Serological and faecal markers of irritable bowel syndrome: a systematic review and meta-analysis

The irritable bowel syndrome (IBS) has long been considered a functional disorder, but recent work has demonstrated clear biological signatures in immune, microbiome and enteric nervous systems of patients with IBS. Despite this new knowledge, there is still no clear biological marker of IBS, with patient symptom reporting and exclusion of organic disease the main criteria for diagnosis. We aimed to perform a systematic review and meta-analysis to identify consistent biomarkers for IBS in serum and stool samples.

We searched Medline, EMBASE, Cochrane Library, Web of Science and Scopus to obtain all relevant publications published between 1992 and January 2026. Original, peer-reviewed research articles including adults with IBS and healthy or outpatient controls, and/or patients with organic gastrointestinal conditions (e.g. IBD) were included. All articles had quantification of blood and faecal markers between IBS and controls. Descriptive data presented as median and range or median (interquartile range) was converted to mean ± SD. To account for methodological assay differences between studies, standardised mean difference (SMD) with 95% confidence interval was used as the primary outcome measure for the meta-analyses, with a random effects model fitted to the data.

The search strategy identified 55,444 citations across all databases. 124 studies were included encompassing 14,930 patients with IBS, 7544 healthy/asymptomatic controls and 4317 patients with organic diseases. The top serum discriminators between IBS and healthy controls were TNF-⍺ (13 studies, 1025 controls and 1244 IBS, SMD = 2.74, 95% CI = 0.70, 4.70, p = 0.006), IL-6 (13 studies, 736 controls and 1022 IBS, SMD = 1.87, 95% CI = 0.13, 3.61, p = 0.035) and IFN-ɣ (4 studies, n = 195 controls, n = 372 IBS, SMD = 2.79, 95% CI = 1.07, 4.51, p = 0.002). For faecal markers calprotectin was significantly higher in patients with IBS over controls (11 studies, 1624 controls and 1383 IBS, SMD = 0.75, 95% CI = 0.30, 1.21, p = 0.001), while faecal valerate levels were lower in IBS versus controls (4 studies, 290 controls and 488 IBS, SMD = -0.79, 95% CI = -1.48, -0.11, p = 0.02). For discriminating IBS overall from organic diseases, serum albumin (4 studies, 282 IBS and 312 organic, SMD = 2.15, 95% CI = 0.20, 4.11, p = 0.031) and faecal calprotectin (16 studies, 1591 IBS and 1685 organic, SMD = -1.13, 95% CI = -1.51, -0.75, p < 0.0001) were significantly different. In discriminating IBS subtypes from controls, only diarrhoeal IBS (IBS-D) could be distinguished by albumin (3 studies, 248 controls and 219 IBS-D, SMD = -0.39, 95% CI = -0.68, -0.11, p = 0.007) and IL-6 (4 studies, 153 IBS-D and 169 controls, SMD = 2.53, 95% CI = 0.86, 4.21, p = 0.003). Heterogeneity across the studies ranged from moderate to high, but few overly influential studies were identified between comparisons.

Patients with IBS exhibit increased peripheral cytokine levels that are consistent with reports of increased epithelial permeability and may be important in distinguishing subgroups of IBS patients. Patients with IBS also demonstrated higher faecal calprotectin levels than healthy individuals, although these levels were still significantly lower than patients with organic diseases. Similarly, patients with IBS-D have lower serum albumin levels compared to healthy controls, while patients with organic disease had lower levels compared to patients with IBS, irrespective of subtype. There are clear biological signatures at play in IBS patients that may be useful clinically in establishing IBS diagnosis and may indicate the mechanisms of disease symptoms.

National Health and Medical Research Council Centre for Research Excellence in Digestive Health (NJT, SK) G180219.