Notch Signaling Pathway Is Activated by Sulfate Reducing Bacteria

Abstract

Sulfate Reducing Bacteria (SRB), usually rare residents of the gut, are often found in increased numbers (called a SRB bloom) in inflammatory conditions such as Inflammatory Bowel Disease (IBD), pouchitis, and periodontitis. However, the underlying mechanisms of this association remain largely unknown. Notch signaling, a conserved cell-cell communication pathway, is usually involved in tissue development and differentiation. Dysregulated Notch signaling is observed in inflammatory conditions such as IBD. Lipolysaccharide and pathogens also activate Notch pathway in macrophages. In this study, we tested whether Desulfovibrio, the most dominant SRB genus in the gut, may activate Notch signaling. RAW 264.7 macrophages were infected with Desulfovibrio vulgaris (DSV) and analyzed for the expression of Notch signaling pathway-related proteins. We found that DSV induced protein expression of Notch1 receptor, Notch intracellular domain (NICD) and p21, a downstream Notch target, in a dose-and time-dependent manner. DSV also induced the expression of pro-IL1β, a precursor of IL-1β, and SOCS3, a regulator of cytokine signaling. The gamma secretase inhibitor DAPT or Notch siRNA dampened DSV-induced Notch-related protein expression as well the expression of pro-IL1β and SOCS3. Induction of Notch-related proteins by DSV was not affected by TLR4 -IN -C34(C34), a TLR4 receptor antagonist. Additionally, cell-free supernatant of DSV-infected macrophages induced NICD expression in uninfected macrophages. DSV also activated Notch pathway in the human epithelial cell line HCT116 and in mouse small intestine. Thus, our study uncovers a novel mechanism by which SRB interact with host cells by activating Notch signaling pathway. Our study lays a framework for examining whether the Notch pathway induced by SRB contributes to inflammation in conditions associated with SRB bloom and whether it can be targeted as a therapeutic approach to treat these conditions.

Causal associations between gut microbiota and adverse pregnancy outcomes: A two-sample Mendelian randomization study

“…This study also suggested that increased abundance of Deltaproteobacteria was causally related to a higher risk of PPH. Deltaproteobacteria is a common pathogenic bacterium, which initiates inflammation by activating the Notch signaling pathway and induces the expression of pro-inflammatory factors including pro-IL-1β and SOCS3 (Jin et al, 2016;Singh et al, 2021).…”

Intestinal Alkaline Phosphatase Prevents Sulfate Reducing Bacteria-Induced Increased Tight Junction Permeability by Inhibiting Snail Pathway

“…Our group previously showed that administering DSV into the gut of mice caused impaired memory ( Ritz et al., 2016 ) and slowed intestinal transit ( Ritz et al., 2017 ). Recently, we showed that DSV induced Notch signaling pathway which, in turn, upregulated precursors of proinflammatory cascade ( Singh et al., 2021 ). A recent report showed that a proinflammatory SRB Fusobacterium nucleatum induced increased intestinal permeability ( Liu et al., 2020 ) suggesting that SRB may contribute to disease development by disrupting barrier function.…”

“…While the pathological role of Desulfovibrio spp. has been studied mainly in the context of their effect on inflammatory pathways ( Weglarz et al., 2003 ; Kushkevych et al., 2019 ; Singh et al., 2021 ), whether these bacteria induce leaky gut is not known even though leaky gut is associated with several diseases related to DSV bloom ( Loubinoux et al., 2002 ). Snail is a transcription factor responsible for increased intestinal permeability ( Forsyth et al., 2011 ; Elamin et al., 2014 ; Liu et al., 2020 ) by negatively regulating TJ proteins such as occludin, claudins, ZO-1 as well as AJ proteins such as E-cadherin ( Cano et al., 2000 ; Martinez-Estrada et al., 2006 ).…”

Macrophage polarization in diabetic wound healing

“…Furthermore, the Notch signaling pathway can influence macrophage development indirectly by regulating the expression of macrophage surface marker CD11b [ 36 ]. Relevant studies have pointed out that inhibition of the Notch signal can reduce IL-1β and TNF-α secreted by M1 macrophages, thus reducing the level of inflammatory reaction.…”