Review Article

Diagnosis of Irritable Bowel Syndrome: Role of Potential Biomarkers

Table 1

Biomarkers for IBS diagnosis. 

AuthorsStudy designMethodsPopulationNumber of IBS patientsBiomarkerMain results

Hod et al. (2011) [45]Case controlProspectively selected IBS patients diagnosed according to Rome III criteria. All patients underwent blood sampling for hs-CRP levelsIBS (IBS-C, IBS-D, IBS-M) compared to healthy controls88hs-CRP levels are higher in IBS patients than HC but still in the normal laboratory rangeMean hs-CRP level in patients with IBS versus healthy controls 
(1.17 ± 1.26 mg 
versus 0.72 ± 0.91 mg 
, resp. ( = 0.001))

Hauser et al. (2012) [46]Pilot studyIBS was diagnosed based on Rome III criteria. Patients underwent a medical and laboratory examination (ESR), FBDSI1 and filled in the questionnaires designed to measure their disease-specific and general HRQoL: (IBS-36)2 and (SF-36)3IBS (all patients were included despite disease’s subtype or previous enteric infectious status)86IBS patients with higher ESR (>24 mm/h) expressed lower disease-specific quality of lifeESR positively correlated with disease-related HRQoL 
( = 0.24, < 0.05)

Kennedy et al. (2014) [49]Observational studyFemale IBS participants who met Rome III criteria with exclusion of organic GI disease underwent a single exposure to the TSST4. Salivary cortisol, salivary CRP, SCL5, GI symptoms, mood, and self-reported stress were measuredIBS (female) compared to age-related female healthy controls13Patients with IBS exhibited a greater total cortisol output and exhibit sustained HPA axis activity to acute experimental psychosocial stressRepeated measures ANOVA across all sample collection time points revealed a significant main effect of the TSST 
on salivary cortisol levels ( = 8.34, 
< 0.001, 
= 0.243) 
and a significant main effect of group 
( = 4.96, = 0.035, = 0.16)

FitzGerald et al. (2009) [50]1-day observational studyAll patients with IBS fulfilled Rome II criteria IBS-D and none of the patients were classified as PI-IBS. Blood samples  
were analyzed for ACTH6, cortisol, epinephrine, and norepinephrine. A single measure of cerebrospinal fluid (CSF) concentrations of corticotropin-releasing factor (CRFCSF) and norepinephrine CSF is noted
IBS-D (women) compared to healthy controls13No CRFCSF differences between groups are observed. Women with IBS display blunted ACTH and cortisol responses to the acute stressor (lumbar puncture)The mean CRFCSF was 23.9 (SE = 6.14) in patients with IBS compared 
with 23.0 ± (SE = 2.23) in controls.
A significant interaction of time × group was seen for ACTH, = 3.31, < 0.01, with control participants 
demonstrating a significantly greater increase than patients with IBS immediately after LP

Lembo et al. (2009) [51]Observational study1721 patients with IBS and other FGIDs were included only if they met the Rome II or Rome  III diagnostic criteria for at least 6 months prior to study enrolment and if they had no evidence of an organic, an infectious, or a structural cause of the disease. 10 serum biomarkers were selected from a potential panel of 140 for their ability to differentiate IBS from non-IBS disease in blood samples from patients with IBS and other GI disorders and healthy volunteersIBS (IBS-C, IBS-D, 
IBS-M, IBS-U) and non-IBS patients (healthy individuals, IBD, coeliac disease, and functional GI disorders)
876Blood-based diagnostic test differentiated IBS from non-IBS with 50% sensitivity and 88% specificity, respectivelyThe overall accuracy of the IBS diagnostic test, defined as the percentage of correct predictions, was 70%. The PPV was 81% and the NPV was 64% at a 50% IBS prevalence

Sidhu et al. (2009) [53]Observational studyPatients with Rome II IBS-D were recruited prospectivelyIBS-D219CgA level in serum appears to be transiently elevated in IBS-DCgA levels were followed up for a median duration of 7 months.
81% of IBS patients () had normal CgA levels (0–20 u/L).
12.3% () had values between 20 and 60 u/L, and 6.8% () had CgA levels >60 u/L.
CgA remained elevated >60 u/L on repeated testing in 3.2% of patients of the whole group

Sidhu et al. (2010) [55]Observational studyPatients with IBS were diagnosed according to Rome III criteria. Duodenal and colonic biopsies were obtained from all IBS patientsIBS-C and IBS-D compared to healthy controls41Reduced density of intestinal CgA cells as potential histopathological biomarkerDuodenum CgA cell density healthy control versus IBS total 
(50.5 ± 21 versus 25.6 ± 22, 
< 0.05).  
Colon CgA cell density healthy control versus IBS total 
(33.1 ± 14 versus 21.3 ± 13, 
< 0.001)

Öhman et al. (2012) [39]Observational studyNo data on diagnostic criteria. Fecal samples for analysis of calprotectin, CgA and CgB, and SgII and SgIII were collected from all study subjectsIBS (IBS-C, IBS-D, and IBS-A) compared to healthy controls82Higher levels of CgA and secretogranins II and III in fecal samplesHigher levels of fecal CgA ( = 0.009), SgII ( < 0.001), and SgIII ( < 0.001), but lower levels of CgB ( < 0.001) compared with controls

Tibble et al. (2002) [61]Observational study602 new referrals to a gastroenterology clinic who had symptoms suggestive of IBS or organic intestinal disease were studied to assess the sensitivity, specificity, and odds ratios (ORs) of fecal calprotectin, small intestinal permeability, Rome I criteria, and laboratory markers of inflammation (ESR, CRP, blood count) in distinguishing organic from nonorganic intestinal diseasePatients with IBS symptoms (IBS/IBD)602 (339/263)Cutoff FC level of 30 mg/kg combined with Rome I criteria can serve as a clear proof of IBS with no need for further examinationAt the cutoff value for normality (10 mg/L), fecal calprotectin has a sensitivity of 89% and specificity of 79% for organic disease.
Predictive values of FC at >10 mg/L (OR (95% CI) 27.8 (17.6–43.7), PPV 0.76, NPV 0.89)

Waugh et al. (2013) [62]Systematic reviewA broad search strategy was run in several databases. Studies that provided sufficient data for calculation of sensitivity, specificity, and other diagnostic outcomes were  
Identified. The quality of studies was assessed using 
Quality Assessment of Diagnostic Accuracy Studies
IBS compared to IBD28 studiesCutoff FC level from 50 mcg/g showed 93% of sensitivity and 94% of specificity in differentiating IBD from IBS

Chang et al. (2014) [63]Observational studyNo data on diagnostic criteria for IBS in abstract.
20 healthy control subjects, 26 patients with IBS, and 58 patients with IBD, including 22 with ulcerative colitis (UC) and 36 with Crohn’s disease (CD), were recruited. FC was analyzed in stool samples, and CRP and the ESR were assessed in blood samples
IBS/IBD/healthy controls26Significantly higher stool FC levels in IBS patients than serum CRP levelsIn patients with IBD and IBS, significant increases in fecal calprotectin and CRP levels were observed (694.8 ± 685.0 µg/g in IBD versus 85.8 ± 136.1 µg/g in IBS and 0.851 ± 1.200 mg/dL in IBD versus 0.16 ± 0.23 mg/dL in IBS, resp.; < 0.0001)

Tkalcic et al. (2014) [64]Observational studyProspectively selected IBS patients diagnosed according to Rome III criteria. All patients underwent stool sampling for FC level and fulfilled HRQoL questionnaires (IBS-36)2 and (SF-36)3IBS48FC level correlates with reduced physical component of health related quality of life (HRQoL)Physical component of HRQoL was predicted by calprotectin ( = −0.34; < 0.01), depression ( = −0.31; < 0.05), anxiety ( = −0.27; < 0.05), and symptom severity ( = −0.25; < 0.05)

Langhorst et al. (2009) [65]Observational studyNo data on diagnostic criteria for IBS in abstract.
Fecal specimens were collected from a total of 100 participants. Exclusion criteria: current use of probiotics and antibiotics, IBS patients CRP or leukocytes, a history of bacterial overgrowth, or infectious gastrointestinal disease over the last 6 months
IBS and UC and healthy controls46Significantly elevated levels of HBD-2 in patients with IBS compared with HCs and similar to those with active UCHBD-2 levels were highest in active UC (106.9 ± 91.5 ng/g), almost as high in IBS 
(76.0 ± 67.9 ng/g), and lowest for HCs (29.9 ± 16.1 ng/g). Scheffe post hoc tests revealed significant differences ( < 0.001) between the groups of patients (UC and IBS) versus HCs

1FBDSI: Functional Bowel Disorder Severity Index, 2IBS-36: Irritable Bowel Syndrome Quality of Life Questionnaire, 3SF-36: Medical Outcome Study Short Form 36, 4TSST: Trier Social Stress Test, 5SCL: skin conductance level, and 6ACTH: adrenocorticotropic hormone.