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Biomarkers for IBS: ready for prime time?Giovanni Barbara

Evidence is mounting that molecular mechanisms underlie gut dysfunction and symptom generation in IBS. Although it is still an uphill struggle, this mounting evidence is a good starting point for the discovery of one or more IBS biomarkers.Barbara, G. Nat. Rev. Gastroenterol. Hepatol. advance online publication 2 December 2014; doi:10.1038/nrgastro.2014.217

Biomarkers are objectively measurable indicators of normal or pathological pro-cesses, or pharmacological responses to a therapeutic intervention.1 Robust biomark-ers are urgently needed for common condi-tions such as IBS. A study by Camilleri et al.2 examined the diagnostic performance of three biomarkers that are common in IBS and are susceptible to therapeutic inter-vention. The biomarkers included colonic transit time, bile acid synthesis and excre-tion, and intestinal permeability, all of which were assessed with noninvasive methods. Taken together, faecal bile acid levels and colonic transit time were able to discrimi-nate between healthy individuals as controls and patients with IBS, or between the differ-ent IBS subgroups based on bowel habit (that is, constipation-predominant or diarrhoea-predominant IBS) with 60% sensi tivity and 75–90% specificity. The authors concluded that these biomarkers hold promise for diag-nostic purposes and for the identification of treatable mechanisms in IBS.

Up to one-third of people in Western countries report symptoms attributable to the gastrointestinal tract, including abdomi-nal pain, bloating, constipation or diar-rhoea. The majority of these patients have no evidence of organic abnormalities on routine laboratory or imaging examination and fulfil the criteria for the so-called func-tional gastrointestinal disorders. Chronic constipation and IBS together account

for up to 80% of the outpatient diagnoses for functional gastrointestinal disorders in the USA.3 Unfortunately, the term ‘functional’ is often improperly interpreted as ‘idiopathic’ or ‘cryptogenetic’. Patients are frequently labelled as neurotic, apprehensive, other-wise healthy individuals with ‘an imaginary disease’. Physicians might be torn between minimizing patient concern about symp-toms and the anxiety of missing a serious disease. As a consequence, they might pre-scribe avoidable, expensive examinations, which contribute to the huge economic burden of IBS.3 The lack of evident tissue pathology has generated confusion and mystification surrounding the true nature of IBS and disillusion in the pharmaceutical industry, which is worried about investing in drug development directed to uncertain molecular targets.4

The identification of robust biomarkers would represent a major step forward in IBS research (Box 1). This progress would legitimize the nature of IBS symptom devel-opment, facilitate the homogenization of patients for enrolment in clinical trials and advance drug development. A biomarker would also represent a powerful tool for clinicians to overcome current diagnostic uncertainty (for example, for confirm-ing the diagnosis and discriminating IBS from organic disease) and guide treatment through the identification of relevant sub-groups responding to specific therapies. The identification of an IBS biomarker seems closer than ever because relevant molecu-lar mechanisms have been discovered in subsets of patients with IBS. Suitable bio-marker candidates include: polymorphisms in genes encoding cytokines; increased

epithelial permeability; neuroendocrine abnormalities; low-grade mucosal immune activation; and gut microbial changes.5

Nonetheless, we are not quite there yet. Biomarkers should meet basic require-ments, such as a reasonable diagnostic per-formance, noninvasiveness, reproducibility, low costs and applicability on a large scale. Unfortunately, most studies claiming the identification of IBS biomarkers fall short on these requirements. This failure is in part related to the heterogeneous nature of IBS. Too many subgroups of patients with differ-ent pathophysiological mechanisms exist to hope that a single biomarker can embrace all of them. The highly significant correla-tion coefficient (r = 0.75, P <0.001) of mast cells found in close proximity to colonic nerves with severity of abdominal pain in patients with IBS requires endoscopy and is too cumber some to be a clinically useful biomarker.6 Deep molecular analysis of faecal microbiota signatures showed a nice separation between patients with IBS and healthy controls,7 but selective and specific IBS signatures have subsequently shown to be restricted to subgroups of patients only.8 Certainly, serum biomarkers are much more attractive. Unfortunately, the diagnostic per-formance of a pool of 10 serum biomarkers was disappointingly low9 and improved only when the original list was extended to 34 biomarkers.10

Methodological concerns regarding current research also exist. Most studies claiming the identification of biomarkers for IBS suffer from small sample size or failure to include relevant controls. Diagnostic per-formance (for example, sensitivity, specificity

Box 1 | Implications of an IBS biomarker

■ Improve diagnosis ■ Predict prognosis ■ Help discriminate patients with IBS from

healthy individuals ■ Help to discriminate IBS from other

organic diseases ■ Reduce disease-related costs ■ Help identify relevant subgroups

responding to specific therapies ■ Help homogenize patients for inclusion

in clinical trials ■ Improve and boost drug development ■ Monitor drug efficacy

‘‘Robust biomarkers are urgently needed for common conditions such as IBS’’

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or likelihood ratios) is not always properly assessed. Camilleri and colleagues2 overcame many of the above-mentioned limitations as they combined different biomarkers and applied noninvasive techniques in a fairly large group of patients with IBS. The major limitation of this study is that the assess-ment of the two relevant biomarkers (bile acid metabolism and intestinal transit) relies on techniques not available on a large scale. One might wonder if the sophisti-cated scintigraphic method for detection of intestinal transit could be substituted with the zero cost, universally available Bristol Stool Scale, which has previously shown a good correlation with intestinal transit times. Another limitation of this study, which is common to other studies, is the lack of inclusion of relevant organic diseases in the study population. Inclusion of such patients could have provided useful clinical information on the diagnostic performance of these tests to exclude common disorders such as coeliac disease or IBD. One might predict that the diagnostic accuracy would then be low, as changes in gut transit time,

bile acid malabsorption and increased intes-tinal p ermeability are common in these disorders too.

For the time being, the search for IBS bio-markers has provided inconclusive results. However, researchers have been so far much more engaged in the detection of abnormal organic findings rather than in the applic-ability of biomarkers as diagnostic tools or predictors of therapeutic responses. The next steps should involve integration of potential biomarkers with clinical features in methodo logically sound studies specifi-cally designed for the identification of one (or more likely multiple) IBS biomarkers.

Department of Medical and Surgical Sciences, University of Bologna, St Orsola—Malpighi Hospital, Building No. 5, Via Massarenti, 9, I‑40138 Bologna, Italy. giovanni.barbara@unibo.it

Competing interestsThe author declares no competing interests

1. Atkinson, A. J. Jr et al. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69, 89–95 (2001).

2. Camilleri, M. et al. Validating biomarkers of treatable mechanisms in irritable bowel syndrome. Neurogastroenterol. Motil. http://dx.doi.org/10.1111/nmo.12421.

3. Peery, A. F. et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 143, 1179–1187 (2012).

4. Barbara, G. & Stanghellini, V. Biomarkers in IBS: when will they replace symptoms for diagnosis and management? Gut 58, 1571–1575 (2009).

5. Camilleri, M. Peripheral mechanisms in irritable bowel syndrome. N. Engl. J. Med. 367, 1626–1635 (2012).

6. Barbara, G. et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126, 693–702 (2004).

7. Rajilic-Stojanovic, M. et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology 141, 1792–1801 (2011).

8. Jeffery, I. B. et al. An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut 61, 997–1006 (2012).

9. Lembo, A. J. et al. Use of serum biomarkers in a diagnostic test for irritable bowel syndrome. Aliment. Pharmacol. Ther. 29, 834–842 (2009).

10. Jones, M. P. et al. A biomarker panel and psychological morbidity differentiates the irritable bowel syndrome from health and provides novel pathophysiological leads. Aliment. Pharmacol. Ther. 39, 426–437 (2014).

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