Postinfectious IBS: What is new with the recent Rome update?

The Rome Foundation Working Team Report1 brings together a wealth of data and reminds us just how productive this area of research has been for the understanding of the mechanisms underlying functional bowel disorders. Clinicians are presented daily with patients meeting the Rome criteria for irritable bowel and will be well aware of how heterogeneous and baffling their symptoms can be. There is often, though by no means invariably, a chronic history of many years during which bowel symptoms fluctuate and are associated with anxiety, depression and multiple somatic symptoms. However, which is cause and which effect is unclear.

The development of new irritable bowel syndrome (IBS) symptoms after a bout of acute gastroenteritis in a previously well patient, so called post infective IBS (PI-IBS), would at first sight appear to be an ideal natural experiment to untangle this web. One of the earliest reports suggested that PI-IBS patients had less psychological abnormalities than those with chronic IBS.2 However, that conclusion has not been borne out by subsequent prospective studies in which anxiety, depression and somatization have all been shown to be significant risk factors for developing PI-IBS.3  Furthermore, those that get infected may be predisposed to infection having differing immune response and gut microbiota.

The characteristics of the acute illness are also important and as a recent meta-analysis points out PI-IBS develops after both bacterial and viral gastroenteritis in 13.8 and 6 percent respectively, while Giardiasis is followed by PI-IBS in a significantly higher rate of 35 to 40 percent.4  Symptom markers of severity of the acute attack such prolonged diarrhea more than seven days and bloody stools all increase the risk 2.6- and 1.9-fold respectively. The lesser rate after viral gastroenteritis is perhaps not surprising given the known lesser degree of inflammatory damage to the bowel wall compared to bacterial gastroenteritis such as Campylobacter and Shigella, which can produce a severe colitis. However, the much greater rates of PI-IBS seen after the Giardiasis outbreak in Bergen, Norway suggests a rather different mechanism.5 The Rome report gives an excellent account of the different animal models which have been used to try to define the underlying mechanisms. As animal studies have shown, normally the highly diverse microbiota in health shows marked colonization resistance. Pathogens overcome this and proliferate by eliciting a response which makes the colonic environment hostile to the normal symbionts. This includes watery diarrhea which alkalinizes the ascending colon, increasing primary bile acids and destroying the unstirred layers which are essential to create the anaerobic environment the normal strict anaerobes require. While the recolonization process usually results in near complete restitution, this is not always the case and it may be that certain individuals are near a “tipping point” whereby a different, less healthy microbiota results, which may in part be responsible for symptoms. Several studies have shown that PI-IBS is characterized by an excess of members of the Bacteroidetes phylum6,7 but whether  this makes them less stable and more likely to develop dysbiosis as suggested by the Rome report remains to be established.

One of the earliest reports suggested that PI-IBS patients had less psychological abnormalities than those with chronic IBS. However, that conclusion has not been borne out by subsequent prospective studies in which anxiety, depression and somatization have all been shown to be significant risk factors for developing PI-IBS.

One feature of acute enteritis is a breakdown in barrier function allowing bacteria to penetrate the inner mucus layer and enter the epithelial cells. The demonstration that this was a feature not only of PI-IBS but also other sorts of IBS lead to the discovery of abnormal tight junctions in some IBS patients, especially those with diarrhea. Several small studies using glutamine8 or xyloglucans9 to target abnormal permeability have suggested that this might be a promising therapeutic approach, but these need to be confirmed by other groups. Recent animal work with Giardiasis suggests that although the initial damage was limited to the upper small bowel after a month barrier function was impaired throughout the gut, perhaps due to a break in host immune tolerance of normal commensals which may now elicit an inflammatory response.

While much remains to be learned about PI-IBS, the practical implications are that patients can, to some extent, be reassured that PI-IBS is a well-recognized phenomenon which will in many cases resolve over some months but may last longer. Psychological disorders as well specific immune predisposition may be important risk factors and should be looked for and treated on their own merits. Specific treatment with anti-inflammatory drugs including prednisolone10 and mesalazine11 though logical, have been shown to be ineffective and are not recommended. Treatment should be guided by the predominant symptoms which are most commonly though not invariably those of diarrhea or mixed subtype. Anxiety/depression should be treated on its own merits. Those with diarrhea may well respond to 5HT3 receptor antagonists,12 tryptophan hydroxylase inhibitors , loperamide,  eluxadoline or rifaximin but none so far have been shown to be particularly effective for PI-IBS. Resetting any disturbance of the microbiota is again logical but awaits a more definitive account of the “dysbiosis.”   

Dr. Spiller has given a lecutre for Alfa Wassermann and received research support from Sanofi.

References

1. Barbara G., Grover M., Bercik P., Corsetti M., Ghoshal U.C., Ohman L., et al. Rome Foundation Working Team Report on Post-Infection Irritable Bowel Syndrome. Gastroenterology. 2019;156(1):46-58.
2. Chaudhary N.A., Truelove S.C. The irritable colon syndrome. A study of the clinical features, predisposing causes, and prognosis in 130 cases. Q J Med. 1962; 31:307-322.
3. Card T., Enck P., Barbara G., Boeckxstaens G.E., Santos J., Azpiroz F., et al. Post-infectious IBS: Defining its clinical features and prognosis using an internet-based survey. United European Gastroenterology Journal. 2018;doi:2050640618779923.
4. Klem F., Wadhwa A., Prokop L.J., Sundt W.J., Farrugia G., Camilleri M., et al. Prevalence, risk factors, and outcomes of irritable bowel syndrome after infectious enteritis: A systematic review and meta-analysis. Gastroenterology. 2017;152(5):1042-1054.
5. Moyo S.J., Hanevik K., Blomberg B., Kommedal O., Nordbo S.A., Maselle S., et al. Prevalence and molecular characterisation of human adenovirus in diarrhoeic children in Tanzania; a case control study. BMC Infect Dis. 2014;14:666.
6. Jalanka J., Salonen A., Fuentes S., De Vos W.M. Microbial signatures in post-infectious irritable bowel syndrome–toward patient stratification for improved diagnostics and treatment. Gut Microbes. 2015;6(6):364-369.
7. Sundin J., Rangel I., Fuentes S., Heikamp-de J., I, Hultgren-Hornquist E., De Vos W.M., et al. Altered faecal and mucosal microbial composition in post-infectious irritable bowel syndrome patients correlates with mucosal lymphocyte phenotypes and psychological distress. Aliment Pharmacol Ther. 2015;41(4):342-351.
8. Zhou Q, Verne ML, Fields JZ, Lefante JJ, Basra S, Salameh H et al. Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome. Gut. 2019; 68(6):996-1002.
9. Trifan A., Burta O., Tiuca N., Petrisor D.C., Lenghel A., Santos J. Efficacy and safety of Gelsectan for diarrhoea-predominant irritable bowel syndrome: A randomised, crossover clinical trial. United European Gastroenterol J. 2019;7(8):1093-1101.
10. Dunlop S.P., Jenkins D., Neal K.R., Naesdal J., Borgaonker M., Collins S.M., et al. Randomized, double-blind, placebo-controlled trial of prednisolone in post-infectious irritable bowel syndrome. Aliment Pharmacol Ther. 2003;18(1):77-84.
11. Tuteja A.K., Fang J.C., Al-Suqi M., Stoddard G.J., Hale D.C. Double-blind placebo-controlled study of mesalamine in post-infective irritable bowel syndrome–a pilot study. Scand J Gastroenterol. 2012;47(10):1159-1164.
12. Mearin F., Lacy B.E., Chang L., Chey W.D., Lembo A.J., Simren M., et al. Bowel disorders. Gastroenterology. 2016;doi:10.1053/j.gastro.2016.02.031.

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