Exopolysaccharide from Bacillus subtilis Induces Anti-Inflammatory M2 Macrophages That Prevent T Cell–Mediated Disease

Abstract

Commensal bacteria contribute to immune homeostasis in the gastrointestinal tract; however, the underlying mechanisms for this are not well understood. A single dose of exopolysaccharide (EPS) from the probiotic spore-forming bacterium Bacillus subtilis protects mice from acute colitis induced by the enteric pathogen Citrobacter rodentium. Adoptive transfer of macrophage-rich peritoneal cells from EPS-treated mice confers protection from disease to recipient mice. In vivo, EPS induces development of anti-inflammatory M2 macrophages in a TLR4-dependent manner, and these cells inhibit T cell activation both in vitro and in C. rodentium-infected mice. In vitro, the M2 macrophages inhibit both CD4+ and CD8+ T cells, and the inhibition of CD4+ T cells is dependent on TGF-β, whereas inhibition of CD8+ T cells is dependent on both TGF-β and PD-L1. We suggest that administration of B. subtilis EPS can be utilized to broadly inhibit T cell activation and thus control T cell-mediated immune responses in numerous inflammatory diseases.

Probiotic Exopolysaccharide Protects against SystemicStaphylococcus aureusInfection, Inducing Dual-Functioning Macrophages That Restrict Bacterial Growth and Limit Inflammation

“…Attenuation of S. aureus bloodstream infection by B. subtilis-derived EPS. EPS prevents systemic inflammation by inducing M2 M⌽ that suppress T cell activation (21), and we hypothesized that EPS could also improve the outcome of systemic infection by S. aureus, where inflammation plays a role in pathogenesis (4,22). We administered EPS 1 day prior to and 1 day after systemic infection with an epidemic strain of S. aureus USA300 (LAC) and found that EPS-treated mice lost less weight than phosphatebuffered saline (PBS)-treated infected controls (Fig.…”

“…1B). Given that EPS limits inflammation in disease caused by infection with C. rodentium (20,21) and reduces weight loss early in systemic S. aureus infection, we assessed if the levels of serum proinflammatory chemokines and cytokines were decreased in EPS-treated mice. Indeed, these mice had lower levels of MCP-1 (CCL2), MIP-1␣ (CCL3), MIP-1␤ (CCL4), tumor necrosis factor (TNF), and gamma interferon (IFN-␥) than did PBS-treated mice at 1 dpi (Fig.…”

“…Further, we found that i.p. injection of EPS results in the induction of peritoneal M⌽ that display an M2 phenotype and inhibit T cell activation in vitro and in vivo (21), suggesting that EPS mediates its protection by inducing anti-inflammatory M2 M⌽. We hypothesized that this anti-inflammatory property of EPS could be used to limit inflammation during systemic S. aureus infection, preserving tissue integrity and thereby improving outcomes.…”

In vitroandin vivoanti‐inflammatory activity of a succinoglycan Riclin fromAgrobacteriumsp. ZCC3656

“…In the past decades, numerous studies have focused on the anti‐inflammatory properties of nonstarch polysaccharides from diverse sources of marine algae (Fernando et al ) and edible mushrooms (Muszyńska et al ). Some bacterial polysaccharides also have been reported for their anti‐inflammatory effects, such as polysaccharides from Bacillus subtilis (Paynich et al ), Paenibacillus jamilae (Zhong et al ) and Streptococcus thermophilus ASCC 1275 (Li and Shah ). The underlying mechanism of action of these polysaccharides is generally associated with the stimulation of host immune systems.…”

“…) and edible mushrooms(Muszy nska et al 2018). Some bacterial polysaccharides also have been reported for their anti-inflammatory effects, such as polysaccharides from Bacillus subtilis(Paynich et al 2017), Paenibacillus jamilae (ZhongTime after D-GalN/LPS (hThe effect of Riclin in a D-GalN/LPS-challenged mouse model. (a) The effect of Riclin on the survival rate of mice.…”