Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide1. Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-κB signalling2–5, raising the question as to whether other host factors participate in antiviral responses in intestinal mucosa. The mechanism by which enteric viruses are sensed and restricted in vivo, especially by NOD-like receptor (NLR) inflammasomes, is largely unknown. Here we uncover and mechanistically characterize the NLR Nlrp9b that is specifically expressed in intestinal epithelial cells and restricts rotavirus infection. Our data show that, via RNA helicase Dhx9, Nlrp9b recognizes short double-stranded RNA stretches and forms inflammasome complexes with the adaptor proteins Asc and caspase-1 to promote the maturation of interleukin (Il)-18 and gasdermin D (Gsdmd)-induced pyroptosis. Conditional depletion of Nlrp9b or other inflammasome components in the intestine in vivo resulted in enhanced susceptibility of mice to rotavirus replication. Our study highlights an important innate immune signalling pathway that functions in intestinal epithelial cells and may present useful targets in the modulation of host defences against viral pathogens.

Escherichia coli is a common inhabitant of the human microbiota and a beacon model organism in biology. However, an understanding of its signaling systems that regulate population-level phenotypes known as quorum sensing remain incomplete. Here, we define the structure and biosynthesis of autoinducer-3 (AI-3), a metabolite of previously unknown structure involved in the pathogenesis of enterohemorrhagic E. coli (EHEC). We demonstrate that novel AI-3 analogs are derived from threonine dehydrogenase (Tdh) products and “abortive” tRNA synthetase reactions, and they are distributed across a variety of Gram-negative and Gram-positive bacterial pathogens. In addition to regulating virulence genes in EHEC, we show that the metabolites exert diverse immunological effects on primary human tissues. The discovery of AI-3 metabolites and their biochemical origins now provides a molecular foundation for investigating the diverse biological roles of these elusive yet widely distributed bacterial signaling molecules.

Tapinarof is a stilbene drug that is used to treat psoriasis and atopic dermatitis, and is thought to function through regulation of the AhR and Nrf2 signaling pathways, which have also been linked to inflammatory bowel diseases. It is produced by the gammaproteobacterial Photorhabdus genus, which thus represents a model to probe tapinarof structural and functional transformations. We show that Photorhabdus transforms tapinarof into novel drug metabolism products that kill inflammatory bacteria, and that a cupin enzyme contributes to the conversion of tapinarof and related dietary stilbenes into novel dimers. One dimer has activity against methicillin‐resistant Staphylococcus aureus (MRSA) and vancomycin‐resistant Enterococcus faecalis (VRE), and another undergoes spontaneous cyclizations to a cyclopropane‐bridge‐containing hexacyclic framework that exhibits activity against Mycobacterium. These dimers lack efficacy in a colitis mouse model, whereas the monomer reduces disease symptoms.

Escherichia coli is an important model organism in microbiology and a prominent member of the human microbiota 1 . Environmental isolates readily colonize the gastrointestinal tracts of humans and other animals, and they can serve diverse probiotic, commensal, and pathogenic roles in the host 2 – 4 . Certain strains have been associated with the severity of inflammatory bowel disease (IBD) 2 , 5 ; however, the diverse immunomodulatory phenotypes remain largely unknown at the molecular level. Here, we decode a previously unknown E. coli metabolic pathway that produces a family of hybrid pterin-phenylpyruvate conjugates, which we named the colipterins. The metabolites are upregulated by sub-inhibitory levels of the antifolate sulfamethoxazole (SMX), which is used to treat infections, including in IBD patients 6 , 7 . The genes folX/M and aspC/tyrB involved in monapterin biosynthesis 8 – 10 and aromatic amino acid transamination, 11 respectively, were required to initiate the colipterin pathway. We show that the colipterins are antioxidants, harbor diverse immunological activities in primary human tissues, activate anti-inflammatory interleukin-10 (IL-10), and improve colitis symptoms in a colitis mouse model. Our study defines an antifolate stress response in E. coli and links its associated metabolites to a major immunological marker of IBD.

Abstract. Artemisia vestita Wall., a traditional Tibetan medicine, has wide clinical application for inflammatory diseases. However, its molecular mechanism of antiinflammatory effect is poorly understood. In the present study, we investigated the anti-inflammatory activity and underlying mechanism of the ethanol extract from Artemisia vestita (AV-ext) on lipopolysaccharide (LPS)-induced sepsis. Pretreatment with AV-ext significantly decreased the levels of tumor necrosis factor-· (TNF-·) in serum and liver and lung tissues, and improved the survival of mice with experimental sepsis. AV-ext also remarkably reduced the expression levels of TNF-·, interleukin-1ß and cyclooxygenase-2 in LPSstimulated RAW 264.7 macrophages and dose dependently suppressed the activation of mitogen-activated protein kinases (MAPKs), such as p38, extracellular signal-regulated kinase (ERK1/2) and c-Jun NH 2 -terminal kinase (JNK). Furthermore, pretreatment with AV-ext dose dependently inhibited the activation of nuclear factor-κB (NF-κB), as well as the degradation and phosphorylation of inhibitory κB (IκB) in LPS-activated RAW 264.7 macrophages. These results collectively reveal that AV-ext inhibits TNF-· release from macrophages by suppressing MAPK and NF-κB signaling pathways and suggest that AV-ext may be beneficial for the treatment of endotoxin shock or sepsis.