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The Role of GABA in Exacerbating Ulcerative Colitis
Ulcerative colitis (UC) and Crohn’s disease (CD) belong to a group of chronic and relapsing inflammatory bowel diseases (IBD) characterized by gastrointestinal (GI) symptoms (i.e. rectal bleeding, diarrhea and abdominal pain), fever and fatigue (Ma, et al., 2018). While both diseases share similar features, UC extends only from the rectum into the colon, affects only the colonic mucosa, and manifests as incessant areas of inflammation and ulceration, with no sections of normal tissue (Yadav, et al., 2016). A recent study by Benchimol, et al., (2018) showed that Canada has among the highest prevalence of IBD worldwide, with rates of Canadians with IBD expected to rise to 400,000 by 2030 (Benchimol, et al., 2018). With health care costs estimated at $2.6 billion CAD in 2018, IBD places a high burden on both the Canadian health care system and the economy (Benchimol, et al., 2018). The ongoing and debilitating GI symptoms of UC have a multifaceted impact on quality of life, and challenges related to the financial burden of medications and inequitable access to health care services remain an issue (Benchimol, et al., 2018). Treatment involves continuous pharmacotherapy, using aminosalicylates, corticosteroids and immunosuppressive drugs, with up to 80% of patients requiring surgical treatment (Yadav, et al., 2016; Rogler, Biedermann, & Scharl, 2018). Due to its tremendous impact on the individual and society, a large body of research is dedicated to the efforts of understanding the pathogenesis of UC. A recent study by Ma et al. (2018) reveals an unprecedented finding related to the pro-inflammatory effects of gamma-aminobutyric acid (GABA) on the pathogenesis of UC, suggesting new ways of combating the disease.
Although the exact cause of UC is unknown, a complex pathogenesis involving genetic and environmental factors, intestinal mucus barrier impairment, and a dysregulated mucosal inflammatory immune response to abnormal intestinal microbiota are implicated (Lee, Kwon & Cho, 2018; Yadav, et al., 2016). To date, over 160 IBD susceptibility loci have been found, of which 110 are shared between UC and CD (Cleynen, et al., 2016). Many of the disease variants discovered are also grouped in pathways that are relevant for the innate (e.g., NOD2) and adaptive (e.g., HLA) immune system, supporting the notion that UC is an autoimmune disease with an aberrant immune-mediated response against commensal bacterial in the GI tract (Lee, Kwon, & Cho, 2018; Cleymen, et al., 2016). As a result of genetic and environmental factors (i.e. diet, smoking, and geographical areas), an imbalanced and impaired microbiota in the GI tract develops, resulting in neutrophil dysfunction and decreased expression levels of mucin (Yadav, et al., 2016). This causes a weakened intestinal mucosal barrier that allows for bacterial permeation into the epithelial cell layer (Yadav, et al., 2016). Once inside, bacterial components bind to toll-like receptors and epithelial cells, leading to the activation of macrophages within the lamina propria, which stimulates the secretion of pro-inflammatory cytokines, reactive oxygen species, nitric oxide, and leukotrienes (Yadav, et al., 2018). An exaggerated Th2 and Th17 dominated response is also activated, recruiting further immune cells and producing more pro-inflammatory cytokines that further damage the epithelium and causing inflammation (Yadav, et al., 2016; Nemeth, et al., 2016). Immunoglobulin (Ig) secretions have also been shown to play a role. Mucosal secretory IgA concentrations appear less in those with UC, decreasing the antibody’s protective proteolytic function, which contributes to epithelial damage and inflammation (Yadav, et al., 2016). Increased levels of IgG are also associated; however, both Ig mechanisms are complex and complete knowledge has yet to be determined (Yadav, et al., 2016).
As extensive research continues to determine the etiology of UC, a study by Ma, et al. (2018) on colitis-induced mice provides new data that supports a pro-inflammatory function of the GABAergic system in pathogenesis of UC. GABA is an inhibitory neurotransmitter in the central nervous system that is also present in various peripheral tissues, such as the GI tract and immune cells (Ma, et al., 2018). It has been shown to function as a neuromediator in the enteric nervous system, as well as providing anti-inflammatory responses and protection against autoimmune diseases by inhibiting T-cell activation (Aggarwal, Ahuja, & Pauol, 2017; Ma, et al., 2018). In contrast to previous studies that support the anti-inflammatory effects of GABA, the study by Ma, et al. (2018) unexpectedly discovered a pro-inflammatory role of GABA in UC conditions. Inflammation is known to cause many chronic conditions, however, also has a protective function by initiating the primary immune response, eliminating foreign organisms and regenerating injured tissues (Ma, et al., 2018). In normal colons, inflammation triggers the production of pro-inflammatory cytokines (i.e., TNFα, IL-4, and IL- 13) that promote mucin gene expression, eliminate bacteria, and inhibit tissue damage (Ma, et al., 2018). In those with colitic colons, however, GABA was shown to suppress pro-inflammatory cytokines and increase anti-inflammatory cytokine expression, inhibiting the protective effects of inflammation, and causing an ineffective elimination of bacteria and subsequent colonic tissue damage (Ma, et al., 2018). Specifically, the study showed an up-regulation in GABAergic signalling that revealed more GABA production and GABAA receptor expression within the colon mucosa of colitis-induced mice (Ma, et al., 2018). Further results of the study also showed that GABA inhibited colonic mucosal epithelium proliferation and fostered its apoptosis (Ma, et al., 2018). As a result, decreased production of goblet cells and a disruption of intestinal barrier integrity were induced, increasing bacterial permeation, and enhancing immune and inflammatory damages to the colonic mucosa (Ma, et al., 2018).
The results from the study by Ma, et al., (2018) suggest an opposing insight to the well-characterized function of GABA in inhibiting inflammation and improving autoimmune diseases. This new finding can have a clinically significant impact on not only in the treatment of UC, but also suggests caution in administering widely used medications containing GABA receptor agonists (i.e., benzodiazepines, propofol and barbituates) in those with UC (Ma, et al., 2018)
- Aggarwal, S., Ahuja, V., & Paul, J. (2017). Attenuated GABAergic signaling in intestinal epithelium contributes to pathogenesis of ulcerative colitis. Digestive Diseases and Sciences, 62(10), 2768-2779. doi:10.1007/s10620-017-4662-3
- Benchimol, E. I., Bernstein, C. N., Bitton, A., Murthy, S. K., Nguyen, G. C., Lee, K., . . . Kaplan, G. G. (2018). The impact of inflammatory bowel disease in Canada 2018: A scientific report from the Canadian gastro-intestinal epidemiology consortium to crohn’s and colitis Canada. Journal of the Canadian Association of Gastroenterology, doi:10.1093/jcag/gwy052
- Lee, S. H., Kwon, J. e., & Cho, M. (2018). Immunological pathogenesis of inflammatory bowel disease. Intestinal Research, 16(1), 26. doi:10.5217/ir.2018.16.1.26
- Ma, X., Sun, Q., Sun, X., Chen, D., Wei, C., Yu, X., . . . Li, J. (2018). Activation of GABAA receptors in colon epithelium exacerbates acute colitis. Frontiers in Immunology, 9 doi:10.3389/fimmu.2018.00987
- Nemeth, Z. H., Bogdanovski, D. A., Barratt-Stopper, P., Paglinco, S. R., Antonioli, L., & Rolandelli, R. H. (2017). Crohn’s disease and ulcerative colitis show unique cytokine profiles. Cureus, 9(4), e1177.
- Rogler, G., Biedermann, L., & Scharl, M. (2018). New insights into the pathophysiology of inflammatory bowel disease: Microbiota, epigenetics and common signalling pathways. Swiss Medical Weekly, 148(1112), w14599. doi:10.4414/smw.2018.14599
- Yadav, V., Varum, F., Bravo, R., Furrer, E., Bojic, D., & Basit, A. W. (2016). Inflammatory bowel disease: Exploring gut pathophysiology for novel therapeutic targets. Translational Research, 176, 38-68. doi:10.1016/j.trsl.2016.04.009
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