Blood-Based Biomarkers Discriminate IBS from IBD with High Degree of Certainty in Patients with Chronic Diarrhea

Brief: Two blood-based biomarkers, cytolethal distending toxin B (CdtB) and anti-vinculin, have been substantively linked with the occurrence of diarrhea-predominant forms of irritable bowel syndrome (IBS). As a result, an ELISA-based diagnostic test developed by Gemelli Biotech is now able to “rule-in” an IBS diagnosis while “ruling-out” irritable bowel disease (IBD) based on elevated biomarker titers. With testing only available at PacificDx, the clinically-validated ibs-smart™ blood test provides answers for those whom a diagnosis has been uncertain.

Background: Affecting about 40 million Americans, IBS is a chronic disorder characterized by changes in bowel habits, dietary issues, and abdominal discomfort or pain—a non-discriminating and overlapping symptomology common to other functional gastrointestinal disorders. As the most common condition encountered by gastroenterologists, the diagnostic process for an IBS diagnosis is challenging and one of exclusion of other disorders such as inflammatory bowel disease (IBD), microscopic colitis (MC), ulcerative colitis, Crohn’s disease, celiac disease and others. Since 2006, the diagnosis of IBS has been made using a symptom-based classification system known as the Rome criteria, with the most recent edition being Rome IV (Drossman, 2016)—however, this system does not exclude IBD. IBS symptoms occur frequently in patients with active IBD but less often when IBD is in remission. In the U.S., although IBS prevalence rates are shown to be variable, in part due to the difficulty of obtaining a diagnosis (16%, 2017). The adverse impacts shown to occur as a result of high co-morbidity rates, lost productivity, quality of life, and patient and societal economics are unfortunately, more consistent.

Disease mechanisms: The pathophysiology of IBS has an overlapping overabundance of mechanisms contributing to symptomology including gastrointestinal dysmotility, inflammation, visceral hypersensitivity and altered intestinal microbiota. Several studies have reported an increased risk for developing a form of IBS after acute gastroenteritis as well as in people with post-traumatic stress disorder (PTSD). Psychological factors can play an etiological role for perpetuating symptoms, as well as certain/multiple stressors associated with a person’s work and environment. This has led to findings supporting the interdependence between the gut and the brain known as the brain-gut axis (BGA)—pathways among physiological systems that facilitate bi-directional communications. Patients with IBS exhibit differences in the central processing mechanisms of the BGA which align with brain structure, connectivity and functional responsiveness—these differences, while not fully understood, may explain a patient’s clinical presentation. Until these mechanisms are better understood, treatment remains symptom-driven.

IBS subtypes: There are four sub-types what define IBS based on the patient’s stool type and bowel habits, IBS-C (constipation), IBS-D (diarrhea), IBS-M (mixed) and IBS-U (un-subtyped). Recommended diagnostic work-ups are both burdensome and costly— traditionally including a lengthy succession of tests. These include but are not limited to patient history, a dietary chronicle, physical and anorectal exams, lab tests that include: complete blood count, C-reactive protein, fecal calprotectin, celiac disease serology, and imaging procedures that include: colonoscopy and/or upper gastrointestinal endoscopy. Other testing may be recommended based on the presence of ‘alarm signs’ to determine if these symptoms are attributable to IBS. The process of determining an IBS vs. IBD diagnosis has been complex and has furthered efforts for blood-based biomarker development.

IBS blood-based biomarkers: For the diarrhea-predominant sub-types of IBS, the risk of developing IBS is greater following a case of infectious acute gastroenteritis. About 10% of those developing acute gastroenteritis experience alterations in their intestinal microbiome, accompanied by long-term symptoms and often referred to as post-infectious IBS (PI-IBS). Through partnered research and development efforts by Gemelli BioTech and the Medically Associated Science and Technology program and Cedars-Sinai (MAST), two biomarkers have been highly linked with the occurrence of IBS-D and IBS-M. Released by bacteria, cytolethal distending toxin B (CdtB) and anti-vinculin are released into circulation following an acute episode of gastroenteritis. This is most often associated with a foodborne bacterial infection that in turn, generates an autoimmune reaction. Although not all IBS occurs is a result of a foodborne infection, these bacterial species are frequently culprits that produce cytolethal distending toxin that is linked to post-infectious IBS (IBS-PI): Campylobacter jejuni, Salmonella, E.coli and Shigella.

Clinical validation: Gemelli Biotech, a developer of novel diagnostics and therapeutics for the human microbiome, developed and validated an ELISA-blood-based assay for the detection of anti-CdtB and anti-vinculin was in a prospective multicenter clinical trial of 2,681 subjects, ages 18 to 65. The ibs-smart blood test generated a positive predictive value and specificity of 98.6% and greater than 90%, respectively. Significantly elevated titers of anti-CdtB showed distinct discrimination between IBS-D and IBD, celiac disease and healthy control subjects. Anti-vinculin titers were also significantly higher in IBS as compared to the same groups. For a diagnosis of IBS-D vs IBD for both biomarkers, the area-under-the-curves (AUCs) were 0.81 and 0.62, respectively, but less discriminating for celiac disease.

Clinical utility: The ‘diagnosis of exclusion’ approach has been the clinical standard for those patients whose non-specific and overlapping symptoms do not align with any specific diagnosis. This shotgun approach has caused patients to undergo extensive and frequent invasive medical procedures in an effort to obtain a diagnosis by ruling out other conditions and diseases. This process not only engenders discomfort, anxiety and inconvenience for the patient, its expensive and may incur significant out-of-pocket costs. The ibs-smart blood test, with its ability to ‘rule-in’ diarrheal forms of IBS and ‘rule-out’ IBD, streamlines the diagnostic process for patients, removing an unnecessary cascade of diagnostic testing while reducing patient morbidity and cost. For the healthcare provider, a blood test is a routine, convenient method of testing that is easy for most patients and returns rapid results. Indicative of IBS, a positive blood test will help guide clinical and therapeutic management decisions for the patient. Considering a population health and economic perspective related to the 40 million people in the U.S. who have symptomatic IBS— replacing the expensive ‘exclusionary process’ with a single blood-based test diagnostic would substantially reduce the associated economic burden to the healthcare delivery system.

Testing: In partnership with Gemelli Biotech, the ibs-smart test is exclusively available through PacificDx , a premier CLIA-certified molecular laboratory in Irvine California. For the patient, information on obtaining the test please visit: ibs-smart.com


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