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1.
Nat Commun ; 11(1): 5104, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037214

RESUMO

Many intestinal pathogens, including Clostridioides difficile, use mucus-derived sugars as crucial nutrients in the gut. Commensals that compete with pathogens for such nutrients are therefore ecological gatekeepers in healthy guts, and are attractive candidates for therapeutic interventions. Nevertheless, there is a poor understanding of which commensals use mucin-derived sugars in situ as well as their potential to impede pathogen colonization. Here, we identify mouse gut commensals that utilize mucus-derived monosaccharides within complex communities using single-cell stable isotope probing, Raman-activated cell sorting and mini-metagenomics. Sequencing of cell-sorted fractions reveals members of the underexplored family Muribaculaceae as major mucin monosaccharide foragers, followed by members of Lachnospiraceae, Rikenellaceae, and Bacteroidaceae families. Using this information, we assembled a five-member consortium of sialic acid and N-acetylglucosamine utilizers that impedes C. difficile's access to these mucosal sugars and impairs pathogen colonization in antibiotic-treated mice. Our findings underscore the value of targeted approaches to identify organisms utilizing key nutrients and to rationally design effective probiotic mixtures.


Assuntos
Clostridium difficile/patogenicidade , Microbioma Gastrointestinal/fisiologia , Monossacarídeos/metabolismo , Acetilglucosamina/metabolismo , Animais , Antibacterianos , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Separação Celular/métodos , Infecções por Clostridium/microbiologia , Clostridium difficile/genética , Clostridium difficile/crescimento & desenvolvimento , Deutério , Feminino , Mucinas Gástricas/química , Mucinas Gástricas/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Metagenoma , Camundongos Endogâmicos C57BL , Ácido N-Acetilneuramínico/metabolismo , Polissacarídeos/química , Polissacarídeos/metabolismo , Análise Espectral Raman
2.
Front Immunol ; 11: 2192, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072084

RESUMO

During the last years probiotics gained the attention of clinicians for their use in the prevention and treatment of multiple diseases. Probiotics main mechanisms of action include enhanced mucosal barrier function, direct antagonism with pathogens, inhibition of bacterial adherence and invasion capacity in the intestinal epithelium, boosting of the immune system and regulation of the central nervous system. It is accepted that there is a mutual communication between the gut microbiota and the liver, the so-called "microbiota-gut-liver axis" as well as a reciprocal communication between the intestinal microbiota and the central nervous system through the "microbiota-gut-brain axis." Moreover, recently the "gut-lung axis" in bacterial and viral infections is considerably discussed for bacterial and viral infections, as the intestinal microbiota amplifies the alveolar macrophage activity having a protective role in the host defense against pneumonia. The importance of the normal human intestinal microbiota is recognized in the preservation of health. Disease states such as, infections, autoimmune conditions, allergy and other may occur when the intestinal balance is disturbed. Probiotics seem to be a promising approach to prevent and even reduce the symptoms of such clinical states as an adjuvant therapy by preserving the balance of the normal intestinal microbiota and improving the immune system. The present review states globally all different disorders in which probiotics can be given. To date, Stronger data in favor of their clinical use are provided in the prevention of gastrointestinal disorders, antibiotic-associated diarrhea, allergy and respiratory infections. We hereby discuss the role of probiotics in the reduction of the respiratory infection symptoms and we focus on the possibility to use them as an adjuvant to the therapeutic approach of the pandemic COVID-19. Nevertheless, it is accepted by the scientific community that more clinical studies should be undertaken in large samples of diseased populations so that the assessment of their therapeutic potential provide us with strong evidence for their efficacy and safety in clinical use.


Assuntos
Bactérias/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus , Microbioma Gastrointestinal/imunologia , Pandemias , Pneumonia Viral , Probióticos/uso terapêutico , Aderência Bacteriana/imunologia , Encéfalo/imunologia , Encéfalo/microbiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/microbiologia , Infecções por Coronavirus/terapia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/microbiologia , Pneumonia Viral/terapia
3.
Toxicol Lett ; 334: 66-77, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002524

RESUMO

Although colchicine (COL) has been used to treat gout for more than a thousand years, it has been shrouded in a dark history for a long time due to its high toxicity, especially for the gastrointestinal tract. With the widespread clinical application of COL, COL's toxicity to the gastrointestinal tract has raised concerns. This study's objective was to address the exact intestinal toxicity of COL, with particular attention to the effects of COL on gut microbiota homeostasis. The mice were exposed to various dosages of COL (0.1, 0.5, and 2.5 mg kg-1 body weight per day) for a week, and the results showed that COL exposure caused serious intestinal injuries, reducing the relative expression levels of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and tight junction proteins (zo-1, claudin-1, and occludin) in the ileum and colon tissue. The 16S rRNA gene sequencing analysis of mice feces samples revealed that the composition and diversity of intestinal microbiome underwent a profound remodeling at the dosage of 2.5 mg kg-1 body weight per day, which may increase the toxic load in the gut. In addition, elevated levels of diamine oxidase (DAO) and lipopolysaccharide (LPS) in serum indicated that COL increased intestinal permeability, impairing intestinal barrier. In conclusion, our results demonstrate that COL's toxicity to the gut microbiome is compatible with intestinal injuries, inflammatory pathway inhibition, and increased intestinal permeability; our results also represent a novel insight to uncover the adverse reactions of COL in the gastrointestinal tract.


Assuntos
Colchicina/toxicidade , Citocinas/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Animais , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos , Permeabilidade
4.
Toxicol Lett ; 334: 87-93, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002526

RESUMO

The interplays between the metabolic products of intestinal microbiota and the host signaling through xenobiotic receptors, including pregnane X receptor (PXR), are of growing interest, in the context of intestinal health and disease. A distinct class of microbial catabolites is formed from dietary tryptophan, having the indole scaffold in their core structure, which is a biologically active entity. In the current study, we examined a series of ten tryptophan microbial catabolites for their interactions with PXR signaling. Utilizing a reporter gene assay, we identified indole (IND) and indole-3-acetamide (IAD) as PXR agonists. IND and IAD induced PXR-regulated genes CYP3A4 and MDR1 in human intestinal cancer cells. Using time-resolved fluorescence resonance energy transfer, we show that IND (IC50 292 µM) and IAD (IC50 10 µM) are orthosteric ligands of PXR. Binding of PXR in its DNA response elements was enhanced by IND and IAD, as revealed by chromatin immunoprecipitation assay. We demonstrate that tryptophan microbial intestinal metabolites IND and IAD are ligands and agonists of human PXR. These findings are of particular importance in understanding the roles of microbial catabolites in human physiology and pathophysiology. Furthermore, these results are seminal in expanding potential drug repertoire through microbial metabolic mimicry.


Assuntos
Microbioma Gastrointestinal , Ácidos Indolacéticos/metabolismo , Indóis/metabolismo , Mucosa Intestinal , Receptor de Pregnano X/agonistas , Triptofano/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Genes Reporter , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Ligantes , Masculino , Receptor de Pregnano X/genética , Ligação Proteica , Transfecção
5.
Med Microbiol Immunol ; 209(6): 693-703, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32995957

RESUMO

Microbial translocation (MT) and altered gut microbiota have been described in acute leukemic patients and contribute to immune activation and inflammation. However, phage translocation has not been investigated in leukemia patients yet. We recruited 44 leukemic patients and 52 healthy adults and quantified the levels of 3 phages in peripheral blood, which were the most positive phages screened from fecal samples. The content of 16S rRNA in plasma was detected by qPCR to assess the intestinal mucosa of these patients. Spearman's rank correlation was used to analyze the relationship between phage load and the relevant clinical data. We found the most prevalent phages in fecal samples were λ phage, Wphi phage, and P22 phage, and λ phage had the highest detection rate in plasma (68%). Phage content was affected by chemotherapy and course of disease and correlated with the levels of CRP (r = 0.43, p = 0.003), sCD14 (r = 0.37, p = 0.014), and sCD163 (r = 0.44, p = 0.003). Our data indicate that plasma phage load is a promising marker for gut barrier damage and that gut phage translocation correlates with monocyte/macrophage activation and systemic inflammatory response in leukemic patients.


Assuntos
Translocação Bacteriana , Bacteriófagos/isolamento & purificação , Microbioma Gastrointestinal , Mucosa Intestinal/efeitos dos fármacos , Leucemia Mieloide Aguda/sangue , RNA Bacteriano/sangue , RNA Ribossômico 16S/sangue , Viremia/diagnóstico , Adulto , Idoso , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Proteína C-Reativa/análise , Feminino , Humanos , Mucosa Intestinal/microbiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/microbiologia , Leucemia Mieloide Aguda/virologia , Receptores de Lipopolissacarídeos/sangue , Ativação de Macrófagos , Masculino , Pessoa de Meia-Idade , Permeabilidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/microbiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Receptores de Superfície Celular/sangue , Viremia/etiologia
6.
Nature ; 584(7820): 274-278, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760003

RESUMO

Colonization by the microbiota causes a marked stimulation of B cells and induction of immunoglobulin, but mammals colonized with many taxa have highly complex and individualized immunoglobulin repertoires1,2. Here we use a simplified model of defined transient exposures to different microbial taxa in germ-free mice3 to deconstruct how the microbiota shapes the B cell pool and its functional responsiveness. We followed the development of the immunoglobulin repertoire in B cell populations, as well as single cells by deep sequencing. Microbial exposures at the intestinal mucosa generated oligoclonal responses that differed from those of germ-free mice, and from the diverse repertoire that was generated after intravenous systemic exposure to microbiota. The IgA repertoire-predominantly to cell-surface antigens-did not expand after dose escalation, whereas increased systemic exposure broadened the IgG repertoire to both microbial cytoplasmic and cell-surface antigens. These microbial exposures induced characteristic immunoglobulin heavy-chain repertoires in B cells, mainly at memory and plasma cell stages. Whereas sequential systemic exposure to different microbial taxa diversified the IgG repertoire and facilitated alternative specific responses, sequential mucosal exposure produced limited overlapping repertoires and the attrition of initial IgA binding specificities. This shows a contrast between a flexible response to systemic exposure with the need to avoid fatal sepsis, and a restricted response to mucosal exposure that reflects the generic nature of host-microbial mutualism in the mucosa.


Assuntos
Linfócitos B/citologia , Linfócitos B/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Simbiose/imunologia , Administração Intravenosa , Administração Oral , Animais , Clostridiales/imunologia , Clostridiales/isolamento & purificação , Escherichia coli/imunologia , Escherichia coli/isolamento & purificação , Feminino , Vida Livre de Germes , Imunoglobulina A/química , Imunoglobulina A/imunologia , Imunoglobulina G/química , Imunoglobulina G/imunologia , Cadeias Pesadas de Imunoglobulinas/imunologia , Memória Imunológica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasmócitos/citologia , Plasmócitos/imunologia , Priming de Repetição
7.
PLoS One ; 15(8): e0237086, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764782

RESUMO

Paramylon is a novel ß-glucan that is stored by Euglena gracilis Z, which is a unicellular photosynthesizing green alga with characteristics of both animals and plants. Recent studies have indicated that paramylon functions as an immunomodulator or a dietary fiber. Currently, chronic kidney disease (CKD) is a global health problem, and there is no effective preventive treatment for CKD progression. However, paramylon may suppress the progression of CKD via the elimination of uremic toxins or modulation of gut microbiota, leading to the alleviation of inflammation. The aim of this study was to evaluate the effect of paramylon in CKD rat model. Eight-week-old male Wistar rats with a 5/6 nephrectomy were given either a normal diet or a diet containing 5% paramylon for 8 weeks. Proteinuria was measured intermittently. Serum and kidney tissues were harvested after sacrifice. We performed a renal molecular and histopathological investigation, serum metabolome analysis, and gut microbiome analysis. The results showed that paramylon attenuated renal function, glomerulosclerosis, tubulointerstitial injury, and podocyte injury in the CKD rat model. Renal fibrosis, tubulointerstitial inflammatory cell infiltration, and proinflammatory cytokine gene expression levels tended to be suppressed with paramylon treatment. Further, paramylon inhibited the accumulation of uremic toxins, including tricarboxylic acid (TCA) cycle-related metabolites and modulated a part of CKD-related gut microbiota in the CKD rat model. In conclusion, we suggest that paramylon mainly inhibited the absorption of non-microbiota-derived uremic solutes, leading to protect renal injury via anti-inflammatory and anti-fibrotic effects. Paramylon may be a novel compound that can act against CKD progression.


Assuntos
Glucanos/farmacologia , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Administração Oral , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Euglena gracilis/química , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Glucanos/isolamento & purificação , Glucanos/uso terapêutico , Humanos , Mediadores da Inflamação/metabolismo , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Rim/imunologia , Rim/patologia , Masculino , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/uso terapêutico , Proteinúria/sangue , Proteinúria/patologia , Ratos , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/urina , Toxinas Biológicas/sangue , Toxinas Biológicas/metabolismo
8.
PLoS One ; 15(8): e0237182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764797

RESUMO

Necrotizing enterocolitis is the most common gastrointestinal disorder in premature neonates. This disease is characterized by massive epithelial necrosis, gut barrier dysfunction and improper mucosal defense development. Studies have shown that probiotic administration can decrease NEC incidence and mortality. The proposed mechanisms of probiotics for the prevention of NEC are: promotion of intestinal development; improved barrier function through decreased apoptosis and improved mucin production; decreased expression of proinflammatory cytokines IL6, IL8, and TNFα, and modulation of microbiota dysbiosis in preterm infants. However, reported sepsis in the immunocompromised preterm host has deterred routine prophylactic administration of probiotics in the neonatal intensive care unit. We hypothesize that maternal administration of probiotics to pregnant mouse dams can recapitulate the beneficial effects observed in neonates fed with probiotics directly. We exposed pregnant mice to the probiotics and monitored the changes in the developing intestines of the offspring. Pregnant mice were fed daily with the probiotics Lactobacillus acidophilus and Bifidobacterium infantis (LB) from embryonic day15 to 2-week-old postnatally. Intraperitoneal administration of IL-1ß in the pups was used to model proinflammatory insults. Sera were collected at 2 weeks of age and evaluated for inflammatory cytokines by enzyme-linked-immunosorbent-assay and gut permeability by Fluorescein isothiocyanate-dextran tracer assay. Ileal tissues were collected for the evaluation of apoptosis and proliferation of the intestinal epithelium; as well as mucin and tight junction integrity at mucosal surface by immunofluorescent staining. We find that maternal LB exposure facilitated intestinal epithelial cell differentiation, prevented loss of mucin and preserved the intestinal integrity and barrier function and decreased serum levels of IL-1ß, TNF-α and IL-6 in the preweaned offsprings. in LB exposed pups. We demonstrate that maternal probiotic supplementation promotes gut maturation in developing offspring. This is potentially a safe alternative therapy to induce intestinal maturation and prevent prematurity-associated neonatal disorders.


Assuntos
Enterocolite Necrosante/prevenção & controle , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/crescimento & desenvolvimento , Exposição Materna , Probióticos/administração & dosagem , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Animais Recém-Nascidos/microbiologia , Bifidobacterium longum subspecies infantis , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/microbiologia , Enterocolite Necrosante/patologia , Fezes/microbiologia , Feminino , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Interleucina-1beta/administração & dosagem , Interleucina-1beta/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Lactobacillus acidophilus , Camundongos
9.
Ecotoxicol Environ Saf ; 204: 111072, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32758694

RESUMO

Zearalenone (ZEN) is a mycotoxin that causes serious health problems in humans and animals. However, few studies have focused on the destruction of the intestinal barrier caused by ZEN. In this study, rats were exposed to different dosages of ZEN (0, 0.2, 1.0 and 5.0 mg/kg bw) by gavage for 4 weeks. The results showed that 1.0 and 5.0 mg/kg ZEN impaired gut morphology, induced the inflammatory response, reduced mucin expression, increased intestinal permeability, decreased the expression of TJ proteins and activated the RhoA/ROCK pathway. However, 0.2 mg/kg ZEN had no significant effect on intestinal barrier except for reducing the expression of some TJ proteins and mucins. Moreover, exposure to ZEN led to slight imbalance in microbiota. In conclusion, ZEN exposure resulted in intestinal barrier dysfunction by inducing intestinal microbiota dysbiosis, decreasing the expression of TJ proteins, activating the RhoA/ROCK pathway, and inducing the inflammatory response.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Zearalenona/toxicidade , Animais , Relação Dose-Resposta a Droga , Disbiose/induzido quimicamente , Feminino , Microbioma Gastrointestinal/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Jejuno/microbiologia , Jejuno/patologia , Masculino , Mucinas/metabolismo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
11.
PLoS One ; 15(7): e0236199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32673355

RESUMO

Antimicrobial-resistant and novel pathogens continue to emerge, outpacing efforts to contain and treat them. Therefore, there is a crucial need for safe and effective therapies. Ultraviolet-A (UVA) phototherapy is FDA-approved for several dermatological diseases but not for internal applications. We investigated UVA effects on human cells in vitro, mouse colonic tissue in vivo, and UVA efficacy against bacteria, yeast, coxsackievirus group B and coronavirus-229E. Several pathogens and virally transfected human cells were exposed to a series of specific UVA exposure regimens. HeLa, alveolar and primary human tracheal epithelial cell viability was assessed after UVA exposure, and 8-Oxo-2'-deoxyguanosine was measured as an oxidative DNA damage marker. Furthermore, wild-type mice were exposed to intracolonic UVA as an in vivo model to assess safety of internal UVA exposure. Controlled UVA exposure yielded significant reductions in Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Enterococcus faecalis, Clostridioides difficile, Streptococcus pyogenes, Staphylococcus epidermidis, Proteus mirabilis and Candida albicans. UVA-treated coxsackievirus-transfected HeLa cells exhibited significantly increased cell survival compared to controls. UVA-treated coronavirus-229E-transfected tracheal cells exhibited significant coronavirus spike protein reduction, increased mitochondrial antiviral-signaling protein and decreased coronavirus-229E-induced cell death. Specific controlled UVA exposure had no significant effect on growth or 8-Oxo-2'-deoxyguanosine levels in three types of human cells. Single or repeated in vivo intraluminal UVA exposure produced no discernible endoscopic, histologic or dysplastic changes in mice. These findings suggest that, under specific conditions, UVA reduces various pathogens including coronavirus-229E, and may provide a safe and effective treatment for infectious diseases of internal viscera. Clinical studies are warranted to further elucidate the safety and efficacy of UVA in humans.


Assuntos
Infecções Bacterianas/terapia , Micoses/terapia , Infecções Oportunistas/terapia , Terapia Ultravioleta/métodos , Viroses/terapia , Animais , Apoptose/efeitos da radiação , Bactérias/efeitos da radiação , Infecções Bacterianas/microbiologia , Sobrevivência Celular/efeitos da radiação , Colo/microbiologia , Colo/efeitos da radiação , Coronavirus Humano 229E/efeitos da radiação , Dano ao DNA/efeitos da radiação , Modelos Animais de Doenças , Enterovirus Humano B/efeitos da radiação , Feminino , Células HeLa , Humanos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/efeitos da radiação , Masculino , Camundongos , Micoses/microbiologia , Infecções Oportunistas/microbiologia , Cultura Primária de Células , Terapia Ultravioleta/efeitos adversos , Viroses/virologia , Leveduras/efeitos da radiação
12.
Proc Natl Acad Sci U S A ; 117(32): 19168-19177, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719135

RESUMO

The emergence of superbugs developing resistance to antibiotics and the resurgence of microbial infections have led scientists to start an antimicrobial arms race. In this context, we have previously identified an active RiPP, the Ruminococcin C1, naturally produced by Ruminococcus gnavus E1, a symbiont of the healthy human intestinal microbiota. This RiPP, subclassified as a sactipeptide, requires the host digestive system to become active against pathogenic Clostridia and multidrug-resistant strains. Here we report its unique compact structure on the basis of four intramolecular thioether bridges with reversed stereochemistry introduced posttranslationally by a specific radical-SAM sactisynthase. This structure confers to the Ruminococcin C1 important clinical properties including stability to digestive conditions and physicochemical treatments, a higher affinity for bacteria than simulated intestinal epithelium, a valuable activity at therapeutic doses on a range of clinical pathogens, mediated by energy resources disruption, and finally safety for human gut tissues.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Clostridiales/química , Peptídeos/química , Peptídeos/farmacologia , Antibacterianos/isolamento & purificação , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Peptídeos/isolamento & purificação
13.
Proc Natl Acad Sci U S A ; 117(32): 19376-19387, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719140

RESUMO

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are associated with dysbiosis of the gut microbiome. Emerging evidence suggests that small-molecule metabolites derived from bacterial breakdown of a variety of dietary nutrients confer a wide array of host benefits, including amelioration of inflammation in IBDs. Yet, in many cases, the molecular pathways targeted by these molecules remain unknown. Here, we describe roles for three metabolites-indole-3-ethanol, indole-3-pyruvate, and indole-3-aldehyde-which are derived from gut bacterial metabolism of the essential amino acid tryptophan, in regulating intestinal barrier function. We determined that these metabolites protect against increased gut permeability associated with a mouse model of colitis by maintaining the integrity of the apical junctional complex and its associated actin regulatory proteins, including myosin IIA and ezrin, and that these effects are dependent on the aryl hydrocarbon receptor. Our studies provide a deeper understanding of how gut microbial metabolites affect host defense mechanisms and identify candidate pathways for prophylactic and therapeutic treatments for IBDs.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células CACO-2 , Colite Ulcerativa/dietoterapia , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Miosina não Muscular Tipo IIA/metabolismo , Permeabilidade , Receptores de Hidrocarboneto Arílico/genética , Triptofano/administração & dosagem
14.
PLoS One ; 15(6): e0235020, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584855

RESUMO

The pathogenesis of Salmonella Typhimurium depends on the bacterium's ability to survive and replicate within host cells. The formation and maintenance of a unique membrane-bound compartment, termed the Salmonella-containing vacuole (SCV), is essential for S. Typhimurium pathogenesis. SCV-bound S. Typhimurium induces formation of filamentous tubules that radiate outwards from the SCV, termed Salmonella-induced filaments (SIFs). SIF formation is concomitant with the onset of replication within host epithelial cells. SIF biogenesis, formation and maintenance of the SCV, and the intracellular positioning of the SCV within the host cell requires translocation of bacterial proteins (effectors) into the host cell. Effectors secreted by the type III secretion system encoded on Salmonella pathogenicity island 2 (T3SS2) function to interfere with host cellular processes and promote both intracellular survival and replication of S. Typhimurium. Seven T3SS2-secreted effectors, SifA, SopD2, PipB2, SteA, SseJ, SseF, and SseG have previously been implicated to play complementary, redundant, and/or antagonistic roles with respect to SIF biogenesis, intracellular positioning of the SCV, and SCV membrane dynamics modulation during infection. We undertook a systematic study to delineate the contribution of each effector to these processes by (i) deleting all seven of these effectors in a single S. Typhimurium strain; and (ii) deleting combinations of multiple effectors based on putative effector function. Using this deletion mutant library, we show that each of SIF biogenesis, intracellular SCV localization, intramacrophage replication, colonization, and virulence depends on the activities of multiple effectors. Together, our data demonstrates the complex interplay between these seven effectors and highlights the necessity to study T3SS2-secreted effectors as groups, rather than studies of individual effectors.


Assuntos
Proteínas de Bactérias , Translocação Bacteriana/genética , Ilhas Genômicas , Mucosa Intestinal , Infecções por Salmonella , Salmonella typhimurium , Fatores de Virulência , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Feminino , Células HeLa , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Células RAW 264.7 , Infecções por Salmonella/genética , Infecções por Salmonella/metabolismo , Infecções por Salmonella/patologia , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidade , Células THP-1 , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
15.
PLoS One ; 15(6): e0233910, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502215

RESUMO

Farmers face difficulties in redeeming their investment in larger litter sizes since this comes with larger litter heterogenicity, lower litter resilience and risk of higher mortality. Dietary oligosaccharides, given to the sow, proved beneficial for the offspring's performance. However, giving oligosaccharides to the suckling piglet is poorly explored. Therefore, this field trial studied the effect of dietary short-chain fructo-oligosaccharides (scFOS; 1g/day; drenched) supplementation to low (LBW, lower quartile), normal (NBW, two intermediate quartiles) and high (HBW, upper quartile) birth weight piglets from birth until 7 or 21 days of age. Performance parameters, gut microbiome and short-chain fatty acids profile of feces and digesta were assessed at birth (d 0), d 7, weaning (d 21.5) and 2 weeks post-weaning (d 36.5). Additional parameters reflecting gut health (intestinal integrity and morphology, mucosal immune system) were analysed at d 36.5. Most parameters changed with age or differed with the piglet's birth weight. Drenching with scFOS increased body weight by 1 kg in NBW suckling piglets and reduced the post-weaning mortality rate by a 100%. No clear difference in the IgG level, the microbiota composition and fermentative activity between the treatment groups was observed. Additionnally, intestinal integrity, determined by measuring intestinal permeability and regenerative capacity, was similar between the treatment groups. Also, intestinal architecture (villus lenght, crypt depth) was not affected by scFOS supplementation. The density of intra-epithelial lymphocytes and the expression profiles (real-time qPCR) for immune system-related genes (IL-10, IL-1ß, IL-6, TNFα and IFNγ) were used to assess mucosal immunity. Only IFNγ expression, was upregulated in piglets that received scFOS for 7 days. The improved body weight and the reduced post-weaning mortality seen in piglets supplemented with scFOS support the view that scFOS positively impact piglet's health and resilience. However, the modes of action for these effects are not yet fully elucidated and its potential to improve other performance parameters needs further investigation.


Assuntos
Ração Animal , Criação de Animais Domésticos/métodos , Suplementos Nutricionais , Oligossacarídeos/administração & dosagem , Sus scrofa/fisiologia , Fenômenos Fisiológicos da Nutrição Animal/imunologia , Animais , Animais Lactentes/fisiologia , Peso Corporal/fisiologia , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Sus scrofa/microbiologia , Desmame
16.
BMC Infect Dis ; 20(1): 394, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493232

RESUMO

BACKGROUND: Talaromyces marneffei is a highly pathogenic fungus that can cause life-threatening fatal systemic mycosis. Disseminated Talaromycosis marneffei affects multiple organs, including the lungs, skin, and reticuloendothelial system. However, T. marneffei infection has rarely been reported in human immunodeficiency virus (HIV)-negative infants with multiple intestinal perforations and diffuse hepatic granulomatous inflammation. CASE PRESENTATION: We present the case of an HIV-negative 37-month-old boy who has had recurrent pneumonia since infancy and was infected with disseminated Talaromycosis. Contrast-enhanced computed tomography of the whole abdomen showed hepatomegaly and intestinal wall thickening in the ascending colon and cecum with mesenteric lymphadenopathy. Colonoscopy showed a cobblestone pattern with erosion, ulcer, polypoid lesions, and lumen deformation ranging from the colon to the cecum. T. marneffei was isolated from the mucous membrane of the colon, liver, and bone marrow. After antifungal treatment and surgery, his clinical symptoms significantly improved. Whole-exome sequencing using the peripheral blood of the patient and his parents' revealed a heterozygous missense mutation in exon 17 of the STAT3 gene (c.1673G>A, p.G558D). CONCLUSIONS: In T. marneffei infection-endemic areas, endoscopic examination, culture, or histopathology from the intestine tissue should be performed in disseminated Talaromycosis patients with gastrointestinal symptoms. Timely and systemic antifungal therapy could improve the prognosis. Immunodeficiency typically should be considered in HIV-negative infants with opportunistic infections.


Assuntos
Hepatopatias/diagnóstico , Micoses/diagnóstico , Fator de Transcrição STAT3/genética , Talaromyces/isolamento & purificação , Antifúngicos/uso terapêutico , Pré-Escolar , Colonoscopia , Diagnóstico Diferencial , Humanos , Mucosa Intestinal/microbiologia , Perfuração Intestinal , Hepatopatias/tratamento farmacológico , Hepatopatias/microbiologia , Masculino , Mutação de Sentido Incorreto , Micoses/tratamento farmacológico , Micoses/microbiologia , Tomografia Computadorizada por Raios X
17.
Am J Surg Pathol ; 44(9): 1274-1281, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32568824

RESUMO

Syphilis is a sexually transmitted disease caused by the spirochetal bacterium Treponema pallidum that has been of public health concern for centuries. In the United States, it is currently a reportable disease and one which is recently generating increasing case numbers especially in at risk populations of immune deficiency and men who have sex with men. The present series examines biopsies from 13 patients collected over a 12-year period from a general hospital network in north suburban Cook County, Illinois. There were 13 patients (11 male: 2 female) with varied presentations, including primary ulcerated anogenital chancres, mucosal lesions, peculiar rashes, and alopecia. The reason(s) for biopsy were not clear from the clinical record, as a clinical consideration of syphilis was recorded in only 3 cases. Histologic examination of the mucocutaneous lesions encompassed a spectrum of findings including ulceration, psoriasiform hyperplasia, intense mixed band-like inflammation at the dermal-epidermal junction with a prominent plasma cell component. The contemporary availability of an effective immunostain is a valuable diagnostic adjunct. The organisms generally parallel the intensity of the inflammatory infiltrate but the distribution may vary and rarely, organisms may be absent despite serologic confirmation. Previous corkscrew morphology of the organism described ultrastructurally is reflected in the immunostained representation. Although the diagnosis of syphilis remains a clinical one in most cases, some patients will have unusual presentations and biopsies will be done. The awareness of the pathologist will facilitate prompt and effective treatment.


Assuntos
Cancro/patologia , Mucosa Intestinal/patologia , Mucosa Bucal/patologia , Reto/patologia , Pele/patologia , Sífilis Cutânea/patologia , Treponema pallidum/patogenicidade , Adulto , Alopecia/microbiologia , Biópsia , Cancro/microbiologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Illinois , Mucosa Intestinal/microbiologia , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/microbiologia , Valor Preditivo dos Testes , Reto/microbiologia , Pele/microbiologia , Sífilis Cutânea/microbiologia , Adulto Jovem
18.
PLoS Genet ; 16(6): e1008866, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32530914

RESUMO

Escherichia coli is mostly a commensal of birds and mammals, including humans, where it can act as an opportunistic pathogen. It is also found in water and sediments. We investigated the phylogeny, genetic diversification, and habitat-association of 1,294 isolates representative of the phylogenetic diversity of more than 5,000 isolates from the Australian continent. Since many previous studies focused on clinical isolates, we investigated mostly other isolates originating from humans, poultry, wild animals and water. These strains represent the species genetic diversity and reveal widespread associations between phylogroups and isolation sources. The analysis of strains from the same sequence types revealed very rapid change of gene repertoires in the very early stages of divergence, driven by the acquisition of many different types of mobile genetic elements. These elements also lead to rapid variations in genome size, even if few of their genes rise to high frequency in the species. Variations in genome size are associated with phylogroup and isolation sources, but the latter determine the number of MGEs, a marker of recent transfer, suggesting that gene flow reinforces the association of certain genetic backgrounds with specific habitats. After a while, the divergence of gene repertoires becomes linear with phylogenetic distance, presumably reflecting the continuous turnover of mobile element and the occasional acquisition of adaptive genes. Surprisingly, the phylogroups with smallest genomes have the highest rates of gene repertoire diversification and fewer but more diverse mobile genetic elements. This suggests that smaller genomes are associated with higher, not lower, turnover of genetic information. Many of these genomes are from freshwater isolates and have peculiar traits, including a specific capsule, suggesting adaptation to this environment. Altogether, these data contribute to explain why epidemiological clones tend to emerge from specific phylogenetic groups in the presence of pervasive horizontal gene transfer across the species.


Assuntos
Escherichia coli/genética , Evolução Molecular , Transferência Genética Horizontal , Variação Genética , Genoma Bacteriano/genética , Animais , Animais Selvagens/microbiologia , Austrália , Galinhas/microbiologia , Farmacorresistência Bacteriana/genética , Escherichia coli/isolamento & purificação , Escherichia coli/patogenicidade , Fezes/microbiologia , Água Doce/microbiologia , Tamanho do Genoma , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Sequências Repetitivas Dispersas/genética , Mucosa Intestinal/microbiologia , Carne/microbiologia , Anotação de Sequência Molecular , Filogenia , Microbiologia do Solo , Fatores de Virulência/genética , Sequenciamento Completo do Genoma
20.
Nat Commun ; 11(1): 2471, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424203

RESUMO

Gut microbes are linked to host metabolism, but specific mechanisms remain to be uncovered. Ceramides, a type of sphingolipid (SL), have been implicated in the development of a range of metabolic disorders from insulin resistance (IR) to hepatic steatosis. SLs are obtained from the diet and generated by de novo synthesis in mammalian tissues. Another potential, but unexplored, source of mammalian SLs is production by Bacteroidetes, the dominant phylum of the gut microbiome. Genomes of Bacteroides spp. and their relatives encode serine palmitoyltransfease (SPT), allowing them to produce SLs. Here, we explore the contribution of SL-production by gut Bacteroides to host SL homeostasis. In human cell culture, bacterial SLs are processed by host SL-metabolic pathways. In mouse models, Bacteroides-derived lipids transfer to host epithelial tissue and the hepatic portal vein. Administration of B. thetaiotaomicron to mice, but not an SPT-deficient strain, reduces de novo SL production and increases liver ceramides. These results indicate that gut-derived bacterial SLs affect host lipid metabolism.


Assuntos
Bacteroides/fisiologia , Ceramidas/metabolismo , Microbioma Gastrointestinal , Redes e Vias Metabólicas , Esfingolipídeos/metabolismo , Animais , Células CACO-2 , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Vida Livre de Germes , Humanos , Resistência à Insulina , Mucosa Intestinal/microbiologia , Fígado/metabolismo , Redes e Vias Metabólicas/genética , Camundongos , Mutação/genética , Serina C-Palmitoiltransferase/deficiência , Serina C-Palmitoiltransferase/genética , Serina C-Palmitoiltransferase/metabolismo
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