Gastrointestinal Motility Assays
Our state-of-the-art organ bath model is designed to investigate the impact of test compounds on gastrointestinal (GI) motility. These studies are essential for understanding how drugs can therapeutically affect GI motility, addressing conditions such as diarrhea, constipation, gastroparesis, and disorders of gastrointestinal sphincters or the gallbladder. Additionally, our assays can be used to assess the safety profile of new compounds. By utilizing full-thickness circular or longitudinal muscle strips from the gastrointestinal tract, we provide precise and reliable data on the effects of your test article, facilitating the development of effective and safe GI therapies.
The gastrointestinal tract is a highly complex organ with discrete motor control of various regions, each of which might be influenced by drug activity. Intestinal motility can be influenced by myogenic and neural mechanisms, both centrally and locally. The GI tract is often considered to have a “mini-brain”- the enteric nervous system- due to the density and complexity of its innervation. The myenteric plexus, which lies between the inner circular and outer longitudinal smooth muscle, provides motor innervation to both smooth muscle layers, with parasympathetic and sympathetic inputs. A further muscle layer, less often studied in vitro, is the muscularis mucosa. This lies within the mucosa and is innervated via the submucous plexus. In vitro/ex vivo investigations in isolated fresh tissues from the GI tract are possible along most of its length1.
At REPROCELL, we have conducted studies in a wide range of tissues for both efficacy and safety2 assessment. Examples of isolated tissues from the gastrointestinal tract and its accessory organs, which can be studied ex vivo, as shown.
Why is it important to study fresh tissues rather than cells?
Studying intact tissues rather than isolated cells is crucial because gastrointestinal smooth muscle functions as an integrated network. Using tissues allows us to examine both excitatory and inhibitory enteric motor neurons. We measure contractile activity with force transducers and stimulate neurons electrically to observe their responses. This method activates cholinergic and non-cholinergic excitatory neurons, as well as non-adrenergic inhibitory neurons. By pharmacologically blocking excitatory neurons, we can reveal inhibitory neuronal activity and study how test drugs influence the strength of neuronally-evoked contractions.
These smooth muscle contraction studies are complemented by Ussing chamber experiments, which provide valuable insights into the behavior of isolated mucosa. This includes aspects like fluid secretion3, ion channel function, and drug absorption or metabolism.
Investigations in ex vivo gastrointestinal tract have proven valuable in the development of many prokinetic or anti-diarrhoeal medications.
The functions of 5-hydroxytryptamine receptors and the development of 5-HT4 agonists, such as prucalopride4 for the treatment of chronic constipation, involved studies in various animal tissues6, before being investigated in human tissues. Studies in human tissues, such as coronary arteries, were also key to demonstrating the selective affinity of prucalopride for 5-HT4 receptors over other 5-HT receptors, avoiding the risk of cardiovascular side effects5.
The structure and function of the gastrointestinal tract vary significantly across species, making it crucial to compare in vitro data from multiple species to ensure its relevance and applicability to humans.
We will be pleased to support translational studies across preclinical species; please contact REPROCELL for further information.
Diagram of the organ bath model we use to measure Gastrointestinal motility.
References
- From the organ bath to the whole person: a review of a human colonic motility. Wattchow et al. ANZ Journal of Surgery, 94, 3 (2023).
- Gastrointestinal Safety Pharmacology in Drug Discovery and Development. Al-Saffar et al. Handbook of experimental pharmacology, 229 (2015).
- Linaclotide activates guanylate cyclase-C/cGMP/protein kinase-II-dependent trafficking of CFTR in the intestine. Ahsan et al. Physiological Reports, 5, 11 (2023).
- Prucalopride for constipation. Camilleri M, Deiteren A. Drug Evaluations, 11, 3 (2010).
- Nonclinical Cardiovascular Studies of Prucalopride, a Highly Selective 5-Hydroxytryptamine 4 Receptor Agonist. Conlon et al. Journal of Pharmacology and Experimental Therapeutics, 390, 1, (2017).
- Functions of peripheral 5-hydroxytryptamine receptors, especially 5-hydroxytryptamine4 receptor, in gastrointestinal motility. Taniyama et al. Journal of Gastroenterology. 35, 8 (2000).
