Stool-Based Biomarkers to Differentiate Between IBD and IBS

What are IBD and IBS?

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are two different gastrointestinal tract issues affecting millions of people every day. Although there is some overlap between symptoms of IBD and IBS, differences still remain in regards to pathologies, risks of developing related complications, and treatment options. Therefore, it is vital to properly distinguish between IBD and IBS. Researchers and gastroenterologists have been focused on investigating the use of stool-based biomarkers to differentiate between IBD and IBS.

Inflammatory Bowel Disease

Inflammatory bowel disease is a chronic disease with forms involving the lower bowel parts or the entire GI tract, causing symptoms like abdominal pain, diarrhea, fever and weight loss. An estimated two million people in North America suffer from IBD seemingly caused by an overactive mucosal immune system¹. Crohn’s Disease and ulcerative colitis (UC) are the major groups of inflammatory conditions that make up IBD and are incurable, serious and chronic organic diseases of the intestinal tract. The symptoms of IBD are distressing, embarrassing and even debilitating.

Crohn’s and ulcerative colitis share many of the same physiological characteristics but they differ in type of inflammation as well as the location of inflammation along the gastrointestinal tract. While Crohn’s can affect any part of the GI tract and UC is most often localized to the large intestine.

Irritable Bowel Syndrome

Irritable bowel syndrome is a non-organic functional disorder. It expresses similar symptoms to IBD such as cramping, bloating, diarrhea, and constipation. An estimated thirty million people in North America are affected by IBS symptoms, resulting in over 3.5 million physician visits annually and accounting for roughly 30% of visits to gastroenterologists². Although the causes of IBS have not been fully identified, research has indicated that issues with the gut-brain axis and stress may be related to triggering IBS². One of the main differences between IBD and IBS is that in IBS, the GI tract is not permanently damaged by inflammation³.

Stool-Based Biomarkers to Differentiate Between IBD and IBS

Both organic IBD and non-organic functional disorders like IBS exhibit very similar symptoms. A considerable issue in clinical gastroenterology is to differentially diagnose patients with IBD from IBS. As the field evolves to accept and approve new tests for clinically diagnosing patients, researchers are working hard to provide evidence that certain biomarkers are more informative than others when it comes to differentiating between the two disorders.

To date, researchers have identified several stool-based biomarkers to differentiate between IBD and IBS. These become especially crucial when taking the next step towards deciding how to manage the disease (e.g. therapeutic intervention, etc.). Those biomarkers include the following:

• Calprotectin
• Alpha-1 Antitrypsin
• Lysozyme
• Secretory IgA
• Albumin
• Beta-Defensin 2
• Bile Acids

Calprotectin

Calprotectin (MRP 8/14, S100 A8/A9) has proven to be one of the most valuable biomarkers for differentiating between IBD and IBS. Calprotectin is an immunomodulatory protein accounting for up to 60% of cytosolic protein in neutrophil granulocytes and macrophages. Calprotectin plays a central role in neutrophil defenses and inflammatory pathologies. Studies show under conditions of mucosal inflammation, calprotectin is released into the gastrointestinal lumen and serves as a useful biomarker for accurately identifying intestinal inflammation⁴. These findings demonstrate the importance of measuring calprotectin when studying inflammatory bowel diseases,

Alpha-1 Antitrypsin

Alpha-1 Antitrypsin (A1A) is a linear glycoprotein that is predominantly synthesized in the liver but also by intestinal macrophages, monocytes and epithelial cells. Alpha -1 Antitrypsin is the main serine proteinase inhibitor in human plasma. Fecal A1A has become an important marker for intestinal protein loss and permeability as it is able to resist degradation in the gut due to its anti-proteolytic activity⁵. As a result, it remains intact and it is possible to detect it in the feces using an immunoassay.  Accordingly, the measurement of stool A1A concentration has been studied as a method for evaluating and monitoring chronic inflammatory intestinal diseases, therefore making A1A another of the key stool-based biomarkers to differentiate between IBD and IBS.

Lysozyme

Lysozyme is an enzyme that catalyzes the hydrolysis of specific glycosidic bonds in mucopolysaccharides that make up the cell wall of gram-positive bacteria. Secreted by granulocytes, macrophages, Paneth cells, Brunner’s Glands and normal colonic crypt cells, lysozyme acts as an antibacterial defense in the GI tract⁶. Elevated levels of fecal lysozyme have been identified in colonic IBD when compared to healthy controls^7,8.

Secretory IgA

Secretory IgA represents the first line of defense of the GI mucosa and is central to the normal function of the GI tract as an immune barrier. As the predominant immunoglobulin isotype present in mucosal secretions, it plays an important role in controlling the intestinal milieu in the face of bacteria, parasites, viruses, etc.⁹ Elevated levels of fecal secretory IgA are associated with an upregulated immune response in the GI tract.

Albumin

Albumin is the most abundant protein found in blood. It keeps fluid from leaking out of blood vessels, nourishes tissues and transports important chemicals throughout the body. The concentration of serum albumin drops with inflammation associated with liver damage, kidney disease, malnourishment, etc. However, in the presence of IBD fecal albumin levels have been shown to increase¹⁰.

Beta-Defensin 2

Beta-defensin 2 is also one of the valuable stool-based biomarkers for differentiating between IBD and IBS. The beta-defensins are an integral part of the immune system and contribute with their antimicrobial effect to the barrier function of the intestinal epithelial cells. Reduced beta-defensin 2 expression levels have been shown to occur in the intestinal mucus in the presence of Crohn’s disease¹¹.

Bile Acids

Investigators are working to better understand the role of bile acids in inflammation. Bile acids are synthesized in the liver and secreted via the bile duct into the duodenum. Once in the stomach, bile acids are transported back to the liver following their absorption in the distal ileum and passage through the portal vein¹². Research has shown that in the presence of IBD, reabsorption is impaired and bile acids are excreted in stool¹³.

Conclusion

Although some of the symptoms of IBD and IBS can be similar, differences still remain in regards to pathologies, risks of developing related complications, and treatment options. Researchers have made great strides in recent years to quickly and accurately distinguish between IBD and IBS. Investigators have had success in using stool-based biomarkers to differentiate between IBD and IBS; however, more research is needed in order to validate these biomarkers as clinical tools for differentiation.

Resources

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References

1. Crohn’s & Colitis Foundation of America (CCFA). (2011). Facts about Inflammatory Bowel Diseases. CCFA.org.
2. International Foundation for Functional Gastrointestinal Disorders (IFFGD). (2013). What is IBS? aboutIBS.org.
3. Crohn’s & Colitis Foundation of America (CCFA). (2016). IBS and IBD: Two Very Different Disorders. CCFA.org.
4. Gisbert et al. (2009). Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. Dig Liver Dis, 41(1), 56-66.
5. Arndt et al. (1992). Assessment of Crohn’s Disease activity and alpha 1-antitrypsin in faeces. The Lancet, 340(8826), 1037.
6. Saito et al. (1988). Lysozyme localization in human gastric and duodenal epithelium. An immunocytochemical study. Cell Tissue Res, 251(2), 307-13.
7. Van der Sluys Veer et al. (1998). Fecal lysozyme in assessment of disease activity in inflammatory bowel disease. Dig Dis & Sci, 43(3), 590-5.
8. Klass et al. (1978). Serum and faecal lysozyme in inflammatory bowel disease. Gut, 19, 233-9.
9. Crago et al. (1978). Mucosal antibodies, food allergy and intolerance. Bailliere Tindall/W.B. Saunders. 167-89.
10. Powell-Tuck. (1986). Protein metabolism in inflammatory bowel disease. Gut, 27(S1), 67-71.
11. Harder et al. (2001). Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic. J Biol Chem, 276, 5705-5713.
12. Kullak-Ublick et al. (2004). Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterol, 126, 322-342.
13. Camilleri et al. (2009). Measurement of serum 7alpha-hydroxy-4-cholesten-3-one (or 7alphaC4), a surrogate test for bile acid malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem mass spectrometry. Neurogastroenterol Motil, 21, 734-e43.