RESUMEN
The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones1-5. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco+ immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco+ macrophages. Functional ablation of Marco+ macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco+ immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.
Asunto(s)
Colangitis Esclerosante , Microbioma Gastrointestinal , Inflamación , Hígado , Macrófagos , Enfermedad del Hígado Graso no Alcohólico , Simbiosis , Animales , Femenino , Humanos , Masculino , Ratones , Bacteroidetes/metabolismo , Colangitis Esclerosante/inmunología , Colangitis Esclerosante/microbiología , Colangitis Esclerosante/patología , Microbioma Gastrointestinal/inmunología , Microbioma Gastrointestinal/fisiología , Perfilación de la Expresión Génica , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Interleucina-10/inmunología , Interleucina-10/metabolismo , Hígado/inmunología , Hígado/patología , Hígado/microbiología , Macrófagos/citología , Macrófagos/inmunología , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/microbiología , Enfermedad del Hígado Graso no Alcohólico/patología , Vena Porta , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/metabolismo , Análisis de la Célula Individual , Simbiosis/inmunologíaRESUMEN
Gut commensal bacteria with the ability to translocate across the intestinal barrier can drive the development of diverse immune-mediated diseases1-4. However, the key factors that dictate bacterial translocation remain unclear. Recent studies have revealed that gut microbiota strains can adapt and evolve throughout the lifetime of the host5-9, raising the possibility that changes in individual commensal bacteria themselves over time may affect their propensity to elicit inflammatory disease. Here we show that within-host evolution of the model gut pathobiont Enterococcus gallinarum facilitates bacterial translocation and initiation of inflammation. Using a combination of in vivo experimental evolution and comparative genomics, we found that E. gallinarum diverges into independent lineages adapted to colonize either luminal or mucosal niches in the gut. Compared with ancestral and luminal E. gallinarum, mucosally adapted strains evade detection and clearance by the immune system, exhibit increased translocation to and survival within the mesenteric lymph nodes and liver, and induce increased intestinal and hepatic inflammation. Mechanistically, these changes in bacterial behaviour are associated with non-synonymous mutations or insertion-deletions in defined regulatory genes in E. gallinarum, altered microbial gene expression programs and remodelled cell wall structures. Lactobacillus reuteri also exhibited broadly similar patterns of divergent evolution and enhanced immune evasion in a monocolonization-based model of within-host evolution. Overall, these studies define within-host evolution as a critical regulator of commensal pathogenicity that provides a unique source of stochasticity in the development and progression of microbiota-driven disease.
Asunto(s)
Bacterias , Traslocación Bacteriana , Evolución Biológica , Microbioma Gastrointestinal , Hígado , Bacterias/genética , Bacterias/inmunología , Bacterias/patogenicidad , Traslocación Bacteriana/genética , Pared Celular/genética , Enterococcus/genética , Enterococcus/inmunología , Microbioma Gastrointestinal/genética , Genómica , Interacciones Huésped-Patógeno/inmunología , Humanos , Inflamación/microbiología , Inflamación/patología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Limosilactobacillus reuteri/genética , Limosilactobacillus reuteri/inmunología , Hígado/microbiología , Hígado/patología , Ganglios Linfáticos/microbiología , Mutación , Procesos Estocásticos , Simbiosis/genética , Simbiosis/inmunologíaRESUMEN
The liver connects the intestinal portal vasculature with the general circulation, using a diverse array of immune cells to protect from pathogens that translocate from the gut1. In liver lobules, blood flows from portal triads that are situated in periportal lobular regions to the central vein via a polarized sinusoidal network. Despite this asymmetry, resident immune cells in the liver are considered to be broadly dispersed across the lobule. This differs from lymphoid organs, in which immune cells adopt spatially biased positions to promote effective host defence2,3. Here we used quantitative multiplex imaging, genetic perturbations, transcriptomics, infection-based assays and mathematical modelling to reassess the relationship between the localization of immune cells in the liver and host protection. We found that myeloid and lymphoid resident immune cells concentrate around periportal regions. This asymmetric localization was not developmentally controlled, but resulted from sustained MYD88-dependent signalling induced by commensal bacteria in liver sinusoidal endothelial cells, which in turn regulated the composition of the pericellular matrix involved in the formation of chemokine gradients. In vivo experiments and modelling showed that this immune spatial polarization was more efficient than a uniform distribution in protecting against systemic bacterial dissemination. Together, these data reveal that liver sinusoidal endothelial cells sense the microbiome, actively orchestrating the localization of immune cells, to optimize host defence.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Hígado/inmunología , Hígado/microbiología , Simbiosis/inmunología , Animales , Bacterias/inmunología , Bacterias/aislamiento & purificación , Separación Celular , Quimiocina CXCL9/inmunología , Células Endoteliales/citología , Células Endoteliales/inmunología , Femenino , Humanos , Macrófagos del Hígado/citología , Macrófagos del Hígado/inmunología , Macrófagos del Hígado/metabolismo , Hígado/irrigación sanguínea , Hígado/citología , Linfocitos/inmunología , Masculino , Ratones , Modelos Inmunológicos , Imagen Molecular , Células Mieloides/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Transducción de Señal , Simbiosis/genética , TranscriptomaRESUMEN
The liver is positioned at the interface between two routes traversed by pathogens in disseminating infection. Whereas blood-borne pathogens are efficiently cleared in hepatic sinusoids by Kupffer cells (KCs), it is unknown how the liver prevents dissemination of peritoneal pathogens accessing its outer membrane. We report here that the hepatic capsule harbors a contiguous cellular network of liver-resident macrophages phenotypically distinct from KCs. These liver capsular macrophages (LCMs) were replenished in the steady state from blood monocytes, unlike KCs that are embryonically derived and self-renewing. LCM numbers increased after weaning in a microbiota-dependent process. LCMs sensed peritoneal bacteria and promoted neutrophil recruitment to the capsule, and their specific ablation resulted in decreased neutrophil recruitment and increased intrahepatic bacterial burden. Thus, the liver contains two separate and non-overlapping niches occupied by distinct resident macrophage populations mediating immunosurveillance at these two pathogen entry points to the liver.
Asunto(s)
Macrófagos del Hígado/fisiología , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Hígado/inmunología , Macrófagos/inmunología , Neutrófilos/inmunología , Peritoneo/microbiología , Animales , Comunicación Celular , Autorrenovación de las Células , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Macrófagos del Hígado/microbiología , Hígado/microbiología , Hígado/patología , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Infiltración Neutrófila , Peritoneo/patologíaRESUMEN
Through the use of intravital imaging of the liver, we demonstrate a collaborative role for platelets with Kupffer cells (KCs) in eradicating blood-borne bacterial infection. Under basal conditions, platelets, via the platelet-adhesion receptor GPIb, formed transient 'touch-and-go' interactions with von Willebrand factor (vWF) constitutively expressed on KCs. Bacteria such as Bacillus cereus and methicillin-resistant Staphylococcus aureus (MRSA) were rapidly caught by KCs and triggered platelets to switch from 'touch-and-go' adhesion to sustained GPIIb-mediated adhesion on the KC surface to encase the bacterium. Infected GPIbα-deficient mice had more endothelial and KC damage than did their wild-type counterparts, which led to more fluid leakage, substantial polycythemia and rapid mortality. Our study identifies a previously unknown surveillance mechanism by which platelets survey macrophages that rapidly converts to a critical host response to blood-borne bacteria.
Asunto(s)
Bacillus cereus/inmunología , Plaquetas/microbiología , Macrófagos del Hígado/microbiología , Hígado/microbiología , Staphylococcus aureus Resistente a Meticilina/inmunología , Activación Plaquetaria/inmunología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/inmunología , Animales , Plaquetas/inmunología , Inmunidad Innata/inmunología , Macrófagos del Hígado/inmunología , Hígado/citología , Hígado/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Adhesividad Plaquetaria/inmunología , Organismos Libres de Patógenos EspecíficosRESUMEN
Kupffer cells, the phagocytes of fetal origin that line the liver sinusoids, are key contributors of host defense against enteroinvasive bacteria. Here, we found that infection by Listeria monocytogenes induced the early necroptotic death of Kupffer cells, which was followed by monocyte recruitment and an anti-bacterial type 1 inflammatory response. Kupffer cell death also triggered a type 2 response that involved the hepatocyte-derived alarmin interleukin-33 (IL-33) and basophil-derived interleukin-4 (IL-4). This led to the alternative activation of the monocyte-derived macrophages recruited to the liver, which thereby replaced ablated Kupffer cells and restored liver homeostasis. Kupffer cell death is therefore a key signal orchestrating type 1 microbicidal inflammation and type-2-mediated liver repair upon infection. This indicates that beyond the classical dichotomy of type 1 and type 2 responses, these responses can develop sequentially in the context of a bacterial infection and act interdependently, orchestrating liver immune responses and return to homeostasis, respectively.
Asunto(s)
Macrófagos del Hígado/fisiología , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Hígado/patología , Monocitos/inmunología , Animales , Diferenciación Celular , Células Cultivadas , Vía Alternativa del Complemento , Homeostasis , Inflamación/microbiología , Interleucina-33 , Interleucina-4/metabolismo , Interleucinas/metabolismo , Macrófagos del Hígado/microbiología , Hígado/microbiología , Ratones , Ratones Endogámicos , Monocitos/microbiología , Necrosis , Fagocitosis , Cicatrización de HeridasRESUMEN
A taxogenomic study of three strains (3986T, 51.81, and JF 2415) isolated from rabbits between 1972 and 2000 led to the description of a new Neisseria species. The highest sequence similarity of the 16S rRNA gene was found to Neisseria animalis NCTC 10212T (96.7â%). The 16S rRNA gene similarity above 99â% and average nucleotide identity (ANI) values above 96â% among the strains, indicated that they belong to the same species. At the same time, the strains shared ANI values below 81â% and dDDH values below 24â% with all described Neisseria species. In the bac120 gene phylogenetic tree, the three strains clustered near Neisseria elongata and Neisseria bacilliformis in the Neisseria clade. However, the Neisseria clade is not monophyletic, and includes the type strains of Morococcus cerebrosus, Bergeriella denitrificans, Kingella potus, Uruburuella suis, and Uruburuella testudinis. Neisseria shayeganii clustered outside the clade with members of the genus Eikenella. Amino acid identity (AAI) values were calculated, and a threshold of 71â% was used to circumscribe the genus Neisseria. According to this proposed AAI threshold, strains 3986T, 51.81, and JF 2415 were placed within the genus Neisseria. The cells of the three strains were Gram-stain-negative diplococcobacilli and non-motile. Optimal growth on trypticase soy agar occurred at 37 °C and pH 8.5 in aerobic conditions. Notably, all strains exhibited indole production in the API-NH test, which is atypical for Neisseria and the family Neisseriaceae. The strains exhibited a common set of 68 peaks in their MALDI-TOF MS profiles, facilitating the swift and accurate identification of this species. Based on genotypic and phenotypic data, it is proposed that strains 3986T, 51.81, and JF 2415 represent a novel species within the genus Neisseria, for which the name Neisseria leonii sp. nov. is proposed (type strain 3986T=R726T=CIP 109994T=LMG 32907T).
Asunto(s)
Técnicas de Tipificación Bacteriana , ADN Bacteriano , Hígado , Pulmón , Neisseria , Filogenia , ARN Ribosómico 16S , Análisis de Secuencia de ADN , Animales , Conejos , ARN Ribosómico 16S/genética , Neisseria/aislamiento & purificación , Neisseria/clasificación , Neisseria/genética , ADN Bacteriano/genética , Hígado/microbiología , Pulmón/microbiología , Ácidos Grasos/análisis , Composición de BaseRESUMEN
The gut microbiota, amounting to approximately 100 trillion (1014) microbes represents a genetic repertoire that is bigger than the human genome itself. Evidence on bidirectional interplay between human and microbial genes is mounting. Microbiota probably play vital roles in diverse aspects of normal human metabolism, such as digestion, immune modulation, and gut endocrine function, as well as in the genesis and progression of many human diseases. Indeed, the gut microbiota has been most closely linked to various chronic ailments affecting the liver, although concrete scientific data are sparse. In this narrative review, we initially discuss the basic epidemiology of gut microbiota and the factors influencing their initial formation in the gut. Subsequently, we delve into the gut-liver axis and the evidence regarding the link between gut microbiota and the genesis or progression of various liver diseases. Finally, we summarise the recent research on plausible ways to modulate the gut microbiota to alter the natural history of liver disease.
Asunto(s)
Microbioma Gastrointestinal , Hepatopatías , Hígado , Humanos , Hígado/microbiología , Hepatopatías/microbiología , Animales , Tracto Gastrointestinal/microbiologíaRESUMEN
Yeasts are unicellular eukaryotic microorganisms extensively employed in various applications, notably as an alternative source of protein in feeds, owing to their nutritional benefits. Despite their potential, marine and mangrove yeast species used in the aquaculture industry have received little attention in the Philippines. Pichia kudriavzevii (A2B R1 ISO 3), sourced from bark samples, was selected and mass-produced due to its high protein content and amino acid profile. The dried biomass of P. kudriavzevii was incorporated into the diets of Nile tilapia (Oreochromis niloticus) juveniles at varying inclusion levels (0, 1, 2, and 4 g/kg diet) and its effect on their growth performance, body composition, and liver and intestinal morphology was assessed after 40 days of feeding. The groups that received P. kudriavzevii at a concentration of 2 g/kg diet exhibited higher final body weight, percent weight gain, and specific growth rate in comparison to the other treatment groups. Whole body proximate composition did not vary among the dietary groups. Intestinal and liver histopathology also indicated no abnormalities. These findings suggest the potential of ascomycetous P. kudriavzevii as a beneficial feed additive in Nile tilapia diets, warranting further investigation into its long-term effects and broader applications in fish culture.
Asunto(s)
Alimentación Animal , Acuicultura , Cíclidos , Pichia , Animales , Alimentación Animal/análisis , Cíclidos/crecimiento & desarrollo , Cíclidos/microbiología , Pichia/crecimiento & desarrollo , Pichia/aislamiento & purificación , Pichia/metabolismo , Dieta/veterinaria , Hígado/microbiología , Intestinos/microbiología , Suplementos Dietéticos/análisis , FilipinasRESUMEN
Gut microbiota (GM) has been proven to resist pathogenic infection through nutritional competition, colonization resistance and promotion of the host immune response. However, in clinical practice, GM is mainly used in intestinal diseases, such as Clostridium difficile infection, and there are few reports on its application in the treatment of pathogenic bacterial infections. In this study, GM from healthy mice was transplanted into mice infected with Listeria monocytogenes using fecal microbiota transplantation (FMT) and the effects were observed. We found that GM from healthy mice could reduce the mortality of infected mice and decrease the counts of L. monocytogenes in their liver and spleen. In addition, FMT inhibited the expression of inflammatory factors in the liver and spleen of infected mice. In vitro cell experiments revealed that GM can reduce the count of L. monocytogenes invading Caco-2 cells and inhibit the L. monocytogenes-caused apoptosis. These results indicate that GM can be used to protect mice infected with L. monocytogenes by eliminating the amount of L. monocytogenes in the host and inhibiting the overexpression of inflammatory factors. Hence, this method can potentially replace antibiotics in the treatment of L. monocytogenes infection.
Asunto(s)
Apoptosis , Citocinas , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Listeria monocytogenes , Listeriosis , Animales , Listeriosis/microbiología , Listeriosis/inmunología , Ratones , Citocinas/metabolismo , Humanos , Células CACO-2 , Hígado/microbiología , Bazo/microbiología , FemeninoRESUMEN
Connections between the microbiome and health are rapidly emerging in a wide range of diseases. However, a detailed mechanistic understanding of how different microbial communities are influencing their hosts is often lacking. One method researchers have used to understand these effects are germ-free (GF) mouse models. Differences found within the organ systems of these model organisms may highlight generalizable mechanisms that microbiome dysbioses have throughout the host. Here, we applied multiplexed, quantitative proteomics on the brains, spleens, hearts, small intestines, and colons of conventionally raised and GF mice, identifying associations to colonization state in over 7000 proteins. Highly ranked associations were constructed into protein-protein interaction networks and visualized onto an interactive 3D mouse model for user-guided exploration. These results act as a resource for microbiome researchers hoping to identify host effects of microbiome colonization on a given organ of interest. Our results include validation of previously reported effects in xenobiotic metabolism, the innate immune system, and glutamate-associated proteins while simultaneously providing organism-wide context. We highlight organism-wide differences in mitochondrial proteins including consistent increases in NNT, a mitochondrial protein with essential roles in influencing levels of NADH and NADPH, in all analyzed organs of conventional mice. Our networks also reveal new associations for further exploration, including protease responses in the spleen, high-density lipoproteins in the heart, and glutamatergic signaling in the brain. In total, our study provides a resource for microbiome researchers through detailed tables and visualization of the protein-level effects of microbial colonization on several organ systems.
Asunto(s)
Disbiosis/genética , Microbioma Gastrointestinal/genética , Interacciones Huésped-Patógeno/genética , Proteómica , Animales , Encéfalo/metabolismo , Encéfalo/microbiología , Colon/metabolismo , Colon/microbiología , Disbiosis/microbiología , Corazón/microbiología , Humanos , Intestino Delgado/metabolismo , Intestino Delgado/microbiología , Hígado/metabolismo , Hígado/microbiología , Ratones , Bazo/metabolismo , Bazo/microbiologíaRESUMEN
Microbiome alterations are emerging as one of the most important factors that influence the course of alcohol use disorder (AUD). Recent advances in bioinformatics enable more robust and accurate characterization of changes in the composition of the microbiome. In this study, our objective was to provide the most comprehensive and up-to-date evaluation of microbiome alterations associated with AUD and alcoholic liver disease (ALD). To achieve it, we have applied consistent, state of art bioinformatic workflow to raw reads from multiple 16S rRNA sequencing datasets. The study population consisted of 122 patients with AUD, 75 with ALD, 54 with non-alcoholic liver diseases, and 260 healthy controls. We have found several microbiome alterations that were consistent across multiple datasets. The most consistent changes included a significantly lower abundance of multiple butyrate-producing families, including Ruminococcaceae, Lachnospiraceae, and Oscillospiraceae in AUD compared to HC and further reduction of these families in ALD compared with AUD. Other important results include an increase in endotoxin-producing Proteobacteria in AUD, with the ALD group having the largest increase. All of these alterations can potentially contribute to increased intestinal permeability and inflammation associated with AUD and ALD.
Asunto(s)
Alcoholismo , Microbioma Gastrointestinal , Lactobacillales , Hepatopatías Alcohólicas , Microbiota , Humanos , Alcoholismo/genética , Alcoholismo/microbiología , ARN Ribosómico 16S/genética , Microbioma Gastrointestinal/genética , Hepatopatías Alcohólicas/microbiología , Lactobacillales/genética , Hígado/microbiologíaRESUMEN
Cryptococcosis infection after transplantation is easily overlooked or misdiagnosed. We report a cluster of donor-derived cryptococcosis infection in liver and kidney transplant recipients from the same donor in China. Infections occurred within 1 month after transplantation, and were confirmed by using biopsies and blood tests.
Asunto(s)
Criptococosis , Cryptococcus neoformans , Trasplante de Riñón , Riñón , Trasplante de Hígado , Hígado , Complicaciones Posoperatorias , Criptococosis/diagnóstico , Criptococosis/epidemiología , Cryptococcus neoformans/aislamiento & purificación , Humanos , Huésped Inmunocomprometido , Riñón/microbiología , Trasplante de Riñón/efectos adversos , Hígado/microbiología , Trasplante de Hígado/efectos adversos , Donantes de Tejidos , Resultado del TratamientoRESUMEN
Formyl peptide receptors (FPRs, mouse Fprs) belong to the G protein-coupled receptor superfamily and mediate phagocyte migration in response to bacteria- and host-derived chemoattractants; however, knowledge about their in vivo roles in bacterial pathogenesis is limited. In this study, we investigated the role of Fpr1 and Fpr2 in host defense against Escherichia coli infection. In vitro, we found that supernatants from E. coli cultures induced chemotaxis of wild-type (WT) mouse bone marrow-derived neutrophils and that the activity was significantly reduced in cells genetically deficient in either Fpr1 or Fpr2 and was almost absent in cells lacking both receptors. Consistent with this, E. coli supernatants induced chemotaxis and MAPK phosphorylation in HEK293 cells expressing either recombinant Fpr1 or Fpr2 but not untransfected parental cells. WT bone marrow -derived neutrophils could actively phagocytose and kill E. coli, whereas both activities were diminished in cells lacking Fpr1 or Fpr2; again, an additive effect was observed in cells lacking both receptors. In vivo, Fpr1 and Fpr2 deficiency resulted in reduced recruitment of neutrophils in the liver and peritoneal cavity of mice infected with inactivated E. coli Moreover, Fpr1-/- and Fpr2-/- mice had significantly increased mortality compared with WT mice after i.p. challenge with a virulent E. coli clinical isolate. These results indicate a critical role of Fprs in host defense against E. coli infection.
Asunto(s)
Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/metabolismo , Escherichia coli/inmunología , Receptores de Formil Péptido/inmunología , Receptores de Formil Péptido/metabolismo , Animales , Médula Ósea/inmunología , Médula Ósea/metabolismo , Médula Ósea/microbiología , Células Cultivadas , Quimiotaxis/inmunología , Células HEK293 , Humanos , Hígado/inmunología , Hígado/metabolismo , Hígado/microbiología , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/inmunología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/microbiología , Cavidad Peritoneal/microbiología , Fagocitosis/inmunología , Fosforilación/inmunologíaRESUMEN
Bifidobacterium pseudocatenulatum LI09 could prevent D-galactosamine-induced liver injury. Our previous study has preliminarily determined that different intestinal microbiota profiles existed in the LI09-treated rats. Due to the sample size limitation, some subsequent analyses could not be achieved. In the current study, we conducted different experiments and bioinformatic analyses to characterise the distinct intestinal bacterial microbiota profiles in the LI09-treated rats with liver injury (i.e., LI09 group). Partition around medoids clustering analysis determined two intestinal microbiota profiles (i.e., Cluster_1_LI09 and Cluster_2_LI09) in LI09 group. Compared with Cluster_2_LI09, Cluster_1_LI09 group was determined at less dysbiotic microbial status and with lower level of liver injury. The two microbiota profiles were determined with distinct representative amplicon sequence variants (ASVs), among which, ASV1_Akkermansia and ASV3_Bacteroides were most associated with Cluster_1_LI09 and Cluster_2_LI09, respectively. Multiple representative phylotypes in Cluster_1_LI09 negatively correlating with liver function variables were assigned to Parabacteroides, suggesting Parabacteroides could benefit LI09 on modulating the liver function. In addition, ASV310_Lachnospiraceae, ASV501_Muribaculaceae and ASV484_Lachnospiraceae were determined as network gatekeepers in Cluster_1_LI09 network. The relevant results suggest that some intestinal bacteria could assist LI09 in lowering the intestinal microbial dysbiosis in the rats with liver injury, and their clinical application deserves further investigation.
Asunto(s)
Bifidobacterium pseudocatenulatum , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Microbioma Gastrointestinal , Microbiota , Ratas , Animales , Galactosamina/toxicidad , Hígado/microbiología , Disbiosis , BacteriasRESUMEN
BACKGROUND: Base excision repair (BER), consisting mostly of lesion-specific DNA glycosylases and apurinic/apyrimidinic (AP) endonucleases, is one of the most important DNA repair mechanisms for repair of single nucleobase lesions generated by reactive oxygen and nitrogen species as part of an immune response against bacterial infections. However, few studies have addressed the contribution of BER to bacterial virulence and Listeria monocytogenes BER has thus far remained completely uncharacterized. METHODS: Analysis of the L. monocytogenes EGDe genome identified 7 DNA glycosylases (MutM, MutY, Nth, Tag, Mpg, Ung, and Ung2) and 2 apurinic/apyrimidinic endonucleases (Xth and Nfo) as part of BER. Markerless in-frame deletion mutants were generated for all 9 genes, and mutants were tested for DNA damage survival, mutagenesis, and the ability to colonize a mouse model of infection. RESULTS: Distinct lesion-specific phenotypes were identified for all deletion mutants. Importantly, the Δnth, ΔmutY, and Δnfo mutants were significantly attenuated for virulence in the mouse model and showed much lower colonization of the liver and spleen or were unable to compete with the wild-type strain during in vivo competition assays. CONCLUSIONS: Our results highlight the importance of BER for L. monocytogenes virulence and survival of DNA-damaging insults during host colonization.
Asunto(s)
Reparación del ADN , ADN Bacteriano/metabolismo , Listeria monocytogenes/genética , Listeria monocytogenes/patogenicidad , Listeriosis/microbiología , Macrófagos/microbiología , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Daño del ADN , ADN Glicosilasas/genética , ADN Glicosilasas/metabolismo , Reparación del ADN/genética , ADN Bacteriano/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Femenino , Genes Bacterianos , Humanos , Listeria monocytogenes/crecimiento & desarrollo , Listeria monocytogenes/metabolismo , Hígado/microbiología , Ratones , Ratones Endogámicos BALB C , Eliminación de Secuencia , Bazo/microbiología , Células THP-1RESUMEN
The gut and the liver have a bidirectional communication via the biliary system and the portal vein. The intestinal microbiota and microbial products play an important role for modulating liver diseases such as alcohol-associated liver disease, non-alcoholic fatty liver disease and steatohepatitis, and cholestatic liver diseases. Here, we review the role of the gut microbiota and its products for the pathogenesis and therapy of chronic liver diseases.
Asunto(s)
Microbioma Gastrointestinal , Hepatopatías/microbiología , Hepatopatías/patología , Hígado/microbiología , Hígado/patología , Animales , HumanosRESUMEN
BACKGROUND: In the last few decades, considerable attention has been paid to entomopathogenic fungi as biocontrol agents, however little is known about their mode of action and safety. This study aimed to investigate the toxicity of Aspergillus flavus in insect Spodoptera litura by analyzing the effect of fungal extract on antioxidant and cellular immune defense. In antioxidant defense, the lipid peroxidation (Malondialdehyde content) and antioxidant enzymes activities (Catalase, Ascorbate peroxidase, Superoxide dismutase) were examined. In cellular immune defense, effect of A. flavus extract was analyzed on haemocytes using Scanning Electron Microscopy (SEM). Furthermore, mammalian toxicity was analyzed with respect to DNA damage induced in treated rat relative to control by comet assay using different tissues of rat (blood, liver, and kidney). RESULTS: Ethyl acetate extract of A. flavus was administrated to the larvae of S.litura using artificial diet method having concentration 1340.84 µg/ml (LC50 of fungus). The effect was observed using haemolymph of insect larvae for different time intervals (24, 48, 72 and 96). In particular, Malondialdehyde content and antioxidant enzymes activities were found to be significantly (p ≤ 0.05) increased in treated larvae as compared to control. A. flavus ethyl acetate extract also exhibit negative impact on haemocytes having major role in cellular immune defense. Various deformities were observed in different haemocytes like cytoplasmic leakage and surface abnormalities etc. Genotoxicity on rat was assessed using different tissues of rat (blood, liver, and kidney) by comet assay. Non-significant effect of A. flavus extract was found in all the tissues (blood, liver, and kidney). CONCLUSIONS: Overall the study provides important information regarding the oxidative stress causing potential and immunosuppressant nature of A. flavus against S. litura and its non toxicity to mammals (rat), mammals (rat), suggesting it an environment friendly pest management agent.
Asunto(s)
Aspergillus flavus/fisiología , Mamíferos/metabolismo , Mamíferos/microbiología , Estrés Oxidativo , Spodoptera/microbiología , Animales , Daño del ADN , Riñón/inmunología , Riñón/metabolismo , Riñón/microbiología , Larva/genética , Larva/inmunología , Larva/metabolismo , Larva/microbiología , Hígado/inmunología , Hígado/metabolismo , Hígado/microbiología , Masculino , Malondialdehído/metabolismo , Mamíferos/genética , Mamíferos/inmunología , Ratas , Ratas Wistar , Spodoptera/genética , Spodoptera/inmunología , Spodoptera/metabolismoRESUMEN
Thrombosis is a frequent, life-threatening complication of systemic infection associated with multiple organ damage. We have previously described a novel mechanism of inflammation-driven thrombosis induced by Salmonella Typhimurium infection of mice. Thrombosis in the liver develops 7 days after infection, persisting after the infection resolves, and is monocytic cell dependent. Unexpectedly, thrombosis was not prominent in the spleen at this time, despite carrying a similar bacterial burden as the liver. In this study, we show that thrombosis does occur in the spleen but with strikingly accelerated kinetics compared with the liver, being evident by 24 hours and resolving rapidly thereafter. The distinct kinetics of thrombosis and bacterial burden provides a test of the hypothesis that thrombi form in healthy vessels to trap or remove bacteria from the circulation, often termed immunothrombosis. Remarkably, despite bacteria being detected throughout infected spleens and livers in the early days of infection, immunohistological analysis of tissue sections show that thrombi contain very low numbers of bacteria. In contrast, bacteria are present throughout platelet aggregates induced by Salmonella in vitro. Therefore, we show that thrombosis develops with organ-specific kinetics and challenge the universality of immunothrombosis as a mechanism to capture bacteria in vivo.
Asunto(s)
Hígado/microbiología , Infecciones por Salmonella/complicaciones , Salmonella typhimurium/patogenicidad , Bazo/microbiología , Trombosis/microbiología , Animales , Hígado/inmunología , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Infecciones por Salmonella/microbiología , Bazo/inmunología , Bazo/patología , Trombosis/inmunología , Trombosis/patologíaRESUMEN
BACKGROUND: Whole grain wheat (WGW) products are advocated as a healthy choice when compared with refined wheat (RW). One proposed mechanism for these health benefits is via the microbiota, because WGW contains multiple fibers. WGW consumption has been proposed to ameliorate nonalcoholic fatty liver disease, in which microbiota might play a role. OBJECTIVES: We investigated the effect of WGW compared with RW intervention on the fecal microbiota composition and functionality, and correlated intervention-induced changes in bacteria with changes in liver health parameters in adults with overweight or obesity. METHODS: We used data of a 12-wk double-blind, randomized, controlled, parallel trial to examine the effects of a WGW (98 g/d) or RW (98 g/d) intervention on the secondary outcomes fecal microbiota composition, predicted microbiota functionality, and stool consistency in 37 women and men (aged 45-70 y, BMI 25-35 kg/m2). The changes in microbiota composition, measured using 16S ribosomal RNA gene sequencing, after a 12-wk intervention were analyzed with nonparametric tests, and correlated with changes in liver fat and circulating concentrations of liver enzymes including alanine transaminase, aspartate transaminase, γ-glutamyltransferase, and serum amyloid A. RESULTS: The WGW intervention increased the mean (± SD) relative abundances of Ruminococcaceae_UCG-014 (baseline: 2.2 ± 4.6%, differential change over time (Δ) 0.51 ± 4.2%), Ruminiclostridium_9 (baseline: 0.065 ± 0.11%, Δ 0.054 ± 0.14%), and Ruminococcaceae_NK4A214_group (baseline: 0.37 ± 0.56%, Δ 0.17 ± 0.83%), and also the predicted pathway acetyl-CoA fermentation to butyrate II (baseline: 0.23 ± 0.062%, Δ 0.035 ± 0.059%), compared with the RW intervention (P values <0.05). A change in Ruminococcaceae_NK4A214_group was positively correlated with the change in liver fat, in both the WGW (ρ = 0.54; P = 0.026) and RW (ρ = 0.67; P = 0.024) groups. CONCLUSIONS: In middle-aged overweight and obese adults, a 12-wk WGW intervention increased the relative abundance of a number of bacterial taxa from the family Ruminococcaceae and increased predicted fermentation pathways when compared with an RW intervention. Potential protective health effects of replacement of RW by WGW on metabolic organs, such as the liver, via modulation of the microbiota, deserve further investigation.This trial was registered at clinicaltrials.gov as NCT02385149.