with different pathogens have yielded a wide range (4-36%) of individuals developing PI-IBS after an episode of IGE  . Bacterial IGE seems to be more closely related to the development of long-term PI-IBS phenotype  as compared to viral IGE  . Long-term follow up studies suggest that bacterial pathogen related PI-IBS phenotype may persist for up to 8-10 years after the acute IGE is over , . Epidemiological studies have identified female gender, age <60 yr, smoking, enteritis severity, and pre-enteritis psychological stress as risk factors for development of PI-IBS  . Existing literature supports the role of enterochromaffin (EC) cell hyperplasia, altered barrier function, immune dysregulation and potentially mast cell activation in the pathophysiology of PI-IBS. However, a number of prior studies have been conducted after epidemics often involving >1 pathogen or in highly selected tertiary referral patients. Thus, there is limited insight into unique pathogen-specific mechanisms from isolated, community-based gastroenteritis cases, and into physiological and clinical sequelae based on the pathogen and host characteristics.
| Epidemiology|| |
Gastrointestinal infections with isolated (bacterial, viral), mixed (> 1 bacteria, bacteria and a virus), and unspecified (travelers' diarrhoea) pathogens have all been associated with the development of PI-IBS. Most of the larger cohorts are from outbreaks involving bacterial pathogens  . However, in several studies involving outbreaks, the information on the pathogen involved is often not available in all subjects and is only assumed. Although, these studies have shown a wide range (4-36%) of individuals developing PI-IBS, a meta-analysis revealed median prevalence of 10 per cent (compared to 1.2% in controls)  . This also showed a relative risk ranging between 2-12 and a pooled odds ratio of 7.3 for development of PI-IBS. The [Table 1] provides a comprehensive list of PI-IBS epidemiological studies according to the pathogen involved. An outbreak in Walkerton, Canada in 2000 caused by contamination of municipal water supply from livestock faecal material resulted in acute gastrointestinal illness in over half of the town's 4800 residents has provided significant epidemiological information about PI-IBS  . Although, pathogen information was not available in all cases, mixed bacterial infection with Campylobacter jejuni and Escherichia coli O157:H7 was found be responsible for most of the cases. Two years post-infection, a PI-IBS rate of 36 per cent among patients that had IGE during the outbreak was seen 
|Table 1: Percentage of individuals developing post-infections - irritable bowel syndrome (PI-IBS) with different enteritides|
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| Risk factors|| |
Age and gender
Age >60 yr was found to be protective for development of PI-IBS in a large community survey (relative risk: 0.36)  . Younger age was found to be an independent risk factor for PI-IBS development in the Walkerton outbreak cohort  . However, other studies did not confirm an effect of age on PI-IBS development , . Studies have debated the effect of gender on PI-IBS development when the effect was either not found  or was lost once psychological variables were controlled for , . However, in other larger studies  including the Walkerton outbreak cohort  , female gender was identified as a risk factor. This goes along with the increased prevalence of IBS and other FGIDs in women.
Smoking : A single study showed smoking to be associated with PI-IBS development (odds ratio: 4.8)  . However, smoking can be a marker for psychological distress, hence associating with PI-IBS, which makes it harder to draw any conclusions based on the limited evidence.
Antibiotic use : Prevalence of PI-IBS following Salmonella enteritidis enteritis was not found be different among groups that did or did not use antibiotics (17.6 vs 9.3%, not significant) in one study  . However, another post-Salmonella study showed an increase in the prevalence of persistent GI symptoms in a group that received antibiotics (9.5 vs 2.9%)  . A travelers' diarrhoea study showed antibiotic use to be associated with development of PI-IBS (relative risk: 4.1)  . It is quite plausible that antibiotic induced changes in commensal microflora can persist in vulnerable subset of hosts predisposing them to long-term changes in gut physiology resulting in development of PI-IBS.
Psychological factors: There was an increased prevalence of anxiety, depression, somatization, and neurotic traits at the time of IGE in the group that developed PI-IBS  . Patients who develop IBS report more adverse life events in preceding three months and hypochondriasis scores  and these features predicted PI-IBS development independent of the anxiety and neuroticism scores. A study also showed depression to be a risk factor (relative risk: 3.2)  . Another study showed higher levels of perceived stress, anxiety, somatization, negative illness beliefs at the time of acute enteritis to be associated with PI-IBS. Depression was not found to be a risk factor in this study  . The influence of psychological stress on PI-IBS is interesting and under-studied. Catecholamines and other stress mediators have been shown to play a role in modulating pathogenic infectivity and host epithelial-microbial interactions  which can play a role in increasing severity of enteritis and subsequent development of post-infectious phenotype.
Enteritis severity: Shigella enteritis lasting >14 days was more significantly associated with PI-IBS development as compared to illness lasting <8 days (relative risk: 4.6)  . Similarly, another mixed bacterial enteritis study showed greater likelihood of PI-IBS development with illness lasting >3 weeks vs <8 days (relative risk: 11.4)  . Diarrhoea >7 days was associated with PI-IBS development in the Walkerton outbreak cohort  . Additionally, presence of bloody stools, abdominal cramps, and > 10lb weight loss was also found to be associated with PI-IBS in this cohort. A single study examining the role of bacterial pathogenicity factors showed Campylobacater jejuni strain producing toxin with elongating effects on the Chinese hamster ovary cells was associated with increased risk of developing persistently deranged bowel habits  . Overall, this suggests that enteritis severity appears to play a role in the development of PI-IBS. However, clinical severity of enteritis might be related to microbial virulence or variations in host response. More needs to be done to elucidate role of microbial virulence factors in development of PI-IBS.
| Clinical features|| |
In the absence of a biomarker or a universally accepted definition for PI-IBS, the Rome criteria  for defining IBS are usually used to define PI-IBS. This requires presence of recurrent abdominal pain or discomfort at least three days/month in the last three months associated with two or more of the following: (i) improvement with defaecation, (ii) onset associated with a change in frequency of stool, and (iii) onset associated with a change in form (appearance) of stool. These historical characteristics must be fulfilled for the last three months with symptom onset at least six months prior to diagnosis. To characterize as PI-IBS, the individual must not meet criterion for IBS prior to the infection and the acute IGE must be characterized either by presence of positive stool cultures or presence of ≥2 of the following: fever, vomiting, or diarrhoea. The stool cultures are often not available since a number of individuals develop acute IGE as travelers' diarrhoea. The PI-IBS phenotype is most commonly IBS-D  and IBS subtype phenotypic clusters have been found to remain stable over time  . Previous treatment for anxiety or depression was reported less frequently in PI-IBS than non-PI-IBS (26 vs 54%).
| Natural history|| |
The Walkerton outbreak cohort investigators reported the 8 year follow up data and the prevalence of IBS dropped to 15.4 per cent after 8 years, still remaining significantly increased compared with controls without history of acute IGE (OR 3.12; 95% CI 1.99 to 5.04)  . This suggests that PI-IBS phenotype persists for a prolonged duration. Another study showed that symptoms persist for upto 10 years following the initial infection  . A recent analysis of the defense database showed an increased risk of dyspepsia, constipation, and gastroesophageal reflux disease among military recruits who had suffered from IGE from norovirus  . In another food-borne outbreak study of norovirus, 23.6 per cent reported symptoms consistent with PI-IBS at three months vs 3.4 per cent who remained well (odds ratio: 6.9). However, at 6, 12, and 24 months, the prevalence of IBS was similar among exposed versus non-exposed individuals  . Vomiting during the IGE episode independently predicted risk of PI-IBS at three months  . From a recent viral outbreak in Italy, 13 per cent of IGE patients were found to have PI-IBS at 12 months, and most of these were mixed-IBS (IBS-M). This study also showed that the presence and severity of symptoms progressively diminished at 12 month follow up as compared to the 6 month survey  . Both these studies suggest that post-viral IBS may be a more transient phenomenon as compared to bacterial PI-IBS. This might be related to a lesser degree of initial epithelial damage and host inflammatory response caused by viral as compared to bacterial pathogens.
| Mechanisms|| |
Mucosal cellular changes: Post-Campylobacter IBS is characterized by an increase in rectal mucosal enterochromaffin (EC) cells, lamina propria T-lymphocytes , , CD8 intraepithelial lymphocytes and calprotectin-immunoreactive (ir) cells  . Post-Shigella IBS is characterized by increase in ileal mast cells and nerve fibers immunoreactive for neuron-specific enolase, substance P, and 5-hydroxytryptamine (5-HT, serotonin) seen adjacent to the mast cells  . Another study showed an increase in 5-HT-ir EC cells, peptide YY (PYY)-ir EC cells, intraepithelial lymphocytes, CD3, CD8 lymphocytes, mast cells and CD68 cells  . Colonic mucosal supernatants from PI-IBS patients resulting from unspecified IGE caused stimulation of peritoneal mast cell protease-activated receptor (PAR 2 ) mRNA expression  . Another study looking at mucosal tissue, however, showed decrease in mast cell PAR 4 expression but unchanged PAR 2 expression  . Mast cell numbers were unchanged but activated mast cells and tryptase concentration were increased in supernatants from PI-IBS patients (unspecified IGE). Similar to post-Campylobacter IBS, increased mean chronic inflammatory cells 
EC cells, lamina propria T lymphocytes without any changes in mast cell numbers were seen  . Overall, EC cell hyperplasia and activation seem to play a significant role in pathophysiology of PI-IBS, however, the role of mast cells is unclear at this time.
Alterations in gut permeability:
An increase in 0-6 h lactulose/mannitol (L/M) ratio initially and at 12 wk has been observed after acute IGE with C. jejuni; however, it is unclear if these patients met criteria for IBS  . Another study showed increase in 3-6 h Cr  EDTA excretion initially after Campylobacter gastroenteritis and at 6 months, however, this cohort is also not confirmed to have IBS phenotype  . Increased L/M excretion after overnight collection has also been reported in PI-IBS patients from the Walkerton outbreak cohort  . Using  Cr-EDTA excretion, proximal small bowel permeability was found to be altered in PI-IBS (unspecified pathogen); however, in this study non-PI-IBS patients had greater alterations in small bowel permeability as compared to PI-IBS patients  . In vivo permeability alterations or ex vivo changes in mucosal barrier function are unknown in PI-IBS resulting from other bacterial or viral pathogens.
Cytokine expression: No differences were seen in mucosal interleukin (IL)-10, tumour necrosis factor (TNF)α and IL-1β expression in post-Campylobacter IBS . Peripheral blood mononuclear cell TNFα cytokine expression has been found to be increased in post-Campylobacter IBS, however, no differences were seen in IL-10, or IL-1β expression. This study also showed increased TNFα rs1800629 . Another post-Campylobacter 0study did not show any differences in IL-18 and interferon (INF)γ polymorphisms. Increased terminal ileal and rectosigmoid IL-1β expression in post-Shigella IBS  and rectal IL-1β expression in post-mixed infection IBS have been seen. Patients with PI-IBS following mixed infection showed an increase in peripheral blood mononuclear cell TNF-α, IL-1β, IL-6, and lipopolysaccharide-stimulated IL-6 levels .
Gene expression: The Walkerton outbreak cohort showed variations in three genes to be independently associated with PI-IBS. These are cytokine gene IL6 [rs206986; OR 1.509 (1.031-2.209)], tight junction E-cadherin gene CDH1 [rs16260; OR 1.398 (1.069-1.829) and TLR9 [rs 5743836; OR 1.536 (1.080-2.182)] encoding for pattern recognition receptor for bacteria that detects unmethylated CpG dinucleotide  . Together, this reflects a role of host immune activation and barrier function genetics in the development of IBS in that cohort. In another study  , mucosal expression of CCL11 [chemokine (C-C) motif ligand l], CCL13, Calpain 8 and TNFSF15 (TNF superfamily member 15) increased while NR1D1, G-protein coupled receptor 161 (GPR161) and gamma-aminobutyric acid receptor subunit epsilon (GABRE) decreased post-C. jejuni group (not PI-IBS). TNFα rs1800629 minor allele frequency was increased in post-C. jejuni group compared to healthy controls  . Polymorphisms in IL-18 and INF γ were studied in a C. jejuni/coli gastroenteritis cohort but none were found to be linked with the development of PI-IBS at 6-month follow up  .
| Treatment|| |
The first step in the management should be to illicit the history of IGE preceding the onset of symptoms. This finding can often be a subtle on history and patients may just endorse acute onset of symptoms during or after a travel without recall of classical symptoms of acute IGE. A stool culture is unlikely to be available in most cases. Although PI-IBS is characterized by acute onset of symptoms after a GI infection, many patients provide a history of respiratory illness preceding the onset of IBS. Although, this cannot be typically characterized as PI-IBS, it can be considered to be in the same spectrum of FGIDs. Once PI-IBS is clinically suspected, it is often helpful to educate the patient about the role of gut infections in development of IBS symptoms and a suspected causal link can be helpful in "legitimizing" the disorder. It is also helpful to reassure since the PI-IBS is likely to improve over time than deteriorate, especially if a viral pathogen is suspected to be involved.
Subsequently, the overall clinical management is driven by nature and severity of the symptoms and is not different from management of IBS, details of which can be found elsewhere  . A few clinical trials specific to PI-IBS have been performed. In a randomized, double-blind, placebo controlled trial of prednisolone at a dose of 30 mg/day for three weeks, lamina propria T-lymphocytes decreased but no differences were seen in EC cell counts or clinical endpoints of abdominal pain or diarrhoea  . An open-labelled trial of 18 patients using mesalamine 800 mg three times a day for 30 days showed improvement in scores for abdominal pain, distension, stool frequency and consistency  . This study also showed similar improvements in 43 non-PI-IBS patients treated with same dose and duration of mesalamine. Another double-blind, placebo controlled study using mesalamine (Asacol®) 1.6 g twice a day in 20 patients with PI-IBS showed improvement in global symptoms, abdominal pain, bloating, stool urgency, frequency, or consistency and quality of life  .
| Conclusion|| |
Gastrointestinal infections with pathogenic microbes constitute an important risk factor for development of IBS and other FGIDs. In spite of a significant knowledge of epidemiological risk factors, little is known about pathophysiological mechanisms of PI-IBS. Existing literature supports the role of immune dysregulation, altered barrier function, EC cell activation and host genetics. Much needs to be done to identify novel mechanisms such as the role of microbial pathogenicity factors, alterations in host commensal microbiota, and post-infectious plasticity in the neuromuscular apparatus of the gut. From the stand-point of the host, alterations in gut physiology using deep phenotyping measures in studies of GI transit, sensation and permeability and central nervous system changes using functional brain imaging will be necessary to find subsets of PI-IBS patients with unique physiological alterations. Overall, this subset of IBS provides an opportunity to prospectively recruit patients and study mechanism for PI-IBS and IBS in general. Additionally, studies involving isolated, identifiable pathogens will likely provide more relevant mechanistic information.
| References|| |
|1.||Riddle MS, Murray JA, Porter CK. The incidence and risk of celiac disease in a healthy US adult population. Am J Gastroenterol 2012; 107 : 1248-55. |
|2.||Porter CK, Tribble DR, Aliaga PA, Halvorson HA, Riddle MS. Infectious gastroenteritis and risk of developing inflammatory bowel disease. Gastroenterology 2008; 135 : 781-6. |
|3.||Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroenterology 2009; 136 : 1979-88. |
|4.||Chaudhary NA, Truelove SC. The irritable colon syndrome. A study of the clinical features, predisposing causes, and prognosis in 130 cases. Q J Med 1962; 31 : 307-22. |
|5.||Ilnyckyj A, Balachandra B, Elliott L, Choudhri S, Duerksen DR. Post-traveler's diarrhea irritable bowel syndrome: a prospective study. Am J Gastroenterol 2003; 98 : 596-9. |
|6.||Porter CK, Gloor K, Cash BD, Riddle MS. Risk of functional gastrointestinal disorders in U.S. military following self-reported diarrhea and vomiting during deployment. Dig Dis Sci 2011; 56 : 3262-9. |
|7.||Riddle MS, Gutierrez RL, Verdu EF, Porter CK. The chronic gastrointestinal consequences associated with Campylobacter. Curr Gastroenterol Rep 2012; 14 : 395-405. |
|8.||Marshall JK, Thabane M, Borgaonkar MR, James C. Postinfectious irritable bowel syndrome after a food-borne outbreak of acute gastroenteritis attributed to a viral pathogen. Clin Gastroenterol Hepatol 2007; 5 : 457-60. |
|9.||Marshall JK, Thabane M, Garg AX, Clark WF, Moayyedi P, Collins SM; Walkerton Health Study Investigators. Eight year prognosis of postinfectious irritable bowel syndrome following waterborne bacterial dysentery. Gut 2010; 59 : 605-11. |
|10.||Schwille-Kiuntke J, Enck P, Zendler C, Krieg M, Polster AV, Klosterhalfen S, et al. Postinfectious irritable bowel syndrome: follow-up of a patient cohort of confirmed cases of bacterial infection with Salmonella or Campylobacter. Neurogastroenterol Motil 2011; 23 : e479-88. |
|11.||Thabane M, Simunovic M, Akhtar-Danesh N, Marshall JK. Development and validation of a risk score for post-infectious irritable bowel syndrome. Am J Gastroenterol 2009; 104 : 2267-74. |
|12.||Marshall JK, Thabane M, Garg AX, Clark WF, Salvadori M, Collins SM; Walkerton Health Study Investigators. Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology 2006; 131 : 445-50. |
|13.||Halvorson HA, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome - a meta-analysis. Am J Gastroenterol 2006; 101 : 1894-9. |
|14.||Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: postal survey of patients. BMJ 1997; 314 : 779-82. |
|15.||Moss-Morris R, Spence M. To "lump" or to "split" the functional somatic syndromes: can infectious and emotional risk factors differentiate between the onset of chronic fatigue syndrome and irritable bowel syndrome? Psychosom Med 2006; 68 : 463-9. |
|16.||Mearin F, Perez-Oliveras M, Perello A, Vinyet J, Ibanez A, Coderch J, et al. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterol 2005; 129 : 98-104. |
|17.||Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterol 2003; 125 : 1651-9. |
|18.||Stermer E, Lubezky A, Potasman I, Paster E, Lavy A. Is traveler's diarrhea a significant risk factor for the development of irritable bowel syndrome? A prospective study. Clin Infect Dis 2006; 43 : 898-901. |
|19.||Gwee KA, Graham JC, McKendrick MW, Collins SM, Marshall JS, Walters SJ, et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet 1996; 347 : 150-3. |
|20.||Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut 2004; 53 : 1096-101. |
|21.||Thornley JP, Jenkins D, Neal K, Wright T, Brough J, Spiller RC. Relationship of Campylobacter toxigenicity in vitro to the development of postinfectious irritable bowel syndrome. J Infect Dis 2001; 184 : 606-9. |
|22.||Zanini B, Ricci C, Bandera F, Caselani F, Magni A, Laronga AM, et al; San Felice del Benaco Study Investigators. Incidence of post-infectious irritable bowel syndrome and functional intestinal disorders following a water-borne viral gastroenteritis outbreak. Am J Gastroenterol 2012; 107 : 891-9. |
|23.||Ji S, Park H, Lee D, Song YK, Choi JP, Lee SI. Post-infectious irritable bowel syndrome in patients with Shigella infection. J Gastroenterol Hepatol 2005; 20 : 381-6. |
|24.||McKendrick MW, Read NW. Irritable bowel syndrome - post salmonella infection. J Infect 1994; 29 : 1-3. |
|25.||Sethi S, Garey KW, Arora V, Ghantoji S, Rowan P, Smolensky M, et al. Increased rate of irritable bowel syndrome and functional gastrointestinal disorders after Clostridium difficile infection. J Hosp Infect 2011; 77 : 172-3. |
|26.||Piche T, Vanbiervliet G, Pipau FG, Dainese R, Hebuterne X, Rampal P, et al. Low risk of irritable bowel syndrome after Clostridium difficile infection. Can J Gastroenterol 2007; 21 : 727-31. |
|27.||Neal KR, Barker L, Spiller RC. Prognosis in post-infective irritable bowel syndrome: a six year follow up study. Gut 2002; 51 : 410-3. |
|28.||Saps M, Pensabene L, Di Martino L, Staiano A, Wechsler J, Zheng X, et al. Post-infectious functional gastrointestinal disorders in children. J Pediatr 2008; 152 : 812-6. |
|29.||Rodriguez LA, Ruigomez A. Increased risk of irritable bowel syndrome after bacterial gastroenteritis: cohort study. BMJ 1999; 318 : 565-6. |
|30.||Dizdar V, Gilja OH, Hausken T. Increased visceral sensitivity in Giardia-induced postinfectious irritable bowel syndrome and functional dyspepsia. Effect of the 5HT3-antagonist ondansetron. Neurogastroenterol Motil 2007; 19 : 977-82. |
|31.||Soyturk M, Akpinar H, Gurler O, Pozio E, Sari I, Akar S, et al. Irritable bowel syndrome in persons who acquired trichinellosis. Am J Gastroenterol 2007; 102 : 1064-9. |
|32.||Okhuysen PC, Jiang ZD, Carlin L, Forbes C, DuPont HL. Post-diarrhea chronic intestinal symptoms and irritable bowel syndrome in North American travelers to Mexico. Am J Gastroenterol 2004; 99 : 1774-8. |
|33.||Borgaonkar MR, Ford DC, Marshall JK, Churchill E, Collins SM. The incidence of irritable bowel syndrome among community subjects with previous acute enteric infection. Dig Dis Sci 2006; 51 : 1026-32. |
|34.||Porter CK, Gormley R, Tribble DR, Cash BD, Riddle MS. The incidence and gastrointestinal infectious risk of functional gastrointestinal disorders in a healthy US adult population. Am J Gastroenterol 2011; 106 : 130-8. |
|35.||Tuteja AK, Talley NJ, Gelman SS, Alder SC, Thompson C, Tolman K, et al. Development of functional diarrhea, constipation, irritable bowel syndrome, and dyspepsia during and after traveling outside the USA. Dig Dis Sci 2008; 53 : 271-6. |
|36.||Cumberland P, Sethi D, Roderick PJ, Wheeler JG, Cowden JM, Roberts JA, et al. The infectious intestinal disease study of England: a prospective evaluation of symptoms and health care use after an acute episode. Epidemiol Infect 2003; 130 : 453-60. |
|37.||Parry SD, Stansfield R, Jelley D, Gregory W, Phillips E, Barton JR, et al. Does bacterial gastroenteritis predispose people to functional gastrointestinal disorders? A prospective, community-based, case-control study. Am J Gastroenterol 2003; 98 : 1970-5. |
|38.||Gwee KA, Leong YL, Graham C, McKendrick MW, Collins SM, Walters SJ, et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut 1999; 44 : 400-6. |
|39.||Parry SD, Barton JR, Welfare MR. Factors associated with the development of post-infectious functional gastrointestinal diseases: does smoking play a role? Eur J Gastroenterol Hepatol 2005; 17 : 1071-5. |
|40.||Barbara G, Stanghellini V, Berti-Ceroni C, De Giorgio R, Salvioli B, Corradi F, et al. Role of antibiotic therapy on long-term germ excretion in faeces and digestive symptoms after Salmonella infection. Aliment Pharmacol Ther 2000; 14 : 1127-31. |
|41.||Spence MJ, Moss-Morris R. The cognitive behavioural model of irritable bowel syndrome: a prospective investigation of patients with gastroenteritis. Gut 2007; 56 : 1066-71. |
|42.||Lyte M, Vulchanova L, Brown DR. Stress at the intestinal surface: catecholamines and mucosa-bacteria interactions. Cell Tissue Res 2011; 343 : 23-32. |
|43.||Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterol 2006; 130 : 1480-91. |
|44.||Dunlop SP, Jenkins D, Spiller RC. Distinctive clinical, psychological, and histological features of postinfective irritable bowel syndrome. Am J Gastroenterol 2003; 98 : 1578-83. |
|45.||Thabane M, Simunovic M, Akhtar-Danesh N, Garg AX, Clark WF, Marshall JK. Clustering and stability of functional lower gastrointestinal symptom after enteric infection. Neurogastroenterol Motil 2012; 24 : 546-52. |
|46.||Porter CK, Faix DJ, Shiau D, Espiritu J, Espinosa BJ, Riddle MS. Postinfectious gastrointestinal disorders following norovirus outbreaks. Clin Infect Dis 2012; 55 : 915-22. |
|47.||Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, et al. 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 : 804-11. |
|48.||Kim HS, Lim JH, Park H, Lee SI. Increased immunoendocrine cells in intestinal mucosa of postinfectious irritable bowel syndrome patients 3 years after acute Shigella infection - an observation in a small case control study. Yonsei Med J 2010; 51 : 45-51. |
|49.||Han W, Lu X, Jia X, Zhou T, Guo C. Soluble mediators released from PI-IBS patients' colon induced alteration of mast cell: involvement of reactive oxygen species. Dig Dis Sci 2012; 57 : 311-9. |
|50.||Han W, Wang Z, Lu X, Guo C. Protease activated receptor 4 status of mast cells in post infectious irritable bowel syndrome. Neurogastroenterol Motil 2012; 24 : 113-9, e82. |
|51.||Swan C, Duroudier NP, Campbell E, Zaitoun A, Hastings M, Dukes GE, et al. Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFalpha. Gut 2013; 62 : 985-94. |
|52.||Marshall JK, Thabane M, Garg AX, Clark W, Meddings J, Collins SM; WEL Investigators. Intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, Ontario. Aliment Pharmacol Ther 2004; 20 : 1317-22. |
|53.||Dunlop SP, Hebden J, Campbell E, Naesdal J, Olbe L, Perkins AC, et al. Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes. Am J Gastroenterol 2006; 101 : 1288-94. |
|54.||Nielsen H, Steffensen R, Ejlertsen T. Risk and prognosis of campylobacteriosis in relation to polymorphisms of host inflammatory cytokine genes. Scand J Immunol 2012; 75 : 449-54. |
|55.||Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut 2003; 52 : 523-6. |
|56.||Liebregts T, Adam B, Bredack C, Roth A, Heinzel S, Lester S, et al. Immune activation in patients with irritable bowel syndrome. Gastroenterology 2007; 132 : 913-20. |
|57.||Villani AC, Lemire M, Thabane M, Belisle A, Geneau G, Garg AX, et al. Genetic risk factors for post-infectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis. Gastroenterology 2010; 138 : 1502-13. |
|58.||Brandt LJ, Chey WD, Foxx-Orenstein AE, Schiller LR, Schoenfeld PS, Spiegel BM, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104 (Suppl 1): S1-35. |
|59.||Dunlop SP, Jenkins D, Neal KR, Naesdal J, Borgaonker M, Collins SM, et al. Randomized, double-blind, placebo-controlled trial of prednisolone in post-infectious irritable bowel syndrome. Aliment Pharmacol Ther 2003; 18 : 77-84. |
|60.||Bafutto M, Almeida JR, Leite NV, Oliveira EC, Gabriel-Neto S, Rezende-Filho J. Treatment of postinfectious irritable bowel syndrome and noninfective irritable bowel syndrome with mesalazine. Arq Gastroenterol 2011; 48 : 36-40. |
|61.||Tuteja AK, Fang JC, Al-Suqi M, Stoddard GJ, Hale DC. Double-blind placebo-controlled study of mesalamine in post-infective irritable bowel syndrome - a pilot study. Scand J Gastroenterol 2012; 47 : 1159-64. |