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Postinfectious irritable bowel syndrome1

  • Robin C. Spiller
    Correspondence
    Address requests for reprints to: Professor Robin C. Spiller, Division of Gastroenterology, University Hospital, Nottingham, NG7 2UH United Kingdom fax: (44) 0115 9422232
    Affiliations
    Division of Gastroenterology, University Hospital, Nottingham, United Kingdom
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      Abstract

      A small but significant subgroup of patients with irritable bowel syndrome (IBS) report a sudden onset of their IBS symptoms after a bout of gastroenteritis. Population-based surveys show that although a history of neurotic and psychologic disorders, pain-related diseases, and gastroenteritis are all risk factors for developing IBS, gastroenteritis is the most potent. More toxigenic organisms increase the risk 11-fold, as does an initial illness lasting more than 3 weeks. Hypochondriasis and adverse life events double the risk for postinfective (PI)-IBS and may account for the increased proportion of women who develop this syndrome. PI-IBS is associated with modest increases in mucosal T lymphocytes and serotonin-containing enteroendocrine cells. Animal models and some preliminary human data suggest this leads to excessive serotonin release from the mucosa. Both the histologic changes and symptoms in humans may last for many years with only 40% recovering over a 6-year follow-up. Celiac disease, microscopic colitis, lactose intolerance, early stage Crohn’s disease, and bile salt malabsorption should be excluded, as should colon cancer in those over the age of 45 years or in those with a positive family history. Treatment with Loperamide, low-fiber diets, and bile salt- binding therapy may help some patients. Serotonin antagonists are logical treatments but have yet to be evaluated.
      Most busy gastroenterology practices will find that irritable bowel syndrome (IBS) is the final diagnosis in many of their patients. The varied nature of symptoms, with or without psychologic disturbances, has hampered progress in understanding mechanisms. However, within this heterogeneous group there is a small, relatively homogenous subgroup who describe an acute onset of symptoms on the background of a previously entirely normal bowel habit. A recent survey of IBS patients attending either hospital specialists in the United States or general practice in the United Kingdom, suggested that 6% and 17%, respectively, of patients attribute their IBS to an attack of gastroenteritis.
      • Longstreth G.F.
      • Hawkey C.J.
      • Ham J.
      • Jones R.H.
      • Mayer E.A.
      • Naesdal J.
      • Wilson I.K.
      • Peacock R.A.
      • Wiklund K.
      Demographic and clinical characteristics of patients with irritable bowel syndrome (IBS) from three practice settings.
      Anecdotally, in my own referral practice, in which I specifically inquire about mode of onset, I have found 37 postinfective (PI)-IBS out of the last 106 diarrhea-predominant IBS patients.
      • Boulton-Jones R.
      • Spiller R.C.
      Significance of anxiety in IBS outpatients relation to bowel symptoms and final diagnosis.
      This is based on a definition of PI-IBS as an acute onset of Rome II criteria IBS symptoms
      • Thompson W.G.
      • Longstreth G.F.
      • Drossman D.A.
      • Heaton K.W.
      • Irvine E.J.
      • Muller-Lissner S.A.
      Functional bowel disorders and functional abdominal pain.
      with 2 or more of the following: fever, vomiting, diarrhea, and positive stool culture.
      • Dunlop S.P.
      • Jenkins D.
      • Spiller R.C.
      Distinctive histological patterns of chronic inflammatory cells in rectal biopsies of patients with different clinical subtypes of IBS.
      Because the time of onset is well defined and infection is largely a random event, PI-IBS provides a unique natural experiment enabling us to define risk factors for PI-IBS and hopefully insights into IBS in general.

      1. Epidemiology

      One of the earliest reports of PI-IBS relates to unexplained diarrhea and abdominal discomfort seen in British troops returning from the World War II North Africa campaign after amebic dysentery.
      • Stewart G.T.
      Post-dysenteric colitis.
      The term postdysenteric irritable bowel syndrome was first used by Chaudhary and Truelove,
      • Chaudhary N.A.
      • Truelove S.C.
      The irritable colon syndrome.
      who described 130 cases of “irritable colon syndrome,” 34 of whom dated the onset of their symptoms to an attack of either bacillary or amebic dysentery. This retrospective survey suggested that such patients had a reduced incidence of psychologic disturbances and a better prognosis than those without an infectious onset. Surprisingly, there has been a gap of more than 3 decades before this was confirmed by properly designed, prospective studies. The first was an outbreak of Salmonellosis in which 31% of patients developed new IBS symptoms, which were still present 1 year after infection.
      • McKendrick M.W.
      • Read N.W.
      Irritable bowel syndrome—post Salmonella infection.
      A second study from Sheffield
      • Gwee K.A.
      • Graham J.C.
      • McKendrick M.W.
      • Collins S.M.
      • Marshall J.S.
      • Walters S.J.
      • et al.
      Psychometric scores and persistence of irritable bowel after infectious diarrhoea.
      examined 75 individuals admitted to an infectious disease unit with gastroenteritis, 25% of whom developed new IBS when assessed 6 months after infection, an outcome confirmed by a further, more detailed study of mechanisms 3 years later.
      • Gwee K.A.
      • Leong Y.L.
      • Graham C.
      • McKendrick M.W.
      • Collins S.M.
      • Walters S.J.
      • et al.
      The role of psychological and biological factors in postinfective gut dysfunction.
      A community-based study in Nottingham of 357 individuals with culture-positive bacterial gastroenteritis found only 7% met the Rome I criteria for IBS at 6 months, although 25% reported a persistent change in bowel habit. The lower incidence of IBS compared with the Sheffield experience may reflect the milder nature of the initial illness because only 1 in 10 were hospitalized.
      • Neal K.R.
      • 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.
      A further community survey in Nottingham, restricted to just Campylobacter gastroenteritis, confirmed this percentage with 9% in a new cohort of 189 infected individuals.
      • Thornley J.P.
      • Jenkins D.
      • Neal K.
      • Wright T.
      • Brough J.
      • Spiller R.C.
      Relationship of campylobacter toxigenicity in vitro to the development of postinfectious irritable bowel syndrome.
      More recently, there has been a case-control study from Newcastle using Rome II criteria for IBS, indicating an incidence of new PI-IBS over 6 months of 17% compared with just 1.9% of controls, odds ratio 10 (3–31).
      • Parry S.D.
      • Barton J.R.
      • Welfare M.R.
      Does infectious diarrhoea (ID) predispose people to functional gastro-intestinal disorders (FGIDs)? A prospective community case-control study.
      With the exception of the study by Parry et al.,
      • Parry S.D.
      • Barton J.R.
      • Welfare M.R.
      Does infectious diarrhoea (ID) predispose people to functional gastro-intestinal disorders (FGIDs)? A prospective community case-control study.
      the previous studies lacked a control group to define the normal incidence of new IBS in the absence of infection. This was corrected in a large study of 584,308 patients whose records form part of a large general practice research database in the United Kingdom. This database records all interviews with the general practitioner, all prescriptions, and all laboratory results. They found 318 patients with documented bacterial enteritis (54% Campylobacter, 37% Salmonella), 12 of whom had new diagnosis of IBS over the next 12 months, an incidence of 40 (22–70) (mean [95% confidence intervals])/1000 patient years giving a relative risk of 11.9 (6.7–21.0) when compared with uninfected controls with an incidence of just 3.5 (3.4–37)/1000 patient years.
      • Rodriguez L.A.
      • Ruigomez A.
      Increased risk of irritable bowel syndrome after bacterial gastroenteritis cohort study.
      The weakness with this study was that stool cultures are only obtained in around 1 in 10 of all cases of gastroenteritis in the United Kingdom,
      • Wheeler J.G.
      • Sethi D.
      • Cowden J.M.
      • Wall P.G.
      • Rodrigues L.C.
      • Tompkins D.S.
      • et al.
      Study of infectious intestinal disease in England rates in the community, presenting to general practice, and reported to national surveillance. The Infectious Intestinal Disease Study Executive.
      so the general practice research database data will considerably underestimate the frequency of infection and hence the proportion of IBS that is postinfective. A further study using the general practice research database found a medical history of neurotic and psychologic disorders, pain-related diseases, and gastroenteritis all were associated with the occurrence of IBS, the strongest association being with gastroenteritis.
      • Huerta C.
      • Garcia Rodriguez L.A.
      • Wallander M.A.
      • Johansson S.
      Risk of irritable bowel syndrome among asthma patients.
      Gastrointestinal infections are much more common in tropical areas, so one might suspect that PI-IBS might be more common in such regions. However, infection at an early age induces a partial immunity and alters the illness. Thus, Campylobacter in children in the tropics is often a milder illness than that observed in adults in the Western world and may even be asymptomatic.
      • Georges-Courbot M.C.
      • Cassel-Beraud A.M.
      • Gouandjika I.
      • Monges J.
      • Georges A.J.
      A cohort study of enteric campylobacter infection in children from birth to two years in Bangui (Central African Republic).
      Thus, the impact of childhood infection on the risk for developing PI-IBS is uncertain because severity of initial illness, which is an important risk factor, may be less than in adulthood. There are few studies from the tropics that indicate the main subtypes of IBS, but a study from Southern India described 69% having loose motions greater than 5 times/day whereas only 7% described constipation.
      • Kapoor K.K.
      • Nigam P.
      • Rastogi C.K.
      • Kumar A.
      • Gupta A.K.
      Clinical profile of irritable bowel syndrome.
      A recent Chinese study also indicated diarrhea-predominant IBS predominates, affecting 65% of IBS patients vs. just 27% with constipation-predominant IBS.
      • Wei X.
      • Chen M.
      • Wang J.
      The epidemiology of irritable bowel syndrome and functional constipation of Guangzhou residents.
      Furthermore, a recent case-control study from China indicated that a history of dysentery was the strongest risk factor for IBS with a relative risk of 3.0 ± 0.6.
      • Pan G.
      • Lu S.
      • Ke M.
      • Han S.
      • Guo H.
      • Fang X.
      Epidemiologic study of the irritable bowel syndrome in Beijing stratified randomized study by cluster sampling.
      These studies indicate that PI-IBS certainly exists in the tropics, but plainly more studies using similar methods are needed to ascertain just how frequent it is compared with Western countries.

      1.1 Clinical features of postinfective IBS

      The outcome of bacterial enteritis spans a wide spectrum, from a transient bowel disturbance lasting only a few days, to a prolonged diarrheal illness with a bowel disturbance that lasts many years. The Nottingham survey found that 6 months after infection, 25% of patients reported that their bowel habit was not back to normal.
      • Neal K.R.
      • 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.
      The key symptoms of these 90 individuals, mainly diarrhea and abdominal pain are shown in Table 1. Those who met the Rome I criteria for IBS had similar but more frequent symptoms with abdominal pain 3.7 ± 0.4 days/week, urgency 2.8 ± 0.5 days/week, loose stool 3.0 ± 0.3 days/week, and bloating 3 ± 0.5 days/week. A third of them had consulted their general practitioner within the first 6 months. Over the next 6 years the majority sought help with their symptoms and 78% had further investigations such as colonoscopy and barium enema.
      • Neal K.R.
      • Barker L.
      • Spiller R.C.
      Prognosis in post-infective irritable bowel syndrome a six year follow up study.
      Table 1Symptoms 6 Months Before and 6 Months After Bacterial Gastroenteritis in People Who Reported a Persistent Altered Bowel Habit
      SymptomsMean days wk (median)P value Wilcoxon matched pairs
      Before illnessAfter illness
      Abdominal pain0.7 (0)1.7 (0)0.0009
      Loose or watery stools0.8 (0)2.4 (2)<0.0001
      Hard or lumpy stools1.6 (1)1.4 (1)NS
      Straining1.0 (0)1.0 (0)NS
      Urgency0.7 (0)1.8 (1)<0.0001
      Slime or mucus0.43 (0)1.1 (0)0.002
      Bloated1.3 (0)2.7 (2)<0.0001
      NS, not specified.
      Adapted from Neal et al.
      • Neal K.R.
      • 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.
      These reports all excluded pre-existing IBS when calculating the incidence of PI-IBS, but within our survey we identified 21 patients with pre-existing IBS. We found no differences in the features of the infectious illness and symptoms 6 months later except that they took more time off work. This was 38 ± 10 days, significantly greater than those with new PI-IBS (21 ± 5 days) and those in whom the bowel habit returned to normal (14 ± 0.2 days). Thirty-eight percent of pre-existing IBS patients consulted their general practitioner about their bowels over the next 6 months, not significantly different from those with PI-IBS (29%), but much increased compared with just 7% of those whose bowel habit returned to normal. PI-IBS sufferers had a similar number of days with pain as pre-existing IBS but a greater proportion met the Rome II criteria for diarrhea-predominant IBS.
      • Neal K.R.
      • Barker L.
      • Spiller R.C.
      Prognosis in post-infective irritable bowel syndrome a six year follow up study.

      1.2 Risk factors for developing postinfective IBS

      As can be seen from Table 2, the strongest predictor of developing PI-IBS is the duration of the initial illness, possibly a marker of severity. The relative risk steadily increased in proportion to duration, so that when the illness lasted greater than 21 days the risk for developing PI-IBS was 11 times that of those whose illness lasted less than 1 week.
      • Neal K.R.
      • 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.
      Table 2Relative Risks for Development of IBS After Gastroenteritis
      FactorPI-IBSReturn to normalAdjusted relative risk (95% confidence interval)
      N23324
      Sex
      Male61531.0
      Female171713.4 (1.2–9.8)
      Duration of diarrhea (days)
      0–721041.0
      8–1471232.9 (0.6–15)
      15–217446.5 (1.3–34)
      ≥2273811.4 (2.2–58)
      From Neal et al.
      • Neal K.R.
      • 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.

      1.3 Host factors

      Gender was the strongest host factor found in both this survey and in the earlier study from Sheffield
      • Gwee K.A.
      • Leong Y.L.
      • Graham C.
      • McKendrick M.W.
      • Collins S.M.
      • Walters S.J.
      • et al.
      The role of psychological and biological factors in postinfective gut dysfunction.
      with women more than 3 times as likely to develop IBS as men. However, female sex did not affect the severity of initial illness and there are no known gender differences in immune response to infection. Because IBS patients in general are characterized by abnormally high scores on somatization and anxiety
      • Drossman D.A.
      • McKee D.C.
      • Sandler R.S.
      • Mitchell C.M.
      • Cramer E.M.
      • Lowman B.C.
      • et al.
      Psychosocial factors in the irritable bowel syndrome. A multivariate study of patients and nonpatients with irritable bowel syndrome.
      it is not surprising that psychologic features also play a part in the development of PI-IBS. Those scoring high on hypochondriasis had a relative risk of 2.0 (1.7–2.5) whereas adverse life events gave a relative risk of 2.0 (1.7–2.4).
      • Gwee K.A.
      • Leong Y.L.
      • Graham C.
      • McKendrick M.W.
      • Collins S.M.
      • Walters S.J.
      • et al.
      The role of psychological and biological factors in postinfective gut dysfunction.
      Furthermore, when Gwee et al.
      • Gwee K.A.
      • Leong Y.L.
      • Graham C.
      • McKendrick M.W.
      • Collins S.M.
      • Walters S.J.
      • et al.
      The role of psychological and biological factors in postinfective gut dysfunction.
      included various psychologic variables in a multivariate analysis, female sex was no longer a significant risk factor whereas hypochondriasis and adverse life events remained independent risk factors. This suggests that the female predisposition to PI-IBS may relate to a female predominance in psychologic distress.
      The risk factors for reporting a persistent change in bowel habit are similar to those for developing IBS but because the numbers are larger, smaller effects can be detected. Age over 60 years exerts a protective effect vs. ages 19–29, adjusted relative risk of 0.36 (0.1–0.9), perhaps related to the known reduction in immune responsiveness with age. Vomiting also protects, relative risk 0.47 (0.3–0.9), possibly because it reduces the infecting dose.
      • Neal K.R.
      • 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.
      Diet also appears to play a part with a significantly greater percentage of vegetarians reporting a persistent change in bowel habit at 6 months (43% vs. 22%, P < 0.001) (unpublished data).

      1.4 Pathogen factors

      These are undoubtedly important because the risk for developing IBS after Campylobacter and Shigella (approximately 1 in 10) is greater than that for Salmonella (1 in 100).
      • Neal K.R.
      • 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.
      A separate study including only those infected by Campylobacter jejuni characterized the infecting organism by using in vitro tests of toxigenicity. Those that caused the greatest change in cell morphology in vitro were associated with a relative risk of 12.8 (1.6–101) for reporting a persistent change in bowel habit at 6 months.
      • Thornley J.P.
      • Jenkins D.
      • Neal K.
      • Wright T.
      • Brough J.
      • Spiller R.C.
      Relationship of campylobacter toxigenicity in vitro to the development of postinfectious irritable bowel syndrome.
      PI-IBS is unlikely to be limited to bacterial infections. Although no prospective study has been performed, there are several reports of amebic dysentery suggesting that persistent symptoms are common, although they often are attributed erroneously to persistent infection.
      • Anand A.C.
      • Reddy P.S.
      • Saiprasad G.S.
      • Kher S.K.
      Does non-dysenteric intestinal amoebiasis exist?.

      1.5 Genetic factors

      The host response to infection also is influenced strongly by genes determining cytokine production. Polymorphisms that lead to overproduction of the anti-inflammatory cytokines, interleukin 10 and transforming growth factor β, were both underrepresented in an unselected IBS group compared with healthy controls.
      • Chan J.
      • Gonsalkorale W.
      • Perrey M.
      IL-10 and TGF-beta phenotype in irritable bowel syndrome evidence to support an inflammatory component (abstr).
      The high-producing interleukin 10 polymorphism might be predicted to lead to more rapid resolution of the inflammatory response and hence might protect against developing PI-IBS as they do against developing the more severe forms of rheumatoid arthritis.
      • Crawley E.
      • Kay R.
      • Sillibourne J.
      • Patel P.
      • Hutchinson I.
      • Woo P.
      Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis.
      This fits well with the data presented later indicating that a persisting mucosal lymphocytosis predicts the development of PI-IBS.
      • Gwee K.A.
      • Leong Y.L.
      • Graham C.
      • McKendrick M.W.
      • Collins S.M.
      • Walters S.J.
      • et al.
      The role of psychological and biological factors in postinfective gut dysfunction.
      Other polymorphisms governing the inflammatory response to bacterial infections such as nucleotide oligomerization domain (NOD2) and tumor necrosis factor also may be important but none have so far been specifically assessed in PI-IBS.

      1.6 Mucosal abnormalities in postinfective IBS

      Severe Campylobacter enteritis causes ulceration of the terminal ileum and colon associated with rectal bleeding and severe pain.
      • Blaser M.J.
      • Berkowitz I.D.
      • LaForce F.M.
      • Cravens J.
      • Reller L.B.
      • Wang W.L.
      Campylobacter enteritis clinical and epidemiologic features.
      However, this rapidly resolves as was found in a study in which serial biopsy specimens were examined at 2, 6, and 52 weeks after infection with Campylobacter jejuni. The mucosa in most cases looked normal at 2 weeks both macroscopically and by conventional histologic assessment. However, quantitative histology showed evidence of continuing inflammation, with elevated T lymphocyte levels (Figure 1) and newly recruited calprotectin-positive macrophages.
      • Spiller R.C.
      • Jenkins D.
      • Thornley J.P.
      • Hebden J.M.
      • 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.
      These changes gradually decreased over the ensuing 3 months but remained above normal. Furthermore, in a small subgroup of symptomatic individuals (7) who attended a further biopsy procedure at 1 year, the values were still well above the normal range. We also studied 10 patients attending a gastroenterology outpatient’s clinic with a classic story of PI-IBS in whom these same markers also were increased. A similar but more obvious response was seen by immunohistochemical staining with the universal enteroendocrine cell marker, synaptophysin. Synaptophysin-positive cells were increased 5-fold with 85% of individuals having values above the normal range at 2 weeks. Again, those with persistent symptoms at 1 year also had elevated levels (Figure 2, Figure 3), as did the PI-IBS outpatients.
      • Spiller R.C.
      • Jenkins D.
      • Thornley J.P.
      • Hebden J.M.
      • 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.
      At 3 months the T lymphocyte and enteroendocrine cells (EC) count correlated significantly, r = 0.65, P < 0.01. The secretory granules of these enteroendocrine cells also changed, being predominantly PYY in the rectal biopsy specimens of normal controls but mainly serotonin 3 months after Campylobacter infection. PYY has antisecretory properties,
      • Playford R.J.
      • Domin J.
      • Beacham J.
      • Parmar K.B.
      • Tatemoto K.
      • Bloom S.R.
      • et al.
      Preliminary report role of peptide YY in defence against diarrhoea.
      whereas serotonin stimulates intestinal secretions; so this switch may well contribute to the looser, more frequent stools characterizing PI-IBS. The findings of increased EC cells and T lymphocytosis has since been replicated in a larger survey of a further 23 PI-IBS patients.
      • Dunlop S.P.
      • Jenkins D.
      • Spiller R.C.
      Distinctive histological patterns of chronic inflammatory cells in rectal biopsies of patients with different clinical subtypes of IBS.
      Figure thumbnail GR1
      Figure 1Intra-epithelial T lymphocytes in rectal biopsy specimens taken at 2, 6, and 12 weeks, and 1 year after Campylobacter enteritis compared with PI-IBS patients recruited from outpatients. Controls were asymptomatic individuals undergoing negative colonoscopy for investigation of iron deficiency or as part of a family cancer-screening program. Adapted from Spiller et al.
      Figure thumbnail GR2
      Figure 2Low- and high-power view of a rectal biopsy specimen from an individual with PI-IBS showing increased serotonin-positive enteroendocrine cells. Note the heavily stained triangular cells with wispy processes reaching to the intestinal lumen and serotonin-containing granules distributed basally.
      Figure thumbnail GR3
      Figure 3Synaptophysin-positive enteroendocrine cell counts from the same individuals as in .
      Associated with these histologic changes in rectal biopsy specimens, there also was increased small bowel permeability. The ratio of urinary excretion of lactulose to mannitol was strikingly increased both 2 and 6 weeks after infection and also in the PI-IBS outpatients.
      • Spiller R.C.
      • Jenkins D.
      • Thornley J.P.
      • Hebden J.M.
      • 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.
      These abnormalities were comparable with those seen in celiac disease,
      • Bjarnason I.
      • Maxton D.
      • Reynolds A.P.
      • Catt S.
      • Peters T.J.
      • Menzies I.S.
      Comparison of four markers of intestinal permeability in control subjects and patients with coeliac disease.
      suggesting ongoing mucosal inflammation. Many inflammatory cytokines increase gut permeability and stimulate intestinal secretion, possible mediators including interleukin 1, tumor necrosis factor α, and interferon-γ, the latter possibly acting via inducing nitric oxide production.
      • Chavez A.M.
      • Menconi M.J.
      • Hodin R.A.
      • Fink M.P.
      Cytokine-induced intestinal epithelial hyperpermeability role of nitric oxide.
      These cytokines also cause accumulation of fluid in the intestinal lumen both by stimulating secretion and inhibiting absorption. Interleukin 1β-induced bicarbonate secretion is abolished by indomethacin, suggesting that it acts indirectly by stimulating prostaglandin production. Tumor necrosis factor-induced increase in permeability may be owing to increased apoptosis that leaves breaches in the epithelial barrier. These concepts derive largely from in vitro models, but in vivo tumor necrosis factor α antibodies have been shown to reverse the abnormally increased gut permeability in Crohn’s disease,
      • Suenaert P.
      • Bulteel V.
      • Lemmens L.
      • Noman M.
      • Geypens B.
      • Van Assche G.
      • et al.
      Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease.
      giving some support for the extrapolation of such data to the human situation.
      Activation of inducible cyclooxygenase-2 enzymes can be shown in an animal model of PI-IBS to persist in the smooth muscle layer long after infection has ceased.
      • Barbara G.
      • De Giorgio R.
      • Deng Y.
      • Vallance B.
      • Blennerhassett P.
      • Collins S.M.
      Role of immunologic factors and cyclooxygenase 2 in persistent postinfective enteric muscle dysfunction in mice.
      This is associated with alterations in neuromuscular function that can be reduced substantially by COX-2 inhibitors,
      • Barbara G.
      • De Giorgio R.
      • Deng Y.
      • Vallance B.
      • Blennerhassett P.
      • Collins S.M.
      Role of immunologic factors and cyclooxygenase 2 in persistent postinfective enteric muscle dysfunction in mice.
      but these have yet to be tried in PI-IBS in humans.

      1.7 Role of serotonin

      The increase in enteroendocrine cells appears to be relatively nonspecific in response to mucosal injury and inflammation. Increased serotonin EC cells have been documented in a range of animal models such as trinitrobenzene sulfonic acid colitis
      • Linden D.R.
      • Sharkey K.A.
      • Mawe G.M.
      Inflammation is associated with an increased availability of serotonin from enterochromaffin cells in the guinea pig distal colon.
      and Trichinella infection,
      • Wheatcroft J.
      • Wakelin D.
      • Jenkins D.
      • Spiller R.C.
      Increased entero-endocrine cell numbers in the Trichinella spiralis infected mouse model of post-infectious bowel dysfunction.
      as well as celiac disease and after Campylobacter infection in humans.
      • Spiller R.C.
      • Jenkins D.
      • Thornley J.P.
      • Hebden J.M.
      • 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.
      The functional significance is shown by increased release of serotonin by stroking the mucosa with a glass rod in the trinitrobenzene sulfonic acid model of EC hyperplasia.
      • Linden D.R.
      • Sharkey K.A.
      • Mawe G.M.
      Inflammation is associated with an increased availability of serotonin from enterochromaffin cells in the guinea pig distal colon.
      Although small amounts of serotonin are released from serotonergic neurons, the majority comes from EC cells, which are the source of 90% of the mucosal serotonin. Serotonin released by contact of chyme with the mucosa acts to stimulate pancreatic and intestinal secretions acting through 5HT3 receptors. It also stimulates enterocyte secretion and peristalsis acting through 5HT4 and 5HT1P receptors. The 5HT4 agonists prucalopride and Tegaserod both stimulate intestinal transit and are associated with increased fluidity of stools and relief of constipation.
      • Prather C.M.
      • Camilleri M.
      • Zinsmeister A.R.
      • McKinzie S.
      • Thomforde G.
      Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome.
      ,
      • Camilleri M.J.
      • McKinzie S.
      • Burton D.
      • Thomforde G.M.
      • Zinsmeister A.R.
      • Bouras E.P.
      Prucalopride accelerates small bowel and colonic transit in patients with chronic functional constipation (FC) or constipation-predominant irritable bowel syndrome (C-IBS).
      Furthermore, there are 5HT3 receptors on extrinsic afferent nerves, especially the vagus, which may stimulate nausea and also intestinal secretions. Thus, increased 5HT release as a result of increased EC numbers would be predicted to lead to frequent loose stools that are characteristic of postinfectious IBS. The role in pain sensation is uncertain but in some models 5HT3 antagonists can block nociceptive pathways,
      • Kozlowski C.M.
      • Green A.
      • Grundy D.
      • Boissonade F.M.
      • Bountra C.
      The 5-HT(3) receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat.
      suggesting increased serotonin release may promote hyperalgesia.
      Serotonin also may exert its effects via a proinflammatory effect on the immune system. Subcutaneous serotonin injection induces hyperemia and by its action on 5HT2 receptors on venules, which facilitates tissue homing of lymphocytes and other inflammatory cells.
      • Mossner R.
      • Lesch K.P.
      Role of serotonin in the immune system and in neuroimmune interactions.

      1.8 Physiologic changes in postinfectious IBS

      The symptoms of frequent loose stools have been associated with rapid colonic transit in patients with diarrhea-predominant IBS.
      • Cann P.A.
      • Read N.W.
      • Brown C.
      Irritable bowel syndrome relationship of disorders in the transit of a single solid meal to symptom patterns.
      This only has been studied once in postinfectious IBS in a rather small number of patients.
      • Gwee K.A.
      • Leong Y.L.
      • Graham C.
      • McKendrick M.W.
      • Collins S.M.
      • Walters S.J.
      • et al.
      The role of psychological and biological factors in postinfective gut dysfunction.
      As shown in Figure 4, Gwee et al.
      • Gwee K.A.
      • Leong Y.L.
      • Graham C.
      • McKendrick M.W.
      • Collins S.M.
      • Walters S.J.
      • et al.
      The role of psychological and biological factors in postinfective gut dysfunction.
      showed an acceleration of whole-gut transit time and also showed visceral hypersensitivity that would fit well with the symptoms of urgent loose stools and abdominal pain.
      Figure thumbnail GR4
      Figure 4Whole-gut transit assessed by using radio-opaque markers and threshold for discomfort during rectal balloon distention in healthy controls compared with 15 individuals who did and 15 individuals who did not develop PI-IBS after hospitalization for infective gastroenteritis. Note that there was a tendency for all infected individuals to show accelerated transit and increased sensitivity but only those meeting Rome I criteria showed a statistically significant effect. Adapted from Gwee et al.

      1.9 Diagnosis

      PI-IBS should be considered when there is a clear history of acute onset of symptoms on a single day. The previous bowel habit should be within normal limits, that is to say the patient should not meet Rome criteria for IBS and not suffer from frequent (>25% of occasions) abdominal pain/discomfort or disturbances of stool consistency, frequency, or defecation. The illness should have at least 2 of the following: fever, vomiting, diarrhea, or positive stool culture. Characteristically, IBS symptoms continue from the initial diarrheal episode. Diarrhea remits substantially in the following weeks but never returns to normal and urgency with loose stools and abdominal cramps persist. The initial weight loss is usually regained within a few weeks, persistent weight loss would be a reason to consider another diagnosis (see later). Although minor streaks of blood with defecation is common during the acute phase of any profuse diarrheal disease, persistent bleeding is not part of the syndrome and again should be a spur to further investigations.

      1.10 Differential diagnosis

      Acute infections are well recognized to cause transient lactose intolerance, particularly in children after rotavirus infections.
      • Szajewska H.
      • Kantecki M.
      • Albrecht P.
      • Antoniewicz J.
      Carbohydrate intolerance after acute gastroenteritis—a disappearing problem in Polish children.
      However, this appears less relevant after bacterial gastroenteritis in adults in the United Kingdom. A recent study using a breath hydrogen test found no cases of lactose intolerance in 16 cases of postinfectious IBS.
      • Parry S.D.
      • Barton J.R.
      • Welfare M.R.
      Is lactose intolerance implicated in the development of post-infectious bowel symptoms in previously asymptomatic people?.
      However, in areas where lactose intolerance is more common than it is in Northern Europe it may be worth looking for. However, it is only relevant with a milk consumption greater than 240 mL/day because ingestion of less than this does not reliably cause symptoms in those with lactose malabsorption.
      • Lisker R.
      • Aguilar L.
      • Zavala C.
      Intestinal lactase deficiency and milk drinking capacity in the adult.
      Microscopic colitis, which has been described as beginning after acute infections such as Campylobacter jejuni,
      • Perk G.
      • Ackerman Z.
      • Cohen P.
      • Eliakim R.
      Lymphocytic colitis a clue to an infectious trigger.
      should be excluded by flexible sigmoidoscopy and mucosal biopsy examination because such patients respond well to budesonide.
      • Miehlke S.
      • Heymer P.
      • Bethke B.
      • Bastlein E.
      • Meier E.
      • Bartram H.P.
      • et al.
      Budesonide treatment for collagenous colitis a randomized, double-blind, placebo-controlled, multicenter trial.
      Small bowel contamination also should be considered in older patients, particularly those who have predisposing factors such as small bowel surgery, strictures, or achlorhydria. Likewise, the role of drugs, particularly antibiotics but also angiotensin converting enzyme inhibitors, proton pump inhibitors, and statins also should be considered. Crohn’s disease, particularly the colonic form in its early stages, also should be considered because it can easily mimic IBS and may have a long prodrome.
      • Pimentel M.
      • Chow E.J.
      • Lin H.C.
      Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome.
      Anemia, nocturnal symptoms, weight loss, or persistently elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) should lead to further investigations such as colonoscopy or small bowel radiologic or endoscopic evaluation.
      Of all possible alternative diagnoses, celiac disease is the one that should be considered most carefully because about 3% of patients presenting with IBS turn out to have this condition.
      • Sanders D.S.
      • Carter M.J.
      • Hurlstone D.P.
      • Pearce A.
      • Ward A.M.
      • McAlindon M.E.
      • et al.
      Association of adult coeliac disease with irritable bowel syndrome a case-control study in patients fulfilling ROME II criteria referred to secondary care.
      IgA endomysial antibodies are highly sensitive and specific and well worth performing because a gluten-free diet is likely to have a considerable and permanent effect on symptoms. If suspicion is high, then immunoglobulin levels also should be checked because selective IgA deficiency, which is found in around 2% of the population, may cause a false-negative endomysial antibody result and in this case IgG endomysial antibodies should be checked. This is particularly relevant after Giardiasis because those with IgA deficiency may present with recurrent Giardiasis.
      • Lai Ping S.A.
      • Mayer L.
      Gastrointestinal manifestations of primary immunodeficiency disorders.
      In the elderly, diverticular disease also may present with acute diarrhea but such patients are usually over the age of 45 and would warrant colonic imaging because of the change in bowel habit and the need to exclude colonic cancer. This consideration particularly applies if there is a family history of colon cancer when imaging should be considered even earlier.
      • Jones J.
      • Boorman J.
      • Cann P.
      • Forbes A.
      • Gomborone J.
      • Heaton K.
      • et al.
      British Society of Gastroenterology guidelines for the management of the irritable bowel syndrome.

      1.11 Treatment

      General advice for patients with urgency and loose stools of all causes would be to avoid dietary laxatives, particularly bran, green vegetables, and fruits high in poorly absorbed mono- and disaccharides such as sorbitol and mannitol (e.g., plums, prunes).
      • Parker T.J.
      • Naylor S.J.
      • Riordan A.M.
      • Hunter J.O.
      Management of patients with food intolerance in irritable bowel syndrome the development and use of an exclusion diet.
      As already indicated, although transient hypolactasia and milk intolerance is not uncommon in children, in adults it rarely is responsible for PI-IBS. However, if a patient consumes a high lactose diet, a lactose breath hydrogen test should be used to identify lactose intolerance and, if positive, a trial of a lactose-free diet would be warranted.

      1.12 Opiates

      Rapid intestinal transit can be inhibited by opiates such as codeine
      • Barrow L.
      • Steed K.P.
      • Spiller R.C.
      • Maskell N.A.
      • Brown J.K.
      • Watts P.J.
      • et al.
      Quantitative, noninvasive assessment of antidiarrhoeal actions of codeine using an experimental model of diarrhea in man.
      or Loperamide, although sedation and nausea usual limit the use of centrally acting opiates.
      • Palmer K.R.
      • Corbett C.L.
      • Holdsworth C.D.
      Double-blind cross-over study comparing loperamide, codeine and diphenoxylate in the treatment of chronic diarrhea.
      Loperamide, a peripherally acting μ-receptor agonist, is especially active in improving stool consistency
      • Cann P.A.
      • Read N.W.
      • Holdsworth C.D.
      • Barends D.
      Role of loperamide and placebo in management of irritable bowel syndrome (IBS).
      but slightly less effective in controlling pain in IBS.
      • Hovdenak N.
      Loperamide treatment of the irritable bowel syndrome.
      Loperamide should be given as 2 mg after each loose stool up to a maximum of 12 mg/day. However, although this may cure the diarrhea, some patients develop unacceptable bloating and discomfort leading to discontinuation of treatment.

      1.13 Tricyclic antidepressants

      These agents affect multiple receptors with antihistaminic and antimuscarinic effects, as well as both serotonin- and noradrenaline-reuptake inhibition. Low doses (10–20 mg 3 times a day) must be used because IBS patients often are intolerant of drug side effects. The antimuscarinic effects reduce diarrhea while the antihistaminic effects provide sedation, which, when given last thing at night, is useful in treating the insomnia commonly associated with IBS. Tricyclics have been shown to reduce pain in large trials in IBS.
      • Myren J.
      • Lovland B.
      • Larssen S.-E.
      • Larsen S.
      A double-blind study of the effect of trimipramine in patients with the irritable bowel syndrome.
      They also are known to potentiate analgesics, probably by enhancing antinociception. The best evidence for the analgesic effects comes in the treatment of painful diabetic neuropathy
      • Max M.B.
      • Lynch S.A.
      • Muir J.
      • Shoaf S.E.
      • Smoller B.
      • Dubner R.
      Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy.
      in which amitriptyline and desimipramine were found to be significantly more effective than paroxetine. Direct evidence of analgesic effects in the bowel is limited although there is one study that showed a decrease in rectal sensitivity in IBS.
      • Riberdy-Poitras M.
      • Verrier P.
      • Plourde V.
      • Boivin M.
      • Poitras P.
      Amitriptylin for the treatment of IBS.

      1.14 Serotonin antagonists

      5HT3 antagonists slow colonic transit in normal individuals
      • Talley N.J.
      • Phillips S.F.
      • Haddad A.
      • Miller L.J.
      • Twomey C.
      • Zinsmeister A.R.
      • et al.
      GR 38032F (ondansetron), a selective 5HT3 receptor antagonist, slows colonic transit in healthy man.
      and also improve stool consistency and frequency in diarrhea-predominant IBS.
      • Camilleri M.
      • Mayer E.A.
      • Drossman D.A.
      • Heath A.
      • Dukes G.E.
      • McSorley D.
      • et al.
      Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist.
      They also reduce the gastrocolonic response to feeding
      • Prior A.
      • Read N.W.
      Reduction of rectal sensitivity and post-prandial motility by granisetron, a 5 HT3-receptor antagonist, in patients with irritable bowel syndrome.
      that might be expected to improve urgent postprandial defecation, which is a common feature of diarrhea-predominant IBS. A recent study measuring 5HT in peripheral blood suggested an excess release of serotonin in response to a meal in diarrhea-predominant IBS
      • Bearcroft C.P.
      • Perrett D.
      • Farthing M.J.
      Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome a pilot study.
      but whether this is particularly true in PI-IBS remains to be shown. If this is so, then 5HT3 antagonists might be expected to be particularly effective.

      1.15 Bile salt malabsorption

      The brunt of the infectious damage with organisms such as Salmonella and Campylobacter is borne by the terminal ileum and right colon where acute inflammation may be associated with bile salt malabsorption, which may persist. A report of patients with idiopathic bile salt malabsorption described a subset with an acute onset and a particularly severe absorptive defect.
      • Williams A.J.K.
      • Merrick M.V.
      • Eastwood M.A.
      Idiopathic bile acid malabsorption—a review of clinical presentation, diagnosis, and response to treatment.
      Such patients responded well to Cholestyramine, suggesting that colon secretion induced by malabsorbed bile salts was the main cause of diarrhea. A separate series of patients with idiopathic bile salt malabsorption reported a clear history of acute gastroenteritis before the onset of chronic diarrhea in 16 of 29 patients. Of these 16 cases of gastroenteritis, 4 were documented to be caused by Campylobacter and 1 each by Shigella and Salmonella. These patients also responded well to cholestyramine, with mean stool frequency decreasing from 7.2/day to 2.2/day,
      • Niaz S.K.
      • Sandrasegaran K.
      • Renny F.H.
      • Jones B.J.
      Postinfective diarrhoea and bile acid malabsorption.
      suggesting that bile salt malabsorption is well worth considering in PI-IBS patients.

      1.16 Probiotics

      One of the many effects of acute infectious diarrhea is a profound ulceration of colonic flora, with a loss of anaerobes and marked reduction in stool short-chain fatty acid concentration.
      • Tazume S.
      • Ozawa A.
      • Yamamoto T.
      • Takahashi Y.
      • Takeshi K.
      • Saidi S.M.
      • et al.
      Ecological study on the intestinal bacterial flora of patients with diarrhea.
      The associated increase in cecal pH level may well encourage the development of abnormal flora. IBS symptoms have been reported to develop after antibiotic therapy or infections, which some investigators have related to abnormal colonic fermentation of unabsorbed carbohydrates.
      • King T.S.
      • Elia M.
      • Hunter J.O.
      Abnormal colonic fermentation in irritable bowel syndrome.
      Diets excluding a range of poorly digestible nonstarch polysaccharides, found empirically to benefit some IBS patients, were noted to correct abnormally high 24-hour hydrogen production. They also altered the response to a standard lactulose challenge,
      • King T.S.
      • Elia M.
      • Hunter J.O.
      Abnormal colonic fermentation in irritable bowel syndrome.
      suggesting that their beneficial effect may relate to alteration in colonic flora. The concept of normalizing an abnormal colonic flora by introducing nonpathogenic flora has obvious attractions. The most commonly used strains are lactobacilli. Lactobacillus casei sp. strain GG when given as 1010 colony-forming units twice daily, significantly shortened diarrhea in children infected with rotavirus.
      • Isolauri E.
      • Kaila M.
      • Mykkanen H.
      • Ling W.H.
      • Salminen S.
      Oral bacteriotherapy for viral gastroenteritis.
      However, a recent meta-analysis, although confirmatory, suggests the effect is small, reducing the duration of diarrhea by just 1 day.
      • Huang J.S.
      • Bousvaros A.
      • Lee J.W.
      • Diaz A.
      • Davidson E.J.
      Efficacy of probiotic use in acute diarrhea in children a meta-analysis.
      Randomized control trials in unspecified IBS have had variable efficacy and none have examined PI-IBS specifically. One study, although not showing an overall significant benefit, suggested that lactobacilli might specifically benefit those with diarrhea
      • O’Sullivan M.A.
      • O’Morain C.A.
      Bacterial supplementation in the irritable bowel syndrome. A randomised double-blind placebo-controlled crossover study.
      whereas another showed benefit in reducing flatulence and pain in IBS.
      • Nobaek S.
      • Johansson M.L.
      • Molin G.
      • Ahrne S.
      • Jeppsson B.
      Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome.
      Disappointingly, however, these trials suggest that any beneficial effect requires continued ingestion because probiotics do not appear to establish a permanent colonization.

      1.17 Disease-modifying treatments

      All the treatments mentioned earlier are purely symptomatic and do not attempt to alter the underlying condition. If low-grade inflammation underlies postinfectious IBS then anti-inflammatory treatments are logical. We have recently completed a randomized, placebo-controlled trial of prednisolone, 30 mg/day for 3 weeks, which failed to alter either symptoms or EC counts, although it did reduce mucosal lymphocyte counts significantly.
      • Dunlop S.P.
      • Jenkins D.
      • Spiller R.C.
      Distinctive histological patterns of chronic inflammatory cells in rectal biopsies of patients with different clinical subtypes of IBS.
      A small proportion of EC cells in mice have a very long half-life (160 days), which if true in man may suggest that any anti-inflammatory treatment would have to be given for months rather than weeks if it is to reverse EC hyperplasia. We found our patients to be fairly reluctant to take steroids, so any such treatment would have to have a better side-effect profile than prednisolone to be acceptable.
      A different approach we are exploring currently is to use antimicrobials. Prolonged bismuth treatment (2 months) has been reported to have a permanent benefit in microscopic colitis,
      • Fine K.D.
      • Lee E.L.
      Efficacy of open-label bismuth subsalicylate for the treatment of microscopic colitis.
      but whether it would benefit PI-IBS awaits confirmation. Antibiotics have been reported to benefit some IBS patients in whom small bowel contamination has been diagnosed by using the lactulose breath test,
      • Pimentel M.
      • Chow E.J.
      • Lin H.C.
      Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome.
      although the report does not specify if any cases were postinfective. Interpretation of this report is controversial
      • Riordan S.M.
      • McIver C.J.
      • Duncombe V.M.
      • Thomas M.C.
      • Nagree A.
      • Bolin T.D.
      Small intestinal bacterial overgrowth and the irritable bowel syndrome.
      and we await confirmation by others.

      1.18 Prognosis

      Surprisingly, this does not appear to be remarkably different from other types of IBS. When followed-up prospectively for 6 years, 43% of the PI-IBS patients had recovered, only slightly better than the 31% of those with pre-existing IBS.
      • Neal K.R.
      • Barker L.
      • Spiller R.C.
      Prognosis in post-infective irritable bowel syndrome a six year follow up study.
      Similarly, when McKendrick
      • McKendrick M.W.
      Post Salmonella irritable bowel syndrome-5-year review.
      restudied his original patients 5 years after their original illness he likewise found that the majority (9 of 11) remained symptomatic, mainly troubled by episodic diarrhea. This differs somewhat from the rather more optimistic report from Harvey et al.
      • Harvey R.F.
      • Mauad E.C.
      • Brown A.M.
      Prognosis in the irritable bowel syndrome a 5-year prospective study.
      that reported that those with an acute onset fared better than those without. Chaudhary
      • Chaudhary N.A.
      • Truelove S.C.
      The irritable colon syndrome.
      suggested a link between psychologic distress and poorer prognosis and we also found that a psychiatric history tended to adversely affect recovery. This would fit with other reports that persisting chronic stress delays recovery in unspecified IBS.
      • Bennett E.J.
      • Tennant C.C.
      • Piesse C.
      • Badcock C.A.
      • Kellow J.E.
      Level of chronic life stress predicts clinical outcome in irritable bowel syndrome.
      Just what drives persistent symptoms and mucosal abnormalities is unclear, but genetic abnormalities causing delay in down-regulating the immune response to infection may be important susceptibility factors as they are in inflammatory bowel disease. As we understand more about PI-IBS, we may come to see this form of IBS and inflammatory bowel disease as part of a wide spectrum of responses to gastrointestinal infection with important interactions between gut inflammation, colonic flora, and both central and peripheral neuroendocrine systems. Plainly, there remains much to be discovered about this form of IBS, which looks likely to be a fruitful area of inquiry for many years to come.

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