Abstract
Many links between gut microbiota and disease development have been established in recent years, with particular bacterial strains emerging as potential therapeutics rather than causative agents. In this study we describe the immunostimulatory properties of Enterococcus gallinarum MRx0518, a candidate live biotherapeutic with proven anti-tumorigenic efficacy. Here we demonstrate that strain MRx0518 elicits a strong pro-inflammatory response in key components of the innate immune system but also in intestinal epithelial cells. Using a flagellin knock-out derivative and purified recombinant protein, MRx0518 flagellin was shown to be a TLR5 and NF-κB activator in reporter cells and an inducer of IL-8 production by HT29-MTX cells. E. gallinarum flagellin proteins display a high level of sequence diversity and the flagellin produced by MRx0518 was shown to be more potent than flagellin from E. gallinarum DSM100110. Collectively, these data infer that flagellin may play a role in the therapeutic properties of E. gallinarum MRx0518.
Highlights
Enterococcus gallinarum is a commensal Gram-positive species that sits within the Enterococcus casseliflavus clade of the Enterococcus 16 S rRNA phylogenic tree[1,2]
We have recently demonstrated that E. gallinarum MRx0518, a commensal strain that was isolated from a healthy human gut produces robust anti-tumorigenic effects after prophylactic oral dosing in murine models of breast, lung and renal carcinomas[12]
We assessed a panel of pro- and anti-inflammatory cytokines involved in innate immunity and recruitment and activation of adaptive immune cells (IL-8, TNFα, IL-6, IL-10, IL-12p70, IL-23 and IL-1β)
Summary
Enterococcus gallinarum is a commensal Gram-positive species that sits within the Enterococcus casseliflavus clade of the Enterococcus 16 S rRNA phylogenic tree[1,2]. TLR5 interacts with the extracellular monomeric form of bacterial flagellin of both Gram-negative and Gram-positive bacteria, leading to activation of the NF-κB signalling pathway via the adaptor protein MyD88 and the serine kinase IRAK20–22. This can lead to systemic immune responses, stimulating the production of pro-inflammatory mediators including TNF-α, IL-1β, IL-6, IL-8, IL-12 and IL-23. A study by Cai et al has shown that expression and activation of TLR5-associated pathways were elevated in breast carcinomas[23] They demonstrated that flagellin activation of TLR5 in that context resulted in the local release of pro-inflammatory cytokines and anti-tumorigenic effects[23]
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