A “biomarker” (biological marker) is an indicator of a bodily function that can be objectively measured. A wide range of possible biomarkers for IBS have been considered but at present only gut transit measured using radio-isotope markers meet the criteria of reproducibility and availability. While barostat studies perform reasonably in expert centers, to do them reproducibly requires considerable effort and standardization. This makes them unsuitable for widespread use. However radio-isotope tests are expensive and of limited availability so the search for other more convenient markers including blood and stool tests is still an important goal for the future.
What is a biomarker?
A biomarker (biological marker) is an indicator of a physiological or pathological state that can be objectively measured and evaluated. It contrasts with subjective patient reported outcomes by usually having lower variability and therefore greater power to detect effect of treatments or differences between groups. A good example of a biomarker used in other fields is the forced expiratory volume in 1 second (FEV 1 ). This biomarker is an objective measure of respiratory function that assesses airway resistance, which is a critical feature of asthma. It is simple, inexpensive, and reproducible. The standard is to use the best of 3 to allow for learning of the technique. It has been widely used and shown to be reproducible, responsive to treatment, and also to indicate the state of the disease. In pulmonology other measures are also used to study asthma, including mucosal histology obtained from bronchial biopsy, sputum eosinophil counts and sputum culture. The advantages of the FEV 1 when compared with these other more invasive and technically demanding tests are its noninvasiveness, patient acceptability, and its responsiveness to many treatments. It is also apparent that the value of any particular biomarker will depend on the treatment being assessed; for example, if an antibiotic is being tested in infective exacerbation of asthma, then sputum culture might prove more valuable in predicting response.
Criteria for a Useful Biomarker in Irritable Bowel Syndrome
A useful biomarker for irritable bowel syndrome (IBS) would be simple and easy to use. It would be patient acceptable and reproducible (low intrasubject variability). Ideally it should also have low intersubject variability within defined groups. This variability is important because it reduces the number needed to test (NN test) to detect a minimally important difference with an acceptable power, which is particularly important when evaluating new treatments to allow a rapid decision on whether to pursue development or move on to another molecule. Because most studies are done in multiple centers, it is important that the technique of measurement should be readily transferable between centers and, therefore, should not need highly sophisticated equipment or require scarce expertise. Finally, all these things are of little value if the technique is too expensive.
Pathophysiology of IBS relevant to choosing a biomarker
IBS patients are a highly heterogeneous group because the symptoms are quite nonspecific and may reflect numerous pathophysiologies, including altered transit and sensitivity. For the purposes of this article, it is sufficient to say that most authors agree that in any one patient a range of factors, including stress, somatization, anxiety, neuroticism, diet, and prior infection, contribute to symptoms mediating both altered visceral sensitivity and disturbances of bowel transit. Biomarkers that could identify the main mechanism in each individual patient would be of undoubted value.
The other important consideration in using biomarkers to predict or evaluate response to a new therapy is that to be useful, the biomarker should relate to the mode of action of the drug being evaluated. Many recently introduced drugs have altered gastrointestinal (GI) transit, including prokinetics, such as tegaserod, prucalopride, and velusetrag ; and secretagogues aimed at treating constipation, including lubiprostone and linaclotide. Others delay transit, such as the 5HT3 receptor antagonists (alosetron and ondansetron ), or reduce visceral hypersensitivity, such as amitriptyline and the 2,3-benzodiazepine receptor agonist dextofisopam. Although still in development, anti-inflammatory agents, such as mesalazine, have been shown to reduce mast cell numbers or to inhibit release of mast cell mediators, such as ketotifen. Since one of the main purposes of biomarkers is to identify subjects for which a specific treatment may be more appropriate, the majority of this article addresses measures of transit, visceral hypersensitivity, abnormal stress responsiveness, and inflammation. The author also considers newer proposed biomarkers that still require validation but might be useful in the future.
As Table 1 shows, there are many potential biomarkers reflecting different aspects of the pathophysiology of IBS. These biomarkers focus on changes in gut function and the associated microbiota. Of course, it is well recognized that there are important influences of the brain on the gut in IBS but as yet apart from psychometric assessments based on patient reports, the complexity of the brain has defied the development of simple biomarkers. Although differences in brain activation in response to painful stimuli between subjects with IBS and controls can be demonstrated using positron emission tomography scanning or fMRI, the techniques are difficult and results variable between centers. Furthermore, the equipment is extremely expensive, therefore, patterns of brain activation by peripheral stimuli do not meet our criteria for a good biomarker.
| Mechanism | Potential Biomarkers |
|---|---|
| Disordered motility/secretion leading to altered transit and altered stool form | Manometry/transit tests/stool charts |
| Visceral hypersensitivity | Rectal barostat/cutaneous stimulation |
| Abnormal autonomic reactivity | Heart rate variability/response to pain |
| Stress response | Cortisol/response to visceral stimulus |
| Mucosal inflammation | Mucosal biopsy |
| Evidence of immune activation | Serum/peripheral blood mononuclear cells cytokine production |
| Increase fecal proteases | Stool test |
| Altered gut flora | Stool DNA/culture/bacterial metabolite assessment |
| Food allergy | Skin prick test, serum antibodies |
| Genetic polymorphisms | Single-nucleotide polymorphism assays |
Link Between Biomarker and Clinical Response
Although in the end a treatment has to improve patients’ quality of life and how they perceive their symptoms, such measures are always influenced by many factors other than the local GI ones. Thus, all stimuli coming from the gut have to be interpreted in light of previous experiences, current emotional state, and psychological stressors before they are converted to symptom reports. This means that an intervention or drug that alters gut function may have a weak effect on patient-reported outcomes and the size of the clinical trial needed to show the effect is likely to be large, on the order of many hundreds.
Biomarkers as Surrogate Endpoints
By restricting the end points to a biomarker closer to the gut function, variability should be less and hence standardized effect sizes should be larger and the number of individuals needed to test to show an effect much less. This is of considerable value in the development of new drugs. By being more focused and less holistic, these measures are much more likely to be culture independent and hence easier to translate across multiple centers and countries, again a value feature in drug development that is often multinational. A major use of biomarkers is therefore in mode of action or proof of concept studies during phase I and early phase II. Although on its own not acceptable as the only outcome measure in phase III studies, biomarkers might also be valuable as entry criteria to improve responder rates or as secondary end points.
Assessing gut motility
Motor patterns are important in determining transit and also because they may cause pain, a major symptom in IBS that substantially determines perceived severity. The gut is insensitive to many stimuli, including thermal and chemical injury, but is responsive to distension and powerful contractions. Several studies have clearly linked powerful colonic contractions with abdominal pain ( Fig. 1 ).
Although these contractions are crucial to the pain, as a biomarker, manometry’s major problem is the requirement for intestinal intubation. The original studies were done using naso-intestinal intubation, which is extremely arduous, taking several days to properly position the manometry catheter. These uncomfortable experiments have mainly been done with paid volunteers. The number of patient studies is limited and the subjects studied are likely to be a highly selected sample. Furthermore, the technique is expensive and technically demanding and hence impracticable for use as a biomarker. More recently, the technique of retrograde cannulation of the colon at colonoscopy allowing the positioning of probes, which are clipped to the mucosa, has been developed. This technique is much quicker and more patient acceptable but still highly invasive and expensive. Although useful perhaps for the early stages of proof-of-principal concepts, such techniques are unlikely to win widespread use in clinical trials or in clinical practice.
Even if such techniques were patient-acceptable, measures such as the duodenal motility index, although reasonably reproducible, show substantial intersubject variability in normal subjects with a coefficient of variation (CoV) (standard deviation divided by mean) of 13351/30708 (43%), giving a total NN test of 96 (48 per group) to show a 25% change in mean index with a power of 80% in a random controlled trial (RCT) of drug against placebo.
Recordings in the colon show a highly erratic pattern requiring long-term recordings to give meaningful results, which has only been done in a few studies. However, Clemens studied 12 subjects with IBS and reported a CoV of sigmoid motility over 24 hours of just 7%, indicating this would require only 3 subjects per group in a parallel group design, a total of 6 to detect a 25% change with 80% power if they could be persuaded to undergo 24-hour recordings. Almost identical figures were found by Rao in healthy women with a CoV of 7% and just 5% in subjects who were constipated. Alternative measures might be a frequency of specialized propagating pressure waves assessed over 24 hours with an indwelling rectal probe that gives a NN test of approximately 18. Although attractive for proof-of-principle studies, 24-hour intubation is too demanding on subject and investigator to be practical for large clinical studies.
The barostat can be used to assess motility and also tone and compliance. The performance characteristics of colon in tone and motility indices have been recently reported. The intersubject CoV was 22.8% for colonic compliance, 30.8% for fasting tone, and 35.9% for tone 30 minutes postprandially. This finding gave a NN test of 28, 25, and 28, respectively.
Wireless motility-pH capsule
Compared with manometry or a barostat study requiring intubation, this wireless pH, pressure and temperature sensitive capsule has obvious appeal. At 28.8 mm long by 11.7 mm in diameter, it is somewhat larger than a normal tablet but still readily swallowed by most patients. There is none of the pharyngeal discomfort associated with prolonged manometry and the patients are freely mobile. The temperature, pressure, and pH profile enable it to be tracked through the intestine with the sharp rise in pH that occurs on passing from the stomach to the duodenum and the sharp fall in temperature that occurs when the capsule is expelled readily identifying gastric, small bowel, and colonic transit. The rate of transit correlates well with the standard radio-opaque markers, although both show wide variability. The pressure tracings can also be used to derive a motility index based on the area under the curve of the pressure versus time ( Fig. 2 ) however, the clinical utility of this data has not been established. However, the intersubject CoV is high: 88% in constipated IBS and 127% in healthy volunteers. With these values, the NN test to show a 25% change in motility using a parallel group design would be a prohibitive 195 subjects per group.
Related posts:
Inflammation and Microflora
Therapies Aimed at the Gut Microbiota and Inflammation: Antibiotics, Prebiotics, Probiotics, Synbiotics, Anti-inflammatory Therapies
Centrally Acting Therapies for Irritable Bowel Syndrome
The Role of Genetics in IBS
Inflammation and Microflora
Emerging Pharmacological Therapies for the Irritable Bowel Syndrome
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
