Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation.

Multiple studies have implicated microbes in the development of inflammation, but the mechanisms remain unknown. Bacteria in the genus have been identified in the intestinal mucosa of patients with digestive diseases; thus, we hypothesized that promotes intestinal inflammation. The addition of >50 kDa conditioned media, which contain outer membrane vesicles (OMVs), to colonic epithelial cells stimulated secretion of the proinflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor (TNF). In addition, purified OMVs, but not compounds <50 kDa, stimulated IL-8 and TNF production; which was decreased by pharmacological inhibition of Toll-like receptor 4 (TLR4). These effects were linked to downstream effectors p-ERK, p-CREB, and NF-κB. >50-kDa compounds also stimulated TNF secretion, p-ERK, p-CREB, and NF-κB activation in human colonoid monolayers. In mice harboring a human microbiota, pretreatment with antibiotics and a single oral gavage of resulted in inflammation. Compared to mice receiving vehicle control, mice treated with showed disruption of the colonic architecture, with increased immune cell infiltration and depleted mucus layers. Analysis of mucosal gene expression revealed increased levels of proinflammatory cytokines (KC, TNF, IL-6, IFN-γ, and MCP-1) at day 3 and day 5 in -treated mice compared to controls. These proinflammatory effects were absent in mice who received without pretreatment with antibiotics, suggesting that an intact microbiome is protective against -mediated immune responses. These data provide evidence that promotes proinflammatory signaling cascade in the context of a depleted intestinal microbiome. Several studies have identified an increased abundance of in the intestinal tracts of patients with colon cancer, liver cirrhosis, primary sclerosing cholangitis, gastroesophageal reflux disease, HIV infection, and alcoholism. However, the direct mechanism(s) of action of on pathophysiological within the gastrointestinal tract is unclear. These studies have identified that subsp. releases outer membrane vesicles which activate TLR4 and NF-κB to stimulate proinflammatory signals Using mice harboring a human microbiome, we demonstrate that can promote inflammation, an effect which required antibiotic-mediated alterations in the gut microbiome. Collectively, these results suggest a mechanism by which may contribute to intestinal inflammation.