A189 ELUCIDATING THE MECHANISTIC ROLE OF GLP-1R IN THE INFLAMMATORY RESPONSE OF MACROPHAGES AND B CELLS TO DIETARY FIBRES. (4th March 2021)

• Record Type: Journal Article
• Authors: Hanstock, S; Rieger, A; Dickner, R; Jerasi, J; Armstrong, H; Wine, E
• Is Part Of: Journal of the Canadian Association of Gastroenterology. Volume 4(2021)Supplement 1
• Page Start: 205
• Page End: 206
• Publication Date: 2021-03-04
• Subjects: Gastroenterology -- Periodicals; 616.33005
• DOI: 10.1093/jcag/gwab002.187
• Languages: English
• ISSNs: 2515-2084

Abstract

Abstract: Background: Both diet and the microbiome have been implicated in the pathogenesis of inflammatory bowel diseases (IBD). Fibre is not digested; it is fermented by microbes in the large bowel. High fibre intake is related to lower risk for the development of IBD, and a high fibre diet is usually recommended for individuals with IBD. However, work in our lab suggests that select dietary fibres may be pro-inflammatory in a pediatric IBD cohort. Importantly, large bowel dysbiosis in IBD could limit the fermentation of dietary fibres, leading to reduced production of beneficial microbiome metabolites as well as an accumulation of intact fibre in the large bowel. These intact fibres may then interact with immune cells residing in the large bowel, through specific receptors, and perpetuate the inflammatory state seen in IBD. Aims: Based on preliminary findings, we hypothesize that the dietary fibre oligofructose acts through GLP-1R on macrophages and B-cells to regulate the inflammatory environment. We expect to find changes in the expression of cytokines and chemokines, and their receptors. Methods: Changes in immune cell secretions (ELISA) and the expression of selected inflammatory markers (RT-qPCR) were measured to determine potential pathways involved in response to dietary fibres in vitro . Knockdown of proteins of interest (siRNA) was performed to validate the involvement of these pathways in the inflammatory response to dietary fibres. Cells were treated with oligofructose, oligofructose pre-fermented by bacteria, or no fibre. The involvement of the fibre receptor, GLP-1R, was investigated to understand its connection to pathways identified. Results: Qiagen RT 2 profiler array (human inflammatory cytokines and receptors) and cytokine secretion (ELISA) indicated that in response to oligofructose macrophages have a predominantly pro-inflammatory response while B cells have an anti-inflammatory response. Presence of GLP-1R in large bowel and terminal ileum biopsies collected during endoscopy was higher in IBD (Crohn disease n=7; Ulcerative colitis n=7) than non-IBD patients (n=7), and expression was confirmed on both B-cells and macrophages. Knockdown of GLP-1R (siRNA) significantly reduced the pro-inflammatory response (IL-1β ELISA) with oligofructose application in THP-1 macrophage cells Conclusions: Improving our understanding of the mechanistic link between dietary fibres and immune response will aid us in developing a model for the interactions of oligofructose with the GLP-1R in B cells and macrophages. Findings from this study may be able to inform dietary interventions, prebiotic/probiotic administration, and drug development for treatment of IBDs. Funding Agencies: CIHRWeston Foundation