For this new blog, Laurent DIOP, Chief Scientific Officer at ANS Biotech, deals with the topic Irritable bowel syndrome (IBS).
Prior to join ANS Biotech, Laurent contributed to drug and probiotic development projects in digestive well-being and visceral pain among various pharmaceutical and industrial companies. He led R&D programs designed to evaluate the efficacy of new compounds for the treatment of IBS and IBD. Since 2006, and based on his extensive experience, Laurent is the expert of visceral pain at ANS Biotech.
Irritable Bowel Syndrome (IBS) is a common chronic functional bowel disease with prevalence rates from 5 to 22%. IBS is defined by the coexistence of abdominal pain or discomfort and alteration in bowel habits without obvious organic abnormalities.
Pharmacological treatment is recommended only if patients fail to respond to lifestyle and dietary changes.
The prescription drug market for IBS is underserved. There are only six products currently approved and indicated for IBS in the 7 Major Markets and the need for new therapies is real.
Translational pain research, based on preclinical models with a well-understood mechanism, can help to develop new drugs.
IBS: Main characteristics
The global prevalence of IBS, predominant in women (2/3), is 11.2%, with a wide range in prevalence from 1.1% to 45.0% depending on the country and the criteria used to define IBS. IBS is defined by the coexistence of abdominal pain or discomfort and an alteration in bowel habit. The cause of IBS is unknown, though associated pathophysiology includes altered gastrointestinal motility and increased gut sensitivity.
There are many possible causes of symptoms in an irritable bowel, both biochemical and mechanical. The factors involved are food, flatulence, endocrine imbalance, changes in the bacterial flora, malabsorption, postoperative changes and psychosomatic effects. All these factors may, separately or in combination, cause a motor reaction in the bowels. It is a combination of dyskinesia with abdominal pressure or even pain, and hyperkinesia with intestinal contents evacuation and relief of abdominal discomfort. Once symptoms have appeared, they tend to persist or recur for many years. Although 30% of patients report resolution of symptoms within one year, nearly 70% report that symptoms recur within five years. More studies have focused on the visceral sensitivity of IBS patients. It has been found that balloon distension of the sigmoid colon and rectum causes pain at lower volumes in patients with IBS than in healthy subjects. IBS represents a significant therapeutic challenge; currently available therapies provide symptomatic relief at best, and none have been shown to alter the natural history of the disorder.
Visceral innervation: a particular case
Visceral pain from gastrointestinal (GI) organs differs from somatic pain in terms of perception of pain and neurological mechanisms. It is poorly localized and diffuse and often associated with motor and autonomic reflexes such as vomiting, nausea and lower back muscle tension. It is often felt at distant site. It is due to the absence of specific visceral pathways and the low proportion of visceral afferent nerve fibers. The projection of visceral pain to cutaneous sites corresponds to the spinal convergence with visceral input triggering a somatic input through a viscerosensory reflex.
The viscera receive a complex innervation from vagal and spinal afferent nerves. Most viscera are localized in midline structures and have bilateral sensory innervation. In the spinal cord, visceral afferents terminate in superficial laminae of spinal dorsal cord where the somatic nociceptive afferents project. The GI tract has an intrinsic network regulating secretion, motility and blood flow. These enteric neurons interact with extrinsic afferent innervation of the gut.
Several preclinical models have been developed for the understanding of the mechanisms from various origins that drive visceral pain and, subsequently, for the development of new analgesics.
Chemical-induced visceral pain
Algogenic substances injected intraperitoneally have been the most widely used as noxious visceral pain. The writhing test is largely used in the screening test of drugs for novel analgesic or anti-inflammatory drugs. The intraperitoneal administration of algogenic chemicals produces a visceromotor response. It consists of classical visceromotor stretching, writhing or cramps. Algogenic chemicals are acetic acid, phenylquinone, hypertonic saline, bradykinin, CGRP… These substances induce an acute peritoneal inflammation. They produce a visceral pain but also somatic pain (peritoneum). Both visceral and somatic pain are strong motor reflexes which induce muscle spasm and hyperalgesia of somatic pain. These writhing models permit the screening of the new candidate drugs to treat visceral pain.
TNBS-induced visceral hypersensitivity
Balloon distension of hollow organs has extensively been used to evaluate the visceral sensitivity in humans and animals. Alterations of visceral sensory threshold have been shown in the majority of IBS patients. This visceral hypersensitivity seems to be the consequence of previous sensitization of visceral afferent pathways localized at peripheral and/or central levels. In animals, inflammation of the colon can change colonic threshold to distension, indicating a visceral hypersensitivity. This colonic allodynia may be due to the facilitation of spinal transmission of nociceptive messages resulting from primary activation of nociceptors during the development of inflammation. It has been shown that a greater number of pelvic afferent fibers are recruited in TNBS model and that their basal activity is increased leading to visceral hypersensitivity. Research carried out on these experimental models has shown that the role of primary sensory afferents in the transmission of nociceptive messages is complex . It seems that these afferents are not simple pathways for conducting peripheral messages toward the central nervous structures. This complexity resides partly in the diversity of the mediators expressed by the primary afferents, and also in the existence of bidirectional relationships between the primary sensory afferents and the immune system.
It is reasonable to ask how relevant these findings might be to human pathology. Certainly, the visceral hypersensitivity seen in this rat model parallels that found in conditions of IBS in humans, the principal symptoms of which are pain and transit disturbances. This clinical condition has unknown etiology. The post-inflammatory TNBS model has shown reliability and reproducibility across multiple laboratories with high construct validity and translational relevance is robust, and the clinical reference drugs used in IBS patients are active in this model.
Stress-induced visceral hypersensitivity
In IBS patients, the important role of stress in the physiopathology and clinical symptoms have clearly been demonstrated. Indeed, IBS patients also report a history of early child adversity, sexual abuse, threatening life events. Visceral hypersensitivity can be also induced by a stressor as reported in several studies using restraint or perinatal stress in rats. In rats, acute restraint is considered as a mild and non-ulcerogenic stressor activating the HPA axis and resulting in an increased plasma adrenocorticotropin hormone and corticosterone levels.
Several stress-induced hypersensitivity have been developed to explore the influence of acute and chronic stress on visceral pain. In these models, including restraint stress (physical stress) and water avoidance (psychological stress) induce visceral hypersensitivity. Animals models of early life stress have also been developed such as maternal separation. Interestingly, in these stress models, several studies have been documented the sex-related differences. The female prevalence of IBS patients was observed: few pharmacological studies have evaluated the effects of new analgesic compounds in female animals. The stress models are more difficult to implement and cannot be used as screening tools. They have the advantages to investigate the central influence on visceral hypersensitivity.
In conclusion, the need of new analgesic compounds is crucial to treat the symptoms (in particular visceral pain) of patients with IBS. The better understanding of physiological mechanisms in visceral hypersensitivity could help to discover new drugs. There are no one translational animal model for IBS but ANS Biotech has the availability of several visceral pain models for the development of novel approaches to treat IBS.
Advantages to colaborate with ANS Biotech
“ANS Biotech offers tailored solutions for the management of your research projects in visceral pain.
Key features of our models are:
- High translatability to the clinic: pathophysiology and pain evaluation
- Most commonly used model for pain IBS
- Robust reproducibility
- Low inter-individual variability”