Anti‐Inflammatory Effect of Clostridium butyricum‐Derived Extracellular Vesicles in Ulcerative Colitis: Impact on Host microRNAs Expressions and Gut Microbiome Profiles

Abstract

Score: Probiotics extracellular vesicles (EVs) have shown potential as EV-based nanomaterials therapy for the treatment of inflammatory bowel disease (IBD). Although probiotic Clostridium butyricum has been reported to be protective in various models of intestinal inflammation, the therapeutic effects of C. butyricum-derived extracellular vesicles (CbEVs) in IBD remain to be demonstrated. Methods and results: In this study, multi-omics sequencing is combined with an in vitro model of lipopolysaccharide-induced RAW264.7 cells and an in vivo mouse model of dextran sodium sulfate-induced colitis to explore the regulatory impact and mechanism of CbEVs in ulcerative colitis. Through small RNA sequencing, the study finds that microRNA is involved in the alleviation of colonic inflammation under CbEVs treatment. Mechanistically, CbEVs restore miR-199a-3p expression, interacting with map3k4, and thereby suppress proinflammatory MAPK and NF-𝜿B signaling. Additionally, metagenomic sequencing demonstrate that CbEVs alleviate bacterial dysbiosis in colitis mice and significantly reduces the abundance of the bacterial pathogens Escherichia coli and Shigella flexneri. Furthermore, CbEVs regulate the microbial tryptophan metabolites, which further improve intestinal barrier integrity and inhibit the inflammatory response in colitis mice. Conclusion: C. butyricum-derived extracellular vesicles can be a novel agent for the treatment of colitis and miR-199a-3p can be a potential target for IBD treatment.

Bacterial membrane vesicles in the pathogenesis and treatment of inflammatory bowel disease

“… 159 Cb -MVs restored the expression miR-199a-3p, which targets map3k4, thereby suppressing proinflammatory mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, ultimately contributing to Cb -MVs mediated anti-inflammatory effect. 154 Pretreatment with Akk -derived MVs in vitro mitigated the production of the proinflammatory cytokine IL-6 from colonic epithelial cells upon stimulation by pathogenic E. coli MVs. 150 Administration of MVs derived from Ec N to DSS-treated mice significantly reduced levels of proinflammatory cytokines IL-1β, TNF-α, and IL-17 in DSS-treated mice.…”

“…Several studies have shown that miRNAs are significantly altered in colitis, and interaction of MVs with some of these miRNAs can either promote or reverse colitis in mice via different mechanisms. For instance, Cb -MVs restored miR-199a-3p expression, 154 treatment of MVs isolated from feces of colitis mice with miR-200b-3p rescued colitis in mice, 167 Fn -MVs facilitated downregulation of miR-574-5p expression exacerbating colitis. 134 These studies reveal that miRNAs could serve as potential targets for IBD diagnosis, progression, and therapy.…”

“…The downregulation or upregulation of certain miRNAs in the presence of MVs tends to monitor not only the progression of IBD but also the alleviation of inflammation. For instance, the downregulation of miR-574-5p expression by Fn -MVs 134 and restoration of miR-199a-3p expression by Cb -MVs 154 demonstrate that miRNAs are intricately associated with MV exposure in IBD cases. With this knowledge, some specific miRNAs could serve as both diagnostic and potential targets for IBD treatment.…”

“… 167 Regulation of microbial tryptophan metabolites by Cb -MVs enhanced intestinal barrier integrity and reduced inflammatory activities in colitis mice. 154 MVs derived from Akkermansia municiphila , Akk maintain the integrity of the intestinal barrier by the stimulation of the expressions of tight junction molecules, ZO-1 and occludin, as well as mucus in the intestinal lumen of the colon by entering the intestinal epithelial cells. 29 MVs from F .…”

“… 157 Cb -MVs also attenuated colitis in mice and modulated the gut microbiota by significantly reducing levels of pathogenic bacteria, including Escherichia / Shigella , and promoting a relative abundance of butyrate-producing Clostridium sensu stricto -1 and Butyricicoccus . 124 , 154 Another study reported that MVs from normal feces of mice effectively reversed the composition of the intestinal microbiota, restored the intestinal barrier, and rescued colitis. Remarkably, MVs from fecal samples of colitis mice had similar effects after treatment with miR-200b-3pp.…”