[46, 47] Orally ingested commensal bacteria in the food or drink, or derived from oral flora, may be killed by gastric acid or bile acids in the duodenum,[48, 49]

possibly explaining why the duodenal lumen is relatively sterile compared with lower small intestinal lumen. Further data obtained from drosophila suggest that Duox may also affect the composition of intestinal microbiota. Drosophila intestine expresses Duox, which generates superoxide anion via Ca2+-sensitive NADPH oxidase activity.[50] Knockdown of intestinal Duox in drosophila using siRNA increases mortality due to intestinal bacterial overgrowth,[50] suggesting that Duox-mediated intestinal epithelial H2O2 production affects the composition of the http://www.selleckchem.com/products/ulixertinib-bvd-523-vrt752271.html luminal microbiome. These data form the basis of the hypothesis that the duodenal mucosa senses luminal bacteria to produce H2O2, which complements gastric acid and bile acids to curb the viability of foregut microbiota. Bacterial components are recognized by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) or nucleotide-binding oligomerization domain-containing proteins (NODs).[51, 52] TLRs and NODs, primarily studied in immune cells, are also expressed in intestinal epithelial

cells,[53] where they are expressed on the apical membrane of villous and Paneth cells.[53, 54] These results suggest that the duodenal AZD2281 mucosa may recognize luminal bacteria, generating anti-bacterial H2O2 in response. When evoking a mucosal response to bacterial components, we observed that TLR ligands or a NOD2

ligand alone had no effect, whereas the combination of a TLR with NOD2 ligands stimulated HCO3− secretion, accompanied by increased H2O2 output and mucosal PGE2 synthesis,[55] akin to the mucosal response to luminal acid. Ligands for TLR and NOD2 synergistically increase inflammatory responses MRIP in murine macrophages,[56] consistent with our results. Although a delayed (hours-days) inflammatory response to TLR or NOD2 activation is well described, presumably due to genomic activation, this is the first description in mammals of an acute epithelial response to luminal bacterial components, reinforcing the notion that PRR sensing mediates rapid anti-bacterial mucosal responses (Fig. 2). Extracellular ATP activates Duox1, mediating airway epithelial pro-inflammatory responses to bacterial stimuli,[27] similar to our results. Mucosal H2O2 production via Nox1/Duox2 in response to bacterial exposure was reported in human duodenal biopsies,[57] suggesting the anti-bacterial activity of duodenal Duox2. Compared with the lower intestine with its abundant flora, the duodenal lumen is “clean” from bacterial residency.