Controversies and limitations in irritable bowel syndrome studies (2007)

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by recurrent abdominal pain or discomfort associated with altered bowel movements. It affects 8%-22% of the population in Western countries and the prevalence of IBS prevalence is 5%-10% in most Asian communities.1-4 Although IBS is not a life-threatening disease, IBS patients often suffer significantly from the syndrome and have an impaired quality of life because of the chronic nature of the disease and its recurrence rate. IBS also has a significant socioeconomic impact. The pathophysiology underlying IBS remains elusive, however, more and more studies have emerged and the mechanism is expected to be disclosed soon. Nevertheless, IBS is a chronic disease caused by multiple factors, such as psychological factors, heredity, and infections, which have contributed to the uncertainty in establishing an appropriate animal model, detection of hypersensitivity, as well as clinical practice. This article discusses the controversies and limitations which exist in IBS studies, and hope that in so doing, IBS studies will become more standardized. Animal studies Animal models Currently, IBS animal models are classified into several types according to the underlying pathogenesis, as follows:5 psychological, inflammatory, neurocrine, secondary to colorectal distention, and secondary to early adverse life events. There is no question that these models provide approaches to explore the pathogenesis and provide improved therapy. However, the same animal model may result in different outcomes because of the lack of a uniform approach to experimental manipulation in IBS studies. For example, partial restraint stress is a widely used animal model of IBS caused by psychological factors. The experimental process is straightforward and involves wrapping the animal's fore shoulders, upper forelimbs, and thoracic trunk in a confining harness of paper tape to restrict movement. But, how many layers should the paper harness be? How much pressure should be exerted by the wrap? Does the animal need to be anaesthetized before restraining? Since there are no uniform standards, these small differences may significantly influence the establishment of a legitimate and valid model. Detective methods used in animal models Visceral hypersensitivity to noxious, as well as physiologic stimuli, is considered to be a clinical hallmark of IBS.6 Hence, many researchers use the alteration of visceral hypersensitivity as an index to validate a potential model or the effect of intervention and treatment. Usually, colorectal hypersensitivity in animals is expressed by the visceral motor reflex, which is detected by electromyography (EMG) or observed by the abdominal withdrawal reflex (AWR). Another index for hypersensitivity is the cardio reflex, i.e., detection of a change in the carotid artery pressure when the animal is anaesthetized. Since IBS is thought to be correlated with stress, psychology, and the environment, there is a legitimate concern that study methodology may have an influence on the experimental animals. About the EMG As an objective index for the detection of visceral hypersensitivity, EMG is used widely in IBS animal models.7-9 The method of the surgical procedure is as follows: 1) after the animal is anesthetized, the electrodes (Teflon-coated stainless steel wire) are sewn into the external oblique abdominal musculature for EMG recording; 2) the EMG electrodes are then subcutaneously guided to the dorsum of the neck and externalized for future access; 3) after resting for 5-7 days, the animals undergo an EMG. However, the potential influence of the complex surgery on functional IBS in animals is concerning. It has been reported that the subcutaneous implantation of a cotton thread (1 cm in length and 7 mg in weight) induces rapid formation of granulation tissue.10 It was found that the implantation of a cotton thread increased histidine decarboxylase activity in the tissue surrounding the implanted cotton thread, including the skin, the cutaneous muscle layer, the subcutaneous tissues, and the granulation tissue from 1 to 5 days after implantation. Histamine was produced rapidly in the growing granulation tissue,11,12 which was thought to be involved in central nervous system hypersensitivity. We know that the electrode is much larger than the cotton thread, and we presume that the granulation tissue elicited by the electrode is also much greater than that elicited by the cotton thread. The effect of implanting an electrode on the animal is unknown. Influence of limited devices In order to prevent damage to the balloon, the animals are usually placed in limited devices, such as Bollman restrainers for mice and plastic tunnels (6 cm in diameter and 25 cm length) for rats,13,14 in which the animals can not move, escape, or turn around. The animals are typically acclimated to this procedure 3-10 days before colorectal distension to minimize stress reactions during the experiments. Colorectal distension is then performed with different pressures. The process is conducted by a 10-second distension followed by a 5-minute resting period. Each level of distension (10, 30, 40, and 60 mmHg) is repeated 3 times. It takes more than 1 hour to complete the colorectal distension in one animal. We have learned that acute partial restraint stress can significantly enhance the abdominal response to rectal distension as compared with sham partial restraint stress for distension. Moreover, chronic partial restraint stress can also induce a hyperalgesic response at the highest pressure. Both acute and chronic partial restraint stress can increase substance P-induced histamine release in vitro.14 The animals usually exhibit increased defecation rates when in the limited devices. Even though all the experimental animals are under the same experimental conditions, such as the limited devices, we are curious about what effect the limited device will have over functional intestinal disease? Score of the AWR The AWR is an involuntary motor reflex similar to the visceromotor reflex, but has the advantage that it requires no additional surgery to implant recording electrodes and wires in the abdominal muscles. However, the AWR requires observation of contractions in the abdominal wall musculature and this semi-quantitative score is subjective, despite the double-blind methods used in most studies. Clinical studies Questions also exit in clinical studies and practice. It is well known that IBS is diagnosed by the identification of typical symptoms, a normal physical examination, and the exclusion of alarming features. Though the development and refinement of symptom-based criteria of IBS has greatly facilitated the diagnosis of this condition, some physicians lack knowledge about IBS. Charapata et al15 studied 166 physicians and found that the attending physician's knowledge of the Rome criteria was less than 30% among non-gastroenterologists. Only 7% could select the correct positive predictive value of the Rome criteria for IBS and only 20 of 76 attending physicians had used the Rome criteria in practice. Although the study has some limitations, it does illustrate the problems which exist in clinical practice with respect to IBS. Similarly, a study in Taiwan16 showed that more than 90% of registered nurses in tertiary care facilities had very limited knowledge about IBS, while almost one-half of them could not explain IBS clearly to their patients. Agreus17 also found the knowledge of IBS criteria was poor among 136 general practitioners. He suggested that the Rome definition and the Manning criteria were too complicated for use in the busy clinical workday. Moreover, many of the patients presented with poly-symptoms, which made the diagnosis of IBS difficult and many physicians drew their diagnosis based on their clinical impression, rather than applying definitions developed for the purposes of research.18 It is also difficult for the patients to accurately recall details regarding defecation and abdominal pain during the past 6 months. However, animal and clinical studies should still continue, despite the unanswered questions, controversies, and limitations! In our opinion, the following approach may prove useful. Standardize the animal model A specialized team is needed to verify the animal model, standardize the performance details, and monitor the process. Then, the details and standards, as well as the quality-control objectives of the experiment, are released to a magazine or on a public website so that many can use the uniform animal model for further studies. This may provide a comparison in different studies with the same models, which will benefit the evidence-based studies, and also have an important role in making plentiful use of experimental resources worldwide. Make the method more objective and scientific Regarding the question of the invasive detection of visceral hypersensitivity in the subjective assessment of the AWR score, with the development of modern techniques, the collection of images is easy. Wang et al19 used a digital video film to record the facial motor musculature, such as wrinkling the forehead, closing the eyes, and wiggling the nose, and entered the data into a computer so as to analyze the movement of the related muscles with Orisis software. Videomimicography could also be used as an objective approach to evaluate the distance between the lifted animal abdomen and the surface of the platform. It seems that no technical difficulties in data collection occurred; however, the key is to define a standard line and angle when recording. In order to avoid the potential stress of the restraint device, Welting et al20 developed a model using implanted radio telemetry for remote measurement of the visceromotor response to colorectal distension and showed that radio telemetry was a reliable and well-tolerated new tool for evaluating visceral sensitivity in rats. Popularize and modernize the clinical practice More and more cultural patterns have changed with the development of the web and clinical studies of IBS are not an exception. Bushnell et al21 transformed many IBS-related questionnaires into electronic data capture versions. They found that electronic data capture was easy and comparable to paper questionnaires in internal consistency and test-retest reliability, and had greater patient acceptability. Enck et al22 also placed a symptom scale for gastrointestinal symptoms on a genuine website and linked it to the website of the German IBS Patient Group, then asked the patients to report gastrointestinal symptoms. The patients who had finished the questionnaire would immediately receive an assessment of their health-related quality of life by a series of validated scales. The open internet questionnaire made the symptoms and quality of life assessment feasible and comparable to those from other sources of assessments. The internet makes it easy for physicians to diagnose IBS and assess the quality of life of their patients. We hope that a worldwide IBS patient group will be established with the internet for the use of physicians managing patients with IBS throughout the world. The latest information will be released on the internet, and it will be translated into other languages so that people can make full use of the resources and assure that IBS patients receive the best information. We hope that in the near future IBS studies and practice will become much easier and more validated with greater quality control and with the modern internet technology.