RESUMEN
The impact of bacterial members of the microbiota on the development of colorectal cancer (CRC) has become clear in recent years. However, exactly how bacteria contribute to the development of cancer is often still up for debate. The impact of bacteria-derived metabolites, which can influence the development of CRC either in a promoting or inhibiting manner, is undeniable. Here, we discuss the effects of the most well-studied bacteria-derived metabolites associated with CRC, including secondary bile acids, short-chain fatty acids, trimethylamine-N-oxide and indoles. We show that the effects of individual metabolites on CRC development are often nuanced and dose- and location-dependent. In the coming years, the array of metabolites involved in CRC development will undoubtedly increase further, which will emphasize the need to focus on causation and mechanisms and the clearly defined roles of bacterial species within the microbiota.
Asunto(s)
Bacterias , Neoplasias Colorrectales , Microbioma Gastrointestinal , Animales , Humanos , Bacterias/metabolismo , Ácidos y Sales Biliares/metabolismo , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/microbiología , Ácidos Grasos Volátiles/metabolismo , Sulfuro de Hidrógeno/metabolismo , Indoles/metabolismo , Poliaminas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The Gram-negative bacterium Campylobacter jejuni is a major cause of foodborne disease in humans. After infection, C. jejuni rapidly colonizes the mucus layer of the small and large intestine and induces a potent pro-inflammatory response characterized by the production of a large repertoire of cytokines, chemokines, and innate effector molecules, resulting in (bloody) diarrhea. The virulence mechanisms by which C. jejuni causes this intestinal response are still largely unknown. Here we show that C. jejuni releases a potent pro-inflammatory compound into its environment, which activates an NF-κB-mediated pro-inflammatory response including the induction of CXCL8, CXCL2, TNFAIP2 and PTGS2. This response was dependent on a functional ALPK1 receptor and independent of Toll-like Receptor and Nod-like Receptor signaling. Chemical characterization, inactivation of the heptose-biosynthesis pathway by the deletion of the hldE gene and in vitro engineering identified the released factor as the LOS-intermediate ADP-heptose and/or related heptose phosphates. During C. jejuni infection of intestinal cells, the ALPK1-NF-κB axis was potently activated by released heptose metabolites without the need for a type III or type IV injection machinery. Our results classify ADP-heptose and/or related heptose phosphates as a major virulence factor of C. jejuni that may play an important role during Campylobacter infection in humans.
Asunto(s)
Infecciones por Campylobacter/inmunología , Campylobacter jejuni/inmunología , Células Epiteliales/inmunología , Inflamación/inmunología , Intestinos/inmunología , FN-kappa B/metabolismo , Proteínas Quinasas/metabolismo , Infecciones por Campylobacter/metabolismo , Infecciones por Campylobacter/microbiología , Citocinas , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Células HeLa , Humanos , Inmunidad Innata/inmunología , Inflamación/metabolismo , Inflamación/microbiología , Intestinos/microbiología , FN-kappa B/genética , Proteínas Quinasas/genética , Transducción de Señal , Virulencia , Factores de Virulencia/metabolismoRESUMEN
Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here, we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the antimicrobial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence in situ mRNA hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18. Strikingly, deletion of IL-18 from the enteric neurons alone, but not immune or epithelial cells, rendered mice susceptible to invasive Salmonella typhimurium (S.t.) infection. Mechanistically, unbiased RNA sequencing and single-cell sequencing revealed that enteric neuronal IL-18 is specifically required for homeostatic goblet cell AMP production. Together, we show that neuron-derived IL-18 signaling controls tissue-wide intestinal immunity and has profound consequences on the mucosal barrier and invasive bacterial killing.
Asunto(s)
Inmunidad Mucosa/inmunología , Interleucina-18/inmunología , Mucosa Intestinal/inmunología , Animales , Citocinas/inmunología , Sistema Nervioso Entérico/inmunología , Sistema Nervioso Entérico/metabolismo , Células Epiteliales/inmunología , Femenino , Células Caliciformes/inmunología , Interleucina-18/biosíntesis , Mucosa Intestinal/metabolismo , Intestino Delgado/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/inmunología , Ratas , Ratas Sprague-Dawley , Infecciones por Salmonella/inmunología , Salmonella typhimurium/inmunología , Transducción de Señal/inmunologíaRESUMEN
The annotation of the mammalian protein-coding genome is incomplete. Arbitrary size restriction of open reading frames (ORFs) and the absolute requirement for a methionine codon as the sole initiator of translation have constrained the identification of potentially important transcripts with non-canonical protein-coding potential1,2. Here, using unbiased transcriptomic approaches in macrophages that respond to bacterial infection, we show that ribosomes associate with a large number of RNAs that were previously annotated as 'non-protein coding'. Although the idea that such non-canonical ORFs can encode functional proteins is controversial3,4, we identify a range of short and non-ATG-initiated ORFs that can generate stable and spatially distinct proteins. Notably, we show that the translation of a new ORF 'hidden' within the long non-coding RNA Aw112010 is essential for the orchestration of mucosal immunity during both bacterial infection and colitis. This work expands our interpretation of the protein-coding genome and demonstrates that proteinaceous products generated from non-canonical ORFs are crucial for the immune response in vivo. We therefore propose that the misannotation of non-canonical ORF-containing genes as non-coding RNAs may obscure the essential role of a multitude of previously undiscovered protein-coding genes in immunity and disease.