RESUMEN
The small intestine represents a complex and understudied gut niche with significant implications for human health. Indeed, many infectious and non-infectious diseases center within the small intestine and present similar clinical manifestations to large intestinal disease, complicating non-invasive diagnosis and treatment. One major neglected aspect of small intestinal diseases is the feedback relationship with the resident collection of commensal organisms, the gut microbiota. Studies focused on microbiota-host interactions in the small intestine in the context of infectious and non-infectious diseases are required to identify potential therapeutic targets dissimilar from those used for large bowel diseases. While sparsely populated, the small intestine represents a stringent commensal bacterial microenvironment the host relies upon for nutrient acquisition and protection against invading pathogens (colonization resistance). Indeed, recent evidence suggests that disruptions to host-microbiota interactions in the small intestine impact enteric bacterial pathogenesis and susceptibility to non-infectious enteric diseases. In this review, we focus on the microbiota's impact on small intestine function and the pathogenesis of infectious and non-infectious diseases of the gastrointestinal (GI) tract. We also discuss gaps in knowledge on the role of commensal microorganisms in proximal GI tract function during health and disease.
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
One of the major contributors to child mortality in the world is diarrheal diseases, with an estimated 800,000 deaths per year. Many pathogens are causative agents of these illnesses, including the enteropathogenic or enterohemorrhagic forms of Escherichia coli. These bacteria are characterized by their ability to cause attaching and effacing lesions in the gut mucosa. Although much has been learned about the pathogenicity of these organisms and the immune response against them, the role of the intestinal microbiota during these infections is not well characterized. Infection of mice with E. coli requires pre-treatment with antibiotics in most mouse models, which hinders the study of the microbiota in an undisturbed environment. Using Citrobacter rodentium as a murine model for attaching and effacing bacteria, we show that C57BL/6 mice deficient in granzyme B expression are highly susceptible to severe disease caused by C. rodentium infection. Although a previous publication from our group shows that granzyme B-deficient CD4+ T cells are partially responsible for this phenotype, in this report, we present data demonstrating that the microbiota, in particular members of the order Turicibacterales, have an important role in conferring resistance. Mice deficient in Turicibacter sanguinis have increased susceptibility to severe disease. However, when these mice are co-housed with resistant mice or colonized with T. sanguinis, susceptibility to severe infection is reduced. These results clearly suggest a critical role for this commensal in the protection against enteropathogens.
Asunto(s)
Infecciones por Enterobacteriaceae , Escherichia coli , Niño , Humanos , Animales , Ratones , Citrobacter rodentium/genética , Granzimas , Infecciones por Enterobacteriaceae/microbiología , Ratones Endogámicos C57BL , BacteriasRESUMEN
Sporadic colorectal cancer has traditionally been viewed as a malignancy of older individuals. However, as the global prevalence of the disease diagnosed in younger individuals (<50 years) is expected to increase within the next decade, greater recognition is now being given to early-onset colorectal cancer. The cause of the predicted rise in prevalence is largely unknown and probably multifactorial. In this Series paper, we discuss the potential underlying causes of early-onset colorectal cancer, the role of energy balance, biological and genomic mechanisms (including microbiome aspects), and the treatment of early-onset colorectal cancer. We have specifically considered the psychosocial challenges of being diagnosed with colorectal cancer at younger age and the potential financial toxicity that might ensue. This Series paper brings a comprehensive review based on the existing data in the hopes of optimising the overall outcomes for patients with early-onset colorectal cancer.
Asunto(s)
Neoplasias Colorrectales , Edad de Inicio , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Genómica , Humanos , PrevalenciaRESUMEN
Research on Brucella pathogenesis has focused primarily on its ability to cause persistent intracellular infection of the mononuclear phagocyte system. At these sites, Brucella abortus evades innate immunity, which results in low-level inflammation and chronic infection of phagocytes. In contrast, the host response in the placenta during infection is characterized by severe inflammation and extensive extracellular replication of B. abortus. Despite the importance of reproductive disease caused by Brucella infection, our knowledge of the mechanisms involved in placental inflammation and abortion is limited. To understand the immune responses specifically driving placental pathology, we modeled placental B. abortus infection in pregnant mice. B. abortus infection caused an increase in the production of tumor necrosis factor alpha (TNF-α), specifically in the placenta. We found that placental expression levels of Tnfa and circulating TNF-α were dependent on the induction of endoplasmic reticulum stress and the B. abortus type IV secretion system (T4SS) effector protein VceC. Blockade of TNF-α reduced placental inflammation and improved fetal viability in mice. This work sheds light on a tissue-specific response of the placenta to B. abortus infection that may be important for bacterial transmission via abortion in the natural host species.
Asunto(s)
Brucelosis Bovina , Brucelosis , Animales , Brucella abortus/fisiología , Brucelosis/microbiología , Bovinos , Femenino , Inflamación , Ratones , Placenta , Embarazo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Changes in the gut microbiota may underpin many human diseases, but the mechanisms that are responsible for altering microbial communities remain poorly understood. Antibiotic usage elevates the risk of contracting gastroenteritis caused by Salmonella enterica serovars, increases the duration for which patients shed the pathogen in their faeces, and may on occasion produce a bacteriologic and symptomatic relapse. These antibiotic-induced changes in the gut microbiota can be studied in mice, in which the disruption of a balanced microbial community by treatment with the antibiotic streptomycin leads to an expansion of S. enterica serovars in the large bowel. However, the mechanisms by which streptomycin treatment drives an expansion of S. enterica serovars are not fully resolved. Here we show that host-mediated oxidation of galactose and glucose promotes post-antibiotic expansion of S. enterica serovar Typhimurium (S. Typhimurium). By elevating expression of the gene encoding inducible nitric oxide synthase (iNOS) in the caecal mucosa, streptomycin treatment increased post-antibiotic availability of the oxidation products galactarate and glucarate in the murine caecum. S. Typhimurium used galactarate and glucarate within the gut lumen of streptomycin pre-treated mice, and genetic ablation of the respective catabolic pathways reduced S. Typhimurium competitiveness. Our results identify host-mediated oxidation of carbohydrates in the gut as a mechanism for post-antibiotic pathogen expansion.
Asunto(s)
Antibacterianos/farmacología , Metabolismo de los Hidratos de Carbono , Interacciones Huésped-Patógeno/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/crecimiento & desarrollo , Estreptomicina/farmacología , Animales , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Metabolismo de los Hidratos de Carbono/genética , Ciego/efectos de los fármacos , Ciego/enzimología , Ciego/microbiología , Femenino , Galactosa/metabolismo , Gastroenteritis/microbiología , Ácido Glucárico/metabolismo , Glucosa/metabolismo , Mucosa Intestinal/enzimología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Masculino , Ratones , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Operón/genética , Oxidación-Reducción/efectos de los fármacos , Especies de Nitrógeno Reactivo/metabolismo , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidad , Azúcares Ácidos/metabolismoRESUMEN
Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn disease and type 2 diabetes. ER stress induces the unfolded protein response, which involves activation of three transmembrane receptors, ATF6, PERK and IRE1α. Once activated, IRE1α recruits TRAF2 to the ER membrane to initiate inflammatory responses via the NF-κB pathway. Inflammation is commonly triggered when pattern recognition receptors (PRRs), such as Toll-like receptors or nucleotide-binding oligomerization domain (NOD)-like receptors, detect tissue damage or microbial infection. However, it is not clear which PRRs have a major role in inducing inflammation during ER stress. Here we show that NOD1 and NOD2, two members of the NOD-like receptor family of PRRs, are important mediators of ER-stress-induced inflammation in mouse and human cells. The ER stress inducers thapsigargin and dithiothreitol trigger production of the pro-inflammatory cytokine IL-6 in a NOD1/2-dependent fashion. Inflammation and IL-6 production triggered by infection with Brucella abortus, which induces ER stress by injecting the type IV secretion system effector protein VceC into host cells, is TRAF2, NOD1/2 and RIP2-dependent and can be reduced by treatment with the ER stress inhibitor tauroursodeoxycholate or an IRE1α kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1α/TRAF2 signalling pathway provides a novel link between innate immunity and ER-stress-induced inflammation.
Asunto(s)
Estrés del Retículo Endoplásmico , Inflamación/metabolismo , Proteína Adaptadora de Señalización NOD1/metabolismo , Proteína Adaptadora de Señalización NOD2/metabolismo , Transducción de Señal , Animales , Proteínas de la Membrana Bacteriana Externa/metabolismo , Brucella abortus/inmunología , Brucella abortus/patogenicidad , Línea Celular , Ditiotreitol/farmacología , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Endorribonucleasas/antagonistas & inhibidores , Femenino , Humanos , Inmunidad Innata , Inflamación/inducido químicamente , Interleucina-6/biosíntesis , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Proteína Adaptadora de Señalización NOD1/inmunología , Proteína Adaptadora de Señalización NOD2/inmunología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Receptores de Reconocimiento de Patrones/metabolismo , Transducción de Señal/efectos de los fármacos , Factor 2 Asociado a Receptor de TNF/metabolismo , Ácido Tauroquenodesoxicólico/farmacología , Tapsigargina/farmacología , Respuesta de Proteína Desplegada/efectos de los fármacosRESUMEN
In high-income countries, the leading causes of death are noncommunicable diseases (NCDs), such as obesity, cancer, and cardiovascular disease. An important feature of most NCDs is inflammation-induced gut dysbiosis characterized by a shift in the microbial community structure from obligate to facultative anaerobes such as Proteobacteria This microbial imbalance can contribute to disease pathogenesis by either a depletion in or the production of microbiota-derived metabolites. However, little is known about the mechanism by which inflammation-mediated changes in host physiology disrupt the microbial ecosystem in our large intestine leading to disease. Recent work by our group suggests that during gut homeostasis, epithelial hypoxia derived from peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent ß-oxidation of microbiota-derived short-chain fatty acids limits oxygen availability in the colon, thereby maintaining a balanced microbial community. During inflammation, disruption in gut anaerobiosis drives expansion of facultative anaerobic Enterobacteriaceae, regardless of their pathogenic potential. Therefore, our research group is currently exploring the concept that dysbiosis-associated expansion of Enterobacteriaceae can be viewed as a microbial signature of epithelial dysfunction and may play a greater role in different models of NCDs, including diet-induced obesity, atherosclerosis, and inflammation-associated colorectal cancer.
Asunto(s)
Disbiosis , Metabolismo Energético , Microbioma Gastrointestinal , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Enfermedades no Transmisibles/epidemiología , Animales , Colon/metabolismo , Colon/microbiología , Susceptibilidad a Enfermedades , Enterobacteriaceae/metabolismo , Humanos , Obesidad/complicaciones , Obesidad/metabolismo , Oxidación-Reducción , Medición de Riesgo , Factores de RiesgoRESUMEN
KEY POINTS: â¢Nucleotide binding oligomerization domain (Nod)-like receptors regulate cognition, anxiety and hypothalamic-pituitary-adrenal axis activation. â¢Nod-like receptors regulate central and peripheral serotonergic biology. â¢Nod-like receptors are important for maintenance of gastrointestinal physiology. â¢Intestinal epithelial cell expression of Nod1 receptors regulate behaviour. ABSTRACT: Gut-brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre+ Nod1f/f ), but not Nod2, increased susceptibility to stress-induced anxiety-like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.
Asunto(s)
Encéfalo/metabolismo , Mucosa Intestinal/metabolismo , Proteína Adaptadora de Señalización NOD1/metabolismo , Proteína Adaptadora de Señalización NOD2/metabolismo , Serotonina/metabolismo , Transmisión Sináptica , Animales , Ansiedad/etiología , Ansiedad/metabolismo , Encéfalo/fisiología , Células Cultivadas , Cognición , Femenino , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiología , Absorción Intestinal , Mucosa Intestinal/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Neurogénesis , Proteína Adaptadora de Señalización NOD1/genética , Proteína Adaptadora de Señalización NOD2/genética , Estrés Psicológico/etiología , Estrés Psicológico/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.
Asunto(s)
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
Carbapenemase-producing Enterobacteriaceae are an emerging threat to hospitals worldwide, and antibiotic exposure is a risk factor for developing fecal carriage that may lead to nosocomial infection. Here, we review how antibiotics reduce colonization resistance against Enterobacteriaceae to pinpoint possible control points for curbing their spread. Recent work identifies host-derived respiratory electron acceptors as a critical resource driving a post-antibiotic expansion of Enterobacteriaceae within the large bowel. By providing a conceptual framework for colonization resistance against Enterobacteriaceae, these mechanistic insights point to the metabolism of epithelial cells as a possible target for intervention strategies.
Asunto(s)
Antibacterianos/uso terapéutico , Bacterias , Infecciones Bacterianas , Farmacorresistencia Bacteriana , Microbioma Gastrointestinal , Intestinos/microbiología , Animales , Bacterias/genética , Bacterias/metabolismo , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/genética , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/patología , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Humanos , Intestinos/patologíaRESUMEN
Salmonella enterica serotype Typhimurium is able to expand in the lumen of the inflamed intestine through mechanisms that have not been fully resolved. Here we utilized streptomycin-pretreated mice and dextran sodium sulfate (DSS)-treated mice to investigate how pathways for S. Typhimurium iron acquisition contribute to pathogen expansion in the inflamed intestine. Competitive infection with an iron uptake-proficient S. Typhimurium strain and mutant strains lacking tonB feoB, feoB, tonB or iroN in streptomycin pretreated mice demonstrated that ferric iron uptake requiring IroN and TonB conferred a fitness advantage during growth in the inflamed intestine. However, the fitness advantage conferred by ferrous iron uptake mechanisms was independent of inflammation and was only apparent in models where the normal microbiota composition had been disrupted by antibiotic treatment.
Asunto(s)
Gastroenteritis/microbiología , Intestinos/microbiología , Hierro/metabolismo , Redes y Vías Metabólicas/genética , Infecciones por Salmonella/microbiología , Salmonella typhimurium/metabolismo , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Bovinos , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones Endogámicos C57BL , Factores de Virulencia/genética , Factores de Virulencia/metabolismoRESUMEN
The food-borne pathogen Salmonella enterica serovar Typhimurium benefits from acute inflammation in part by using host-derived nitrate to respire anaerobically and compete successfully with the commensal microbes during growth in the intestinal lumen. The S. Typhimurium genome contains three nitrate reductases, encoded by the narGHI, narZYV, and napABC genes. Work on homologous genes present in Escherichia coli suggests that nitrate reductase A, encoded by the narGHI genes, is the main enzyme promoting growth on nitrate as an electron acceptor in anaerobic environments. Using a mouse colitis model, we found, surprisingly, that S. Typhimurium strains with defects in either nitrate reductase A (narG mutant) or the regulator inducing its transcription in the presence of high concentrations of nitrate (narL mutant) exhibited growth comparable to that of wild-type S. Typhimurium. In contrast, a strain lacking a functional periplasmic nitrate reductase (napA mutant) exhibited a marked growth defect in the lumen of the colon. In E. coli, the napABC genes are transcribed maximally under anaerobic growth conditions in the presence of low nitrate concentrations. Inactivation of narP, encoding a response regulator that activates napABC transcription in response to low nitrate concentrations, significantly reduced the growth of S. Typhimurium in the gut lumen. Cecal nitrate measurements suggested that the murine cecum is a nitrate-limited environment. Collectively, our results suggest that S. Typhimurium uses the periplasmic nitrate reductase to support its growth on the low nitrate concentrations encountered in the gut, a strategy that may be shared with other enteric pathogens.
Asunto(s)
Colitis/microbiología , Intoxicación Alimentaria por Salmonella/enzimología , Salmonella typhimurium/crecimiento & desarrollo , Salmonella typhimurium/patogenicidad , Animales , Colitis/enzimología , Modelos Animales de Enfermedad , Ratones , Nitrato Reductasas/metabolismo , Periplasma/enzimología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Salmonella typhimurium/enzimologíaRESUMEN
A recent study published in mBio by Nemet et al. revealed the critical role played by two gut microbiota members in producing the metabolites indoxyl sulfate (IS) and p-cresol sulfate (pCS) (I. Nemet, M. Funabashi,X. S. Li, M. Dwidar, et al., 2023, mBio 14:e01331-23, https://doi.org/10.1128/mbio.01331-23). Understanding microbial pathways leading to IS and pCS production is crucial because they are connected to a pre-thrombotic profile, and having high levels of these metabolites increases the risk of cardiovascular diseases (CVD). Hence, this study can offer vital insights into assessing the risk for CVD and identifying potential treatment targets for this disease.
Asunto(s)
Enfermedades Cardiovasculares , Cresoles , Microbiota , Ésteres del Ácido Sulfúrico , Trombosis , Humanos , IndicánRESUMEN
Inflammation boosts the availability of electron acceptors in the intestinal lumen, creating a favorable niche for pathogenic Enterobacteriaceae. However, the mechanisms linking intestinal inflammation-mediated changes in luminal metabolites and pathogen expansion remain unclear. Here, we show that mucosal inflammation induced by Salmonella enterica serovar Typhimurium (S. Tm) infection increases intestinal levels of the amino acid aspartate. S. Tm used aspartate-ammonia lyase (aspA)-dependent fumarate respiration for growth in the murine gut only during inflammation. AspA-dependent growth advantage was abolished in the gut of germ-free mice and restored in gnotobiotic mice colonized with members of the classes Bacteroidia and Clostridia. Reactive oxygen species (ROS) produced during the host response caused lysis of commensal microbes, resulting in the release of microbiota-derived aspartate that was used by S. Tm, in concert with nitrate-dependent anaerobic respiration, to outcompete commensal Enterobacteriaceae. Our findings demonstrate the role of microbiota-derived amino acids in driving respiration-dependent S. Tm expansion during colitis.
Asunto(s)
Ácido Aspártico , Microbioma Gastrointestinal , Especies Reactivas de Oxígeno , Salmonella typhimurium , Animales , Ratones , Especies Reactivas de Oxígeno/metabolismo , Ácido Aspártico/metabolismo , Colitis/microbiología , Colitis/metabolismo , Ratones Endogámicos C57BL , Enterobacteriaceae/metabolismo , Vida Libre de Gérmenes , Inflamación/microbiología , Inflamación/metabolismo , Infecciones por Salmonella/microbiología , Infecciones por Salmonella/inmunologíaRESUMEN
Salmonella Typhimurium is an enteric pathogen that employs a variety of mechanisms to exploit inflammation resulting in expansion in the intestinal tract, but host factors that contribute to or counteract the luminal expansion are not well-defined. Endoplasmic reticulum (ER) stress induces inflammation and plays an important role in the pathogenesis of infectious diseases. However, little is known about the contribution of ER stress-induced inflammation during Salmonella pathogenesis. Here, we demonstrate that the ER stress markers Hspa5 and Xbp1 are induced in the colon of S. Typhimurium infected mice, but the pro-apoptotic transcription factor Ddit3, that encodes for the protein CHOP, is significantly downregulated. S. Typhimurium-infected mice deficient for CHOP displayed a significant decrease in inflammation, colonization, dissemination, and pathology compared to littermate control mice. Preceding the differences in S. Typhimurium colonization, a significant decrease in Nos2 gene and iNOS protein expression was observed. Deletion of Chop decreased the bioavailability of nitrate in the colon leading to reduced fitness advantage of wild type S. Typhimurium over a napA narZ narG mutant strain (deficient in nitrate respiration). CD11b+ myeloid cells, but not intestinal epithelial cells, produced iNOS resulting in nitrate bioavailability for S. Typhimurium to expand in the intestinal tract in a CHOP-dependent manner. Altogether our work demonstrates that the host protein CHOP facilitates iNOS expression in CD11b+ cells thereby contributing to luminal expansion of S. Typhimurium via nitrate respiration.
RESUMEN
The mouse cecum has emerged as a model system for studying microbe-host interactions, immunoregulatory functions of the microbiome, and metabolic contributions of gut bacteria. Too often, the cecum is falsely considered as a uniform organ with an evenly distributed epithelium. We developed the cecum axis (CecAx) preservation method to show gradients in epithelial tissue architecture and cell types along the cecal ampulla-apex and mesentery-antimesentery axes. We used imaging mass spectrometry of metabolites and lipids to suggest functional differences along these axes. Using a model of Clostridioides difficile infection, we show how edema and inflammation are unequally concentrated along the mesenteric border. Finally, we show the similarly increased edema at the mesenteric border in two models of Salmonella enterica serovar Typhimurium infection as well as enrichment of goblet cells along the antimesenteric border. Our approach facilitates mouse cecum modeling with detailed attention to inherent structural and functional differences within this dynamic organ.
Asunto(s)
Microbioma Gastrointestinal , Animales , Ratones , Ciego , Epitelio , Células Caliciformes , Interacciones Microbiota-HuespedRESUMEN
One of the major contributors to child mortality in the world is diarrheal diseases, with an estimated 800,000 deaths per year. Many pathogens are causative agents of these illnesses, including the enteropathogenic (EPEC) or enterohemorrhagic (EHEC) forms of Escherichia coli. These bacteria are characterized by their ability to cause attaching and effacing lesions in the gut mucosa. Although much has been learned about the pathogenicity of these organisms and the immune response against them, the role of the intestinal microbiota during these infections is not well characterized. Infection of mice with E. coli requires pre-treatment with antibiotics in most mouse models, which hinders the study of the microbiota in an undisturbed environment. Using Citrobacter rodentium as a murine model for attaching and effacing bacteria, we show that C57BL/6 mice deficient in granzyme B expression are highly susceptible to severe disease caused by C. rodentium infection. Although a previous publication from our group shows that granzyme B-deficient CD4+ T cells are partially responsible for this phenotype, in this report we present data demonstrating that the microbiota, in particular members of the order Turicibacterales, have an important role in conferring resistance. Mice deficient in Turicibacter sanguinis have increased susceptibility to severe disease. However, when these mice are co-housed with resistant mice, or colonized with T. sanguinis, susceptibility to severe infection is reduced. These results clearly suggest a critical role for this commensal in the protection against entero-pathogens.
RESUMEN
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.