RESUMEN
Inflammatory diseases of the gastrointestinal tract are frequently associated with dysbiosis, characterized by changes in gut microbial communities that include an expansion of facultative anaerobic bacteria of the Enterobacteriaceae family (phylum Proteobacteria). Here we show that a dysbiotic expansion of Enterobacteriaceae during gut inflammation could be prevented by tungstate treatment, which selectively inhibited molybdenum-cofactor-dependent microbial respiratory pathways that are operational only during episodes of inflammation. By contrast, we found that tungstate treatment caused minimal changes in the microbiota composition under homeostatic conditions. Notably, tungstate-mediated microbiota editing reduced the severity of intestinal inflammation in mouse models of colitis. We conclude that precision editing of the microbiota composition by tungstate treatment ameliorates the adverse effects of dysbiosis in the inflamed gut.
Asunto(s)
Colitis/tratamiento farmacológico , Colitis/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Intestinos/efectos de los fármacos , Intestinos/microbiología , Anaerobiosis/efectos de los fármacos , Animales , Respiración de la Célula/efectos de los fármacos , Disbiosis/tratamiento farmacológico , Disbiosis/microbiología , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/crecimiento & desarrollo , Enterobacteriaceae/metabolismo , Femenino , Inflamación/tratamiento farmacológico , Inflamación/microbiología , Inflamación/patología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Intestinos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Molibdeno/metabolismo , Compuestos de Tungsteno/farmacología , Compuestos de Tungsteno/uso terapéuticoRESUMEN
During Salmonella enterica serovar Typhimurium infection, host inflammation alters the metabolic environment of the gut lumen to favor the outgrowth of the pathogen at the expense of the microbiota. Inflammation-driven changes in host cell metabolism lead to the release of l-lactate and molecular oxygen from the tissue into the gut lumen. Salmonella utilizes lactate as an electron donor in conjunction with oxygen as the terminal electron acceptor to support gut colonization. Here, we investigated transcriptional regulation of the respiratory l-lactate dehydrogenase LldD in vitro and in mouse models of Salmonella infection. The two-component system ArcAB repressed transcription of l-lactate utilization genes under anaerobic conditions in vitro The ArcAB-mediated repression of lldD transcription was relieved under microaerobic conditions. Transcription of lldD was induced by l-lactate but not d-lactate. A mutant lacking the regulatory protein LldR failed to induce lldD transcription in response to l-lactate. Furthermore, the lldR mutant exhibited reduced transcription of l-lactate utilization genes and impaired fitness in murine models of infection. These data provide evidence that the host-derived metabolites oxygen and l-lactate serve as cues for Salmonella to regulate lactate oxidation metabolism on a transcriptional level.
Asunto(s)
Mucosa Intestinal/microbiología , Ácido Láctico/metabolismo , Infecciones por Salmonella/metabolismo , Salmonella typhimurium/crecimiento & desarrollo , Salmonella typhimurium/metabolismo , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Femenino , Regulación Bacteriana de la Expresión Génica , Humanos , Mucosa Intestinal/metabolismo , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Oxígeno/metabolismo , Infecciones por Salmonella/microbiología , Salmonella typhimurium/enzimología , Salmonella typhimurium/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Intestinal inflammation caused by Salmonella enterica serovar Typhimurium increases the availability of electron acceptors that fuel a respiratory growth of the pathogen in the intestinal lumen. Here we show that one of the carbon sources driving this respiratory expansion in the mouse model is 1,2-propanediol, a microbial fermentation product. 1,2-propanediol utilization required intestinal inflammation induced by virulence factors of the pathogen. S. Typhimurium used both aerobic and anaerobic respiration to consume 1,2-propanediol and expand in the murine large intestine. 1,2-propanediol-utilization did not confer a benefit in germ-free mice, but the pdu genes conferred a fitness advantage upon S. Typhimurium in mice mono-associated with Bacteroides fragilis or Bacteroides thetaiotaomicron. Collectively, our data suggest that intestinal inflammation enables S. Typhimurium to sidestep nutritional competition by respiring a microbiota-derived fermentation product.
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Colitis/microbiología , Interacciones Huésped-Patógeno/fisiología , Propilenglicol/metabolismo , Salmonelosis Animal/metabolismo , Salmonella typhimurium/patogenicidad , Animales , Respiración de la Célula/fisiología , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa , Salmonella typhimurium/crecimiento & desarrollo , Factores de Virulencia/metabolismoRESUMEN
Host-associated microbial communities provide critical functions for their hosts. Transition metals are essential for both the mammalian host and the majority of commensal bacteria. As such, access to transition metals is an important component of host-microbe interactions in the gastrointestinal tract. In mammals, transition metal ions are often sequestered by metal binding proteins to limit microbial access under homeostatic conditions. In response to invading pathogens, the mammalian host further decreases availability of these micronutrients by regulating their trafficking or releasing high-affinity metal chelating proteins, a process termed nutritional immunity. Bacterial pathogens have evolved several mechanisms to subvert nutritional immunity. Here, we provide an overview on how metal ion availability shapes host-microbe interactions in the gut with a particular focus on intestinal inflammatory diseases.
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Interacciones Microbiota-Huesped , Intestinos/microbiología , Elementos de Transición/metabolismo , Animales , HumanosRESUMEN
Salmonella enterica subsp. enterica serovar (serotype) Abortusovis is a member of the Enterobacteriaceae. This serotype is naturally restricted to ovine species and does not infect humans. Limited information is available about the immune response of sheep to S. Abortusovis. S. Abortusovis, like Salmonella enterica subsp. enterica serovar Typhi, causes a systemic infection in which, under natural conditions, animals are not able to raise a rapid immune response. Failure to induce the appropriate response allows pathogens to reach the placenta and results in an abortion. Lipopolysaccharides (LPSs) are pathogen-associated molecular patterns (PAMPs) that are specific to bacteria and are not synthesized by the host. Toll-like receptors (TLRs) are a family of receptors that specifically recognize PAMPs. As a first step, we were able to identify the presence of Toll-like receptor 4 (TLR4) on the ovine placenta by using an immunohistochemistry technique. To our knowledge, this is the first work describing the interaction between S. Abortusovis LPS and TLR4. Experiments using an embryonic cell line (HEK293) transfected with human and ovine TLR4s showed a reduction of interleukin 8 (IL-8) production by S. Abortusovis and Salmonella enterica subsp. enterica serovar Paratyphi upon LPS stimulation compared to Salmonella enterica subsp. enterica serovar Typhimurium. Identical results were observed using heat-killed bacteria instead of LPS. Based on data obtained with TLR4 in vitro stimulation, we demonstrated that the serotype S. Abortusovis is able to successfully evade the immune system whereas S. Typhimurium and other serovars fail to do so.
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Lipopolisacáridos/clasificación , Lipopolisacáridos/inmunología , Salmonella/clasificación , Receptor Toll-Like 4/metabolismo , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Clonación Molecular , Femenino , Regulación de la Expresión Génica/fisiología , Células HEK293 , Humanos , Placenta/citología , Placenta/metabolismo , Embarazo , Ovinos , Receptor Toll-Like 4/genéticaRESUMEN
Enteric pathogens such as Salmonella enterica serovar Typhimurium experience spatial and temporal changes to the metabolic landscape throughout infection. Host reactive oxygen and nitrogen species non-enzymatically convert monosaccharides to alpha hydroxy acids, including L-tartrate. Salmonella utilizes L-tartrate early during infection to support fumarate respiration, while L-tartrate utilization ceases at later time points due to the increased availability of exogenous electron acceptors such as tetrathionate, nitrate, and oxygen. It remains unknown how Salmonella regulates its gene expression to metabolically adapt to changing nutritional environments. Here, we investigated how the transcriptional regulation for L-tartrate metabolism in Salmonella is influenced by infection-relevant cues. L-tartrate induces the transcription of ttdBAU, genes involved in L-tartrate utilization. L-tartrate metabolism is negatively regulated by two previously uncharacterized transcriptional regulators TtdV (STM3357) and TtdW (STM3358), and both TtdV and TtdW are required for the sensing of L-tartrate. The electron acceptors nitrate, tetrathionate, and oxygen repress ttdBAU transcription via the two-component system ArcAB. Furthermore, the regulation of L-tartrate metabolism is required for optimal fitness in a mouse model of Salmonella-induced colitis. TtdV, TtdW, and ArcAB allow for the integration of two cues, i.e., substrate availability and availability of exogenous electron acceptors, to control L-tartrate metabolism. Our findings provide novel insights into how Salmonella prioritizes the utilization of different electron acceptors for respiration as it experiences transitional nutrient availability throughout infection. IMPORTANCE: Bacterial pathogens must adapt their gene expression profiles to cope with diverse environments encountered during infection. This coordinated process is carried out by the integration of cues that the pathogen senses to fine-tune gene expression in a spatiotemporal manner. Many studies have elucidated the regulatory mechanisms of how Salmonella sense metabolites in the gut to activate or repress its virulence program; however, our understanding of how Salmonella coordinates its gene expression to maximize the utilization of carbon and energy sources found in transitional nutrient niches is not well understood. In this study, we discovered how Salmonella integrates two infection-relevant cues, substrate availability and exogenous electron acceptors, to control L-tartrate metabolism. From our experiments, we propose a model for how L-tartrate metabolism is regulated in response to different metabolic cues in addition to characterizing two previously unknown transcriptional regulators. This study expands our understanding of how microbes combine metabolic cues to enhance fitness during infection.
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Proteínas Bacterianas , Regulación Bacteriana de la Expresión Génica , Salmonella typhimurium , Tartratos , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo , Ratones , Animales , Tartratos/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Infecciones por Salmonella/microbiología , FemeninoRESUMEN
Enteric pathogens such as Salmonella enterica serovar Typhimurium experience spatial and temporal changes to the metabolic landscape throughout infection. Host reactive oxygen and nitrogen species non-enzymatically convert monosaccharides to alpha hydroxy acids, including L-tartrate. Salmonella utilizes L-tartrate early during infection to support fumarate respiration, while L-tartrate utilization ceases at later time points due to the increased availability of exogenous electron acceptors such as tetrathionate, nitrate, and oxygen. It remains unknown how Salmonella regulates its gene expression to metabolically adapt to changing nutritional environments. Here, we investigated how the transcriptional regulation for L-tartrate metabolism in Salmonella is influenced by infection-relevant cues. L-tartrate induces the transcription of ttdBAU, genes involved in L-tartrate utilization. L-tartrate metabolism is negatively regulated by two previously uncharacterized transcriptional regulators TtdV (STM3357) and TtdW (STM3358), and both TtdV and TtdW are required for sensing of L-tartrate. The electron acceptors nitrate, tetrathionate, and oxygen repress ttdBAU transcription via the two-component system ArcAB. Furthermore, regulation of L-tartrate metabolism is required for optimal fitness in a mouse model of Salmonella-induced colitis. TtdV, TtdW, and ArcAB allow for the integration of two cues, substrate availability and availability of exogenous electron acceptors, to control L-tartrate metabolism. Our findings provide novel insights into how Salmonella prioritizes utilization of different electron acceptors for respiration as it experiences transitional nutrient availability throughout infection.
RESUMEN
In this issue of Cell Chemical Biology, Lettl et al.1 identify complex I as a suitable target for selective killing of Helicobacter pylori. The unique composition of complex I in H. pylori enables precision targeting of the carcinogenic pathogen while sparing representative species of the gut microbiota.
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Microbioma Gastrointestinal , Infecciones por Helicobacter , Helicobacter pylori , Humanos , Infecciones por Helicobacter/tratamiento farmacológicoRESUMEN
Chicks are ideal to follow the development of the intestinal microbiota and to understand how a pathogen perturbs this developing population. Taxonomic/metagenomic analyses captured the development of the chick microbiota in unperturbed chicks and in chicks infected with Salmonella enterica serotype Typhimurium (STm) during development. Taxonomic analysis suggests that colonization by the chicken microbiota takes place in several waves. The cecal microbiota stabilizes at day 12 posthatch with prominent Gammaproteobacteria and Clostridiales. Introduction of S. Typhimurium at day 4 posthatch disrupted the expected waves of intestinal colonization. Taxonomic and metagenomic shotgun sequencing analyses allowed us to identify species present in uninfected chicks. Untargeted metabolomics suggested different metabolic activities in infected chick microbiota. This analysis and gas chromatography-mass spectrometry on ingesta confirmed that lactic acid in cecal content coincides with the stable presence of enterococci in STm-infected chicks. Unique metabolites, including 2-isopropylmalic acid, an intermediate in the biosynthesis of leucine, were present only in the cecal content of STm-infected chicks. The metagenomic data suggested that the microbiota in STm-infected chicks contained a higher abundance of genes, from STm itself, involved in branched-chain amino acid synthesis. We generated an ilvC deletion mutant (STM3909) encoding ketol-acid-reductoisomerase, a gene required for the production of l-isoleucine and l-valine. ΔilvC mutants are disadvantaged for growth during competitive infection with the wild type. Providing the ilvC gene in trans restored the growth of the ΔilvC mutant. Our integrative approach identified biochemical pathways used by STm to establish a colonization niche in the chick intestine during development. IMPORTANCE Chicks are an ideal model to follow the development of the intestinal microbiota and to understand how a pathogen perturbs this developing population. Using taxonomic and metagenomic analyses, we captured the development of chick microbiota to 19 days posthatch in unperturbed chicks and in chicks infected with Salmonella enterica serotype Typhimurium (STm). We show that normal development of the microbiota takes place in waves and is altered in the presence of a pathogen. Metagenomics and metabolomics suggested that branched-chain amino acid biosynthesis is especially important for Salmonella growth in the infected chick intestine. Salmonella mutants unable to make l-isoleucine and l-valine colonize the chick intestine poorly. Restoration of the pathway for biosynthesis of these amino acids restored the colonizing ability of Salmonella. Integration of multiple analyses allowed us to correctly identify biochemical pathways used by Salmonella to establish a niche for colonization in the chick intestine during development.
Asunto(s)
Microbiota , Enfermedades de las Aves de Corral , Salmonelosis Animal , Animales , Pollos/microbiología , Isoleucina , Salmonella typhimurium/metabolismo , Ciego/microbiología , Aminoácidos de Cadena Ramificada/metabolismo , Valina/metabolismo , Salmonelosis Animal/microbiología , Enfermedades de las Aves de Corral/microbiologíaRESUMEN
Salmonella enterica serovar Typhimurium induces intestinal inflammation to create a niche that fosters the outgrowth of the pathogen over the gut microbiota. Under inflammatory conditions, Salmonella utilizes terminal electron acceptors generated as byproducts of intestinal inflammation to generate cellular energy through respiration. However, the electron donating reactions in these electron transport chains are poorly understood. Here, we investigated how formate utilization through the respiratory formate dehydrogenase-N (FdnGHI) and formate dehydrogenase-O (FdoGHI) contribute to gut colonization of Salmonella. Both enzymes fulfilled redundant roles in enhancing fitness in a mouse model of Salmonella-induced colitis, and coupled to tetrathionate, nitrate, and oxygen respiration. The formic acid utilized by Salmonella during infection was generated by its own pyruvate-formate lyase as well as the gut microbiota. Transcription of formate dehydrogenases and pyruvate-formate lyase was significantly higher in bacteria residing in the mucus layer compared to the lumen. Furthermore, formate utilization conferred a more pronounced fitness advantage in the mucus, indicating that formate production and degradation occurred predominantly in the mucus layer. Our results provide new insights into how Salmonella adapts its energy metabolism to the local microenvironment in the gut. IMPORTANCE Bacterial pathogens must not only evade immune responses but also adapt their metabolism to successfully colonize their host. The microenvironments encountered by enteric pathogens differ based on anatomical location, such as small versus large intestine, spatial stratification by host factors, such as mucus layer and antimicrobial peptides, and distinct commensal microbial communities that inhabit these microenvironments. Our understanding of how Salmonella populations adapt its metabolism to different environments in the gut is incomplete. In the current study, we discovered that Salmonella utilizes formate as an electron donor to support respiration, and that formate oxidation predominantly occurs in the mucus layer. Our experiments suggest that spatially distinct Salmonella populations in the mucus layer and the lumen differ in their energy metabolism. Our findings enhance our understanding of the spatial nature of microbial metabolism and may have implications for other enteric pathogens as well as commensal host-associated microbial communities.
Asunto(s)
Liasas , Salmonelosis Animal , Animales , Ratones , Salmonella typhimurium/metabolismo , Serogrupo , Salmonelosis Animal/microbiología , Bacterias , Inflamación , Formiatos/metabolismo , Moco , Piruvatos/metabolismo , Liasas/metabolismoRESUMEN
During intestinal inflammation, host nutritional immunity starves microbes of essential micronutrients such as iron. Pathogens scavenge iron using siderophores, which is counteracted by the host using lipocalin-2, a protein that sequesters iron-laden siderophores, including enterobactin. Although the host and pathogens compete for iron in the presence of gut commensal bacteria, the roles of commensals in nutritional immunity involving iron remain unexplored. Here, we report that the gut commensal Bacteroides thetaiotaomicron acquires iron in the inflamed gut by utilizing siderophores produced by other bacteria including Salmonella, via a secreted siderophore-binding lipoprotein termed XusB. Notably, XusB-bound siderophores are less accessible to host sequestration by lipocalin-2 but can be "re-acquired" by Salmonella , allowing the pathogen to evade nutritional immunity. As the host and pathogen have been the focus of studies of nutritional immunity, this work adds commensal iron metabolism as a previously unrecognized mechanism modulating the interactions between pathogen and host nutritional immunity.
RESUMEN
During intestinal inflammation, host nutritional immunity starves microbes of essential micronutrients, such as iron. Pathogens scavenge iron using siderophores, including enterobactin; however, this strategy is counteracted by host protein lipocalin-2, which sequesters iron-laden enterobactin. Although this iron competition occurs in the presence of gut bacteria, the roles of commensals in nutritional immunity involving iron remain unexplored. Here, we report that the gut commensal Bacteroides thetaiotaomicron acquires iron and sustains its resilience in the inflamed gut by utilizing siderophores produced by other bacteria, including Salmonella, via a secreted siderophore-binding lipoprotein XusB. Notably, XusB-bound enterobactin is less accessible to host sequestration by lipocalin-2 but can be "re-acquired" by Salmonella, allowing the pathogen to evade nutritional immunity. Because the host and pathogen have been the focus of studies of nutritional immunity, this work adds commensal iron metabolism as a previously unrecognized mechanism modulating the host-pathogen interactions and nutritional immunity.
Asunto(s)
Infecciones por Salmonella , Sideróforos , Humanos , Lipocalina 2/metabolismo , Sideróforos/metabolismo , Enterobactina/metabolismo , Bacterias/metabolismo , Hierro/metabolismoRESUMEN
Louis Pasteur's experiments on tartaric acid laid the foundation for our understanding of molecular chirality, but major questions remain. By comparing the optical activity of naturally-occurring tartaric acid with chemically-synthesized paratartaric acid, Pasteur realized that naturally-occurring tartaric acid contained only L-tartaric acid while paratartaric acid consisted of a racemic mixture of D- and L-tartaric acid. Curiously, D-tartaric acid has no known natural source, yet several gut bacteria specifically degrade D-tartaric acid. Here, we investigated the oxidation of monosaccharides by inflammatory reactive oxygen and nitrogen species. We found that this reaction yields an array of alpha hydroxy carboxylic acids, including tartaric acid isomers. Utilization of inflammation- derived D- and L-tartaric acid enhanced colonization by Salmonella Typhimurium and E. coli in murine models of gut inflammation. Our findings suggest that byproducts of inflammatory radical metabolism, such as tartrate and other alpha hydroxy carboxylic acids, create transient nutrient niches for enteric pathogens and other potentially harmful bacteria. Furthermore, this work illustrates that inflammatory radicals generate a zoo of molecules, some of which may erroneously presumed to be xenobiotics.
RESUMEN
BACKGROUND: Intestinal inflammation disrupts the microbiota composition leading to an expansion of Enterobacteriaceae family members (dysbiosis). Associated with this shift in microbiota composition is a profound change in the metabolic landscape of the intestine. It is unclear how changes in metabolite availability during gut inflammation impact microbial and host physiology. RESULTS: We investigated microbial and host lactate metabolism in murine models of infectious and non-infectious colitis. During inflammation-associated dysbiosis, lactate levels in the gut lumen increased. The disease-associated spike in lactate availability was significantly reduced in mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells. Commensal E. coli and pathogenic Salmonella, representative Enterobacteriaceae family members, utilized lactate via the respiratory L-lactate dehydrogenase LldD to increase fitness. Furthermore, mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells exhibited lower levels of inflammation in a model of non-infectious colitis. CONCLUSIONS: The release of lactate by intestinal epithelial cells during gut inflammation impacts the metabolism of gut-associated microbial communities. These findings suggest that during intestinal inflammation and dysbiosis, changes in metabolite availability can perpetuate colitis-associated disturbances of microbiota composition. Video Abstract.
Asunto(s)
Colitis , Microbioma Gastrointestinal , Ratones , Animales , Disbiosis , Escherichia coli/metabolismo , Ácido Láctico/metabolismo , Lactato Deshidrogenasa 5 , Ratones Endogámicos C57BL , Inflamación/patología , Colitis/patología , Enterobacteriaceae/metabolismoRESUMEN
Historically, clinical microbiological laboratories have often relied on isolation of pure cultures and phenotypic testing to identify microorganisms. These clinical tests are often based on specific biochemical reactions, growth characteristics, colony morphology, and other physiological aspects. The features used for identification in clinical laboratories are highly conserved and specific for a given group of microbes. We speculate that these features might be the result of evolutionary selection and thus may reflect aspects of the life cycle of the organism and pathogenesis. Indeed, several of the metabolic pathways targeted by diagnostic tests in some cases may represent mechanisms for host colonization or pathogenesis. Examples include, but are not restricted to, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella enterica, Shigella spp., and enteroinvasive Escherichia coli (EIEC). Here, we provide an overview of how some common tests reflect molecular mechanisms of bacterial pathogenesis.
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Infecciones Bacterianas , Disentería Bacilar , Adaptación al Huésped , Bacterias/inmunología , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/patología , Disentería Bacilar/diagnóstico , Disentería Bacilar/microbiología , Disentería Bacilar/fisiopatología , Humanos , Laboratorios ClínicosRESUMEN
The composition of gut-associated microbial communities changes during intestinal inflammation, including an expansion of Enterobacteriaceae populations. The mechanisms underlying microbiota changes during inflammation are incompletely understood. Here, we analyzed previously published metagenomic datasets with a focus on microbial hydrogen metabolism. The bacterial genomes in the inflamed murine gut and in patients with inflammatory bowel disease contained more genes encoding predicted hydrogen-utilizing hydrogenases compared to communities found under non-inflamed conditions. To validate these findings, we investigated hydrogen metabolism of Escherichia coli, a representative Enterobacteriaceae, in mouse models of colitis. E. coli mutants lacking hydrogenase-1 and hydrogenase-2 displayed decreased fitness during colonization of the inflamed cecum and colon. Utilization of molecular hydrogen was in part dependent on respiration of inflammation-derived electron acceptors. This work highlights the contribution of hydrogenases to alterations of the gut microbiota in the context of non-infectious colitis.
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Ciego/microbiología , Colitis/inducido químicamente , Colitis/microbiología , Colon/microbiología , Infecciones por Escherichia coli/microbiología , Escherichia coli/metabolismo , Microbioma Gastrointestinal , Hidrógeno/metabolismo , Animales , Ciego/metabolismo , Ciego/patología , Colitis/metabolismo , Colitis/patología , Colon/metabolismo , Colon/patología , Bases de Datos Genéticas , Sulfato de Dextran , Modelos Animales de Enfermedad , Disbiosis , Escherichia coli/genética , Escherichia coli/crecimiento & desarrollo , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/patología , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Femenino , Humanos , Hidrogenasas/genética , Hidrogenasas/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Metagenoma , Metagenómica , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , PiroxicamRESUMEN
The intestinal epithelium separates host tissue and gut-associated microbial communities. During inflammation, the host releases reactive oxygen and nitrogen species as an antimicrobial response. The impact of these radicals on gut microbes is incompletely understood. We discovered that the cryptic appBCX genes, predicted to encode a cytochrome bd-II oxidase, conferred a fitness advantage for E. coli in chemical and genetic models of non-infectious colitis. This fitness advantage was absent in mice that lacked epithelial NADPH oxidase 1 (NOX1) activity. In laboratory growth experiments, supplementation with exogenous hydrogen peroxide enhanced E. coli growth through AppBCX-mediated respiration in a catalase-dependent manner. We conclude that epithelial-derived reactive oxygen species are degraded in the gut lumen, which gives rise to molecular oxygen that supports the aerobic respiration of E. coli. This work illustrates how epithelial host responses intersect with gut microbial metabolism in the context of gut inflammation.
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Complejo IV de Transporte de Electrones/fisiología , Escherichia coli/fisiología , Inflamación/metabolismo , Mucosa Intestinal/metabolismo , NADPH Oxidasa 1/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Aerobiosis , Animales , Colitis/inducido químicamente , ADN Bacteriano , Modelos Animales de Enfermedad , Proteínas de Escherichia coli/fisiología , Femenino , Microbioma Gastrointestinal , Interacciones Microbiota-Huesped , Peróxido de Hidrógeno/metabolismo , Inflamación/microbiología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Microbiota , NADPH Oxidasa 1/genética , Oxígeno/metabolismoRESUMEN
During short-lived perturbations, such as inflammation, the gut microbiota exhibits resilience and reverts to its original configuration. Although microbial access to the micronutrient iron is decreased during colitis, pathogens can scavenge iron by using siderophores. How commensal bacteria acquire iron during gut inflammation is incompletely understood. Curiously, the human commensal Bacteroides thetaiotaomicron does not produce siderophores but grows under iron-limiting conditions using enterobacterial siderophores. Using RNA-seq, we identify B. thetaiotaomicron genes that were upregulated during Salmonella-induced gut inflammation and were predicted to be involved in iron uptake. Mutants in the xusABC locus (BT2063-2065) were defective for xenosiderophore-mediated iron uptake in vitro. In the normal mouse gut, the XusABC system was dispensable, while a xusA mutant colonized poorly during colitis. This work identifies xenosiderophore utilization as a critical mechanism for B. thetaiotaomicron to sustain colonization during inflammation and suggests a mechanism of how interphylum iron metabolism contributes to gut microbiota resilience.
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Bacteroides thetaiotaomicron/metabolismo , Colitis/microbiología , Enterobacteriaceae/genética , Microbioma Gastrointestinal , Hierro/metabolismo , Sideróforos/genética , Animales , Bacteroides thetaiotaomicron/genética , Femenino , Genes Bacterianos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , RNA-Seq , SimbiosisRESUMEN
Enteric pathogens have evolved to manipulate the interface between the host and commensal microbial communities, making these pathogenic organisms superb research tools to interrogate the function of the gut microbiota during inflammatory flares. Here, we provide an overview of conceptual insights gained from experimental infection with enteric pathogens, such as Salmonella enterica serovar Typhimurium. Metabolic pathways at the host-microbe intersection will be a particular area of focus. A better understanding of the cellular and molecular mechanisms that control host-microbe interactions during episodes of inflammation may aid in the rational design of microbiota-targeting therapies.
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Microbioma Gastrointestinal , Interacciones Microbiota-Huesped , Salmonella typhimurium/patogenicidad , Simbiosis , Animales , Citrobacter rodentium/fisiología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/patología , Humanos , Inflamación , Redes y Vías Metabólicas , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing E. coli strains, are risk factors for the development of colorectal cancer. Here, we sought to determine whether precision editing of gut microbiota metabolism and composition could decrease the risk for tumor development in mouse models of colitis-associated colorectal cancer (CAC). Expansion of experimentally introduced E. coli strains in the azoxymethane/dextran sulfate sodium colitis model was driven by molybdoenzyme-dependent metabolic pathways. Oral administration of sodium tungstate inhibited E. coli molybdoenzymes and selectively decreased gut colonization with genotoxin-producing E. coli and other Enterobacteriaceae. Restricting the bloom of Enterobacteriaceae decreased intestinal inflammation and reduced the incidence of colonic tumors in two models of CAC, the azoxymethane/dextran sulfate sodium colitis model and azoxymethane-treated, Il10-deficient mice. We conclude that metabolic targeting of protumoral Enterobacteriaceae during chronic inflammation is a suitable strategy to prevent the development of malignancies arising from gut microbiota dysbiosis.