Abstract
The pro-inflammatory mediator receptor activator of nuclear factor-kappa B ligand (RANKL) plays a significant role in the development of rheumatoid arthritis; however, its role in inflammatory bowel disease is unknown. Genome-wide association meta-analysis for Crohn’s disease (CD) identified a variant near the TNFSF11 gene that encodes RANKL and CD risk allele increased expression of RANKL in specific cell lines. This study aims to elucidate if the RANKL inhibitor denosumab can reduce the severity of experimental colitis and modify the gut microbiota composition using murine dinitrobenzenesulfonic acid (DNBS)-experimental model of colitis mimicking CD. In colitic conditions, denosumab treatment significantly decreased the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α within the colonic mucosa. Moreover, colitis was accompanied by disruption of gut microbiota, and preventative treatment with denosumab modulated this disruption. Denosumab treatment also modified the alpha- and beta diversity of colonic mucosa and fecal microbiota. These results provide a rationale for considering denosumab as a future potential therapy in CD; however, more detailed experimental and clinical studies are warranted.
Highlights
Inflammatory bowel disease (IBD) consists of two major types of intestinal disorders, Crohn’s disease (CD) and ulcerative colitis (UC) that are characterized by chronic inflammation and ulceration in different segments of the gastrointestinal tract (Kelsen and Sullivan, 2017; Nemati and Teimourian, 2017)
Compared to ethanol treatment, dinitrobenzenesulfonic acid (DNBS)/Ethanol induced a colitis characterized by an increase of the Disease activity index (DAI) (p = 0.02), weight loss (p = 0.01), blood presence in the feces and a decrease of stool consistency (Figures 2A,B)
In non-colitic conditions (PBS 1%, Ethanol 30%, DNBS/phosphate-buffered saline (PBS)), and colitic conditions (DNBS/Ethanol), denosumab did not affect any of weight loss (Figure 2B), or stool consistency and presence of blood in the feces (Figure 2A)
Summary
Inflammatory bowel disease (IBD) consists of two major types of intestinal disorders, Crohn’s disease (CD) and ulcerative colitis (UC) that are characterized by chronic inflammation and ulceration in different segments of the gastrointestinal tract (Kelsen and Sullivan, 2017; Nemati and Teimourian, 2017). While no curative therapy is available for IBD, the current therapies aim to maintain remission via modulation of the immune system (e.g., Effects of Denosumab in DNBS Experimental Colitis corticosteroids), suppression of inflammatory cytokines (e.g., TNF-α blockers), and/or regulation of the gut microbiome (e.g., intestinal microbiota transplantation). These therapies have potential side effects (Sartor, 2004; De Souza and Fiocchi, 2016); and as such there is demand for safe and cost-effective therapeutic strategies for IBD. Despite the uncertainty in the etiology of IBD, the success of modulating immune responses and the gut microbiome suggests that both intestinal immune dysregulation and gut dysbiosis are involved in IBD pathogenesis (Kelsen and Sullivan, 2017; Lopetuso et al, 2017; Nemati and Teimourian, 2017; Rodriguez de Santiago et al, 2017; Rogler, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
