In contrast to calprotectin, S100A12 is exclusively expressed in relevant amounts by granulocytes, which play an important role in the pathogenesis of IBD. S100A12 is secreted by activated neutrophils and promotes inflammation through the activation of RAGE.26
As neutrophil influx into the intestinal mucosa is closely linked to IBD activity, especially during early steps of inflammation, neutrophil‐derived S100A12 in tissue and exudates strongly correlates with inflammatory activity.9,55
Excretion of the protein into the gut lumen could reflect the number of neutrophils infiltrating the mucosa as well as their activation status. The measurement of S100A12 in feces is not strictly disease specific, but is probably specific for neutrophil activity during bowel inflammation. It was recently reported that S100A12 is detectable in stool samples, where it is evenly distributed and, similar to calprotectin, is stable for 7
Faecal S100A12 was increased in paediatric Crohn's disease patients in whom disease activity was only determined by a clinical score and not by invasive procedures such as colonoscopy. This approach, however, is critical taking into account the observed inaccuracy of clinical indices. The CAI and the CDAI poorly correlate with the invasive assessment of inflammation by endoscopy and histology (which was our gold standard) and depend on interobserver variations.56,57
Not surprisingly, these clinical scores have been found to be of little use in the monitoring of disease activity in a number of studies, including ours.5
Our analysis is the first study to show a strong correlation between endoscopically and histologically confirmed intestinal inflammation and faecal levels of S100A12 both in Crohn's disease and ulcerative colitis. We provide evidence that faecal S100A12 discriminates between IBD and IBS with high accuracy. Furthermore, faecal S100A12 differed significantly between active and inactive IBD. As an important feature, the test for faecal S100A12 performs equally well regardless of disease location. The results for S100A12 improved when we included only patients with ulcerative colitis (sensitivity 91%, specificity 96%). These findings are analogous to calprotectin, which is also more accurate in ulcerative colitis.51
The results are comparable to those reported previously in children with Crohn's disease, although the concentrations determined with our ELISA were lower.28
It appears rather unlikely, however, that the concentrations of S100A12 in stool reach the levels of calprotectin, because the latter protein complex is far more abundant.22
Our results also confirm the fact that neither faecal marker of intestinal inflammation is completely specific for IBD, but rather for intestinal inflammation in general, because the levels of these phagocyte‐derived proteins are also elevated during infectious enteritis.54
In this respect, S100A12 as a specific marker of neutrophil activation may, however, also be very useful in monitoring disease activity.
It was our aim to include only well‐characterised IBD patients, in whom endoscopic investigation with the collection of bowel biopsies was performed, allowing the use of a histology inflammation score as a gold standard. Furthermore, immunohistochemical staining of tissue sections confirmed S100A12 expression in the gut of each patient. We could thereby confirm that infiltrating neutrophils are the main source of faecal S100A12. Although the number of individuals included in this study is rather small as a result of the study design, our data prove that faecal S100A12 strongly correlates with intestinal tissue inflammation. Longitudinal studies will be performed in the future to determine the value of faecal S100A12 in the monitoring of inflammation and the prediction of the disease course.
In conclusion, clinical indices are too indistinct to reflect inflammatory activity in chronic IBD and cannot provide precise information about the patient status. In contrast, most procedures used to confirm inflammation in the gut are too invasive or expensive for routine use, or they require radiation exposure. Whereas most serological biomarkers are of limited use, faecal markers of neutrophil activity can indicate intestinal inflammation. Once bacterial enteritis is ruled out, faecal S100A12 may be an excellent non‐invasive marker of disease activity of IBD superior to other biomarkers including faecal calprotectin, which is also derived from monocytes and potentially from epithelial cells, making it less specific for infiltrating neutrophils. Faecal S100A12 correlates with inflammation and can distinguish chronic IBD from non‐organic disease including IBS, with high sensitivity and specificity. This neutrophil‐derived protein can significantly improve our arsenal of non‐invasive biomarkers of intestinal inflammation.