Pavia Ann Muringathuparambil

Introduction: IBS is a gastrointestinal disease triggered by many factors. Symptoms vary greatly between patients, but abdominal pain and bloating are most common. While a specific cause has yet to be identified, many factors including gene mutations^1,2, gut microbiome imbalances³, and mast cell hyperplasia⁴ are being investigated as possible causes. Studies done with the CACNA1H and Scn5a genes show mutations in these genes result in ion flow changes which cause overexcitation of primary afferent neurons and disruption of the action potentials respectively^1,2. A study done on the gut microbiome showed IBS patients had increased levels of P. aeruginosa which may lead to alterations in sensitivity³. Studies done on the effect of mast cells show increased numbers in IBS patients and proximity to nociceptors. Methods: To assess CACNA1H gene function, KO mice were created. KO mice treated with dextran sodium sulfate (DSS) to induce IBS symptoms showed no sensitivity whereas WT mice showed sensitivity to the DSS¹. To assess Scn5a gene function, it knocked down and results showed a decrease in slow wave peak amplitude when compared with WT mice². Gut microbiome differences between healthy and IBS patients were determined via DGGE and PCR analysis of duodenal and fecal samples³. Mast cell expression was determined via immunofluorescence staining of intestinal biopsies and showed increased expression in the gut of IBS patients⁵. Results: The results of the study on CACNA1H KO mice showed that Ca2+ channels play a role in pain experienced by IBS patients. Similarly, decreases in slow wave peak amplitude in Scn5a gene knocked down mice show the disruption to normal action potentials which may result in disrupted gut motility. Increased P. aeruginosa found in IBS patients is known to inhibit protease activated receptors (PAR2) in the lungs, but its effect in the gut remains unknown³. However, if it does have a similar inhibitory effect in the gut, this would be interesting considering mast cell activation has an excitatory effect on PAR2 receptors in the gut⁶. Immunofluorescence staining of the biopsies showed increases in mast cells in the terminal ileum and proximal colon of IBS patients when compared to healthy individuals but no difference in expression in the distal colon⁵. Conclusion: The results of the studies discussed, further support IBS being a multifactorial disease. As such, the effects of P. aeruginosa and mast cells on PAR2 receptors should be further studied to better understand how these different factors are related.

1.  Scanzi, J., Accarie, A., Muller, E., Pereira, B., Aissouni, Y., Goutte, M., … and Dapoigny, M. (2016). Colonic overexpression of the T-type calcium channel Cav3.2 in a mouse model of visceral hypersensitivity and in irritable bowel syndrome patients. Neurogastroenterology & Motility, 28(11), 1632–1640.
2. Beyder, A., Gibbons, S. J., Mazzone, A., Strege, P. R., Saravanaperumal, S. A., Sha, L., … and Farrugia, G. (2016). Expression and function of the Scn5a-encoded voltage-gated sodium channel Na_v5 in the rat jejunum. Neurogastroenterology & Motility, 28(1), 64–73.
3. Kerckhoffs, Angèle P. M., et al. “Molecular Analysis of Faecal and Duodenal Samples Reveals Significantly Higher Prevalence and Numbers of Pseudomonas Aeruginosa in Irritable Bowel Syndrome.” Journal of Medical Microbiology, vol. 60, no. 2, 2011, pp. 236–245., doi:10.1099/jmm.0.022848-0.
4. Barbara, G., & Stanghellini, V. (2004). Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. doi: https://doi.org/10.1053/j.gastro.2003.11.055
5. Song, Jun, et al. “Mast Cell-Dependent Mesenteric Afferent Activation by Mucosal Supernatant From Different Bowel Segments of Guinea Pigs With Post-Infectious Irritable Bowel Syndrome.” Journal of Neurogastroenterology and Motility, vol. 21, no. 2, 2015, pp. 236–246., doi:10.5056/jnm14095.
6. Aich, Anupam, et al. “Mast Cell-Mediated Mechanisms of Nociception.” International Journal of Molecular Sciences, vol. 16, no. 12, 2015, pp. 29069–29092., doi:10.3390/ijms161226151