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In this issue, Lehmann et al. addresses the high infection risk in liver transplantation by examining the gut microbiome in a patient cohort. By uncovering a predictive role of the microbiome for the clinical course, the study unravels the gut microbiome as a guidepost for infection risk in liver transplantation.
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Microbioma Gastrointestinal , Transplante de Fígado , Microbiota , Humanos , Transplante de Fígado/efeitos adversosRESUMO
Long-term sequelae of coronavirus disease (COVID)-19 are frequent and of major concern. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects the host gut microbiota, which is linked to disease severity in patients with COVID-19. Here, we report that the gut microbiota of post-COVID subjects had a remarkable predominance of Enterobacteriaceae strains with an antibiotic-resistant phenotype compared to healthy controls. Additionally, short-chain fatty acid (SCFA) levels were reduced in feces. Fecal transplantation from post-COVID subjects to germ-free mice led to lung inflammation and worse outcomes during pulmonary infection by multidrug-resistant Klebsiella pneumoniae. transplanted mice also exhibited poor cognitive performance. Overall, we show prolonged impacts of SARS-CoV-2 infection on the gut microbiota that persist after subjects have cleared the virus. Together, these data demonstrate that the gut microbiota can directly contribute to post-COVID sequelae, suggesting that it may be a potential therapeutic target.
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COVID-19 , Microbioma Gastrointestinal , Animais , Camundongos , SARS-CoV-2 , Antibacterianos , Progressão da DoençaRESUMO
Gout is a painful form of inflammatory arthritis characterized by the deposition of monosodium urate (MSU) crystals in the joints. The aim of this study was to investigate the effect of peptide P140 on the inflammatory responses in crystal-induced mouse models of gout and cell models including MSU-treated human cells. Injection of MSU crystals into the knee joint of mice induced neutrophil influx and inflammatory hypernociception. Injection of MSU crystals subcutaneously into the hind paw induced edema and increased pro-inflammatory cytokines levels. Treatment with P140 effectively reduced hypernociception, the neutrophil influx, and pro-inflammatory cytokine levels in these experimental models. Furthermore, P140 modulated neutrophils chemotaxis in vitro and increased apoptosis pathways through augmented caspase 3 activity and reduced NFκB phosphorylation. Moreover, P140 increased the production of the pro-resolving mediator annexin A1 and decreased the expression of the autophagy-related ATG5-ATG12 complex and HSPA8 chaperone protein. Overall, these findings suggest that P140 exerts a significant beneficial effect in a neutrophilic inflammation observed in the model of gout that can be of special interest in the design of new therapeutic strategies.
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Artrite Gotosa , Gota , Camundongos , Humanos , Animais , Ácido Úrico , Fosfopeptídeos/farmacologia , Gota/tratamento farmacológico , Gota/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Neutrófilos/metabolismo , Modelos Animais de Doenças , Artrite Gotosa/tratamento farmacológicoRESUMO
Intestinal mucositis (IM) is a critical side-effect associated with antineoplastic therapy. Treatment available is only palliative and often not effective. However, alternative therapeutic strategies, such as probiotics, have attracted significant attention due to their immune-modulatory action in several diseases. Thus, the present study aims to elucidate the therapeutic potential of the probiotic strain Bifidobacterium longum 51A in a murine model of mucositis induced by irinotecan. Due to the scarcity of studies on dose-response and viability (probiotic vs paraprobiotic), we first evaluated which dose and cell viability would be most effective in treating mucositis. In this study, the oral pretreatment with viable B. longum 51A at a concentration of 1 × 109 CFU/mL reduced the daily disease activity index (p < 0.01), protected the intestinal architecture, preserved the length of the intestine (p < 0.05), and reduced intestinal permeability (p < 0.01), inflammation, and oxidative damage (p < 0.01) induced by irinotecan. Also, treatment with B. longum 51A increased the production of secretory immunoglobulin A (p < 0.05) in the intestinal fluid of mice with mucositis. Furthermore, B. longum 51A reversed the mucositis-induced increase in Enterobacteriaceae bacterial group in the gut (p < 0.01). In conclusion, these results showed that oral administration of B. longum 51A protects mice against intestinal damage caused by irinotecan, suggesting its use as a potential probiotic in therapy during mucositis.
Assuntos
Bifidobacterium longum , Microbioma Gastrointestinal/efeitos dos fármacos , Enteropatias , Irinotecano/efeitos adversos , Mucosite , Probióticos/farmacologia , Animais , Feminino , Enteropatias/induzido quimicamente , Enteropatias/microbiologia , Enteropatias/terapia , Irinotecano/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Mucosite/induzido quimicamente , Mucosite/microbiologia , Mucosite/terapiaRESUMO
The phenotypes of allergic airway diseases are influenced by the interplay between host genetics and the gut microbiota, which may be modulated by probiotics. We investigated the probiotic effects on allergic inflammation in A/J and C57BL/6 mice. C57BL/6 mice had increased gut microbiota diversity compared to A/J mice at baseline. Acetate producer probiotics differentially modulated and altered the genus abundance of specific bacteria, such as Akkermansia and Allistipes, in mouse strains. We induced airway inflammation followed by probiotic treatment and found that only A/J mice exhibited decreased inflammation, and the beneficial effects of probiotics in A/J mice were partially due to acetate production. To understand the relevance of microbial composition colonization in the development of allergic diseases, we implanted female C57BL/6 mice with A/J embryos to naturally modulate the microbial composition of A/J mice, which increased gut microbiota diversity and reduced eosinophilic inflammation in A/J. These data demonstrate the central importance of microbiota to allergic phenotype severity. Video Abstract.
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Microbioma Gastrointestinal , Probióticos , Animais , Feminino , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Sistema RespiratórioRESUMO
Along with respiratory tract disease per se, viral respiratory infections can also cause extrapulmonary complications with a potentially critical impact on health. In the present study, we used an experimental model of influenza A virus (IAV) infection to investigate the nature and outcome of the associated gut disorders. In IAV-infected mice, the signs of intestinal injury and inflammation, altered gene expression, and compromised intestinal barrier functions peaked on day 7 postinfection. As a likely result of bacterial component translocation, gene expression of inflammatory markers was upregulated in the liver. These changes occurred concomitantly with an alteration of the composition of the gut microbiota and with a decreased production of the fermentative, gut microbiota-derived products short-chain fatty acids (SCFAs). Gut inflammation and barrier dysfunction during influenza were not attributed to reduced food consumption, which caused in part gut dysbiosis. Treatment of IAV-infected mice with SCFAs was associated with an enhancement of intestinal barrier properties, as assessed by a reduction in the translocation of dextran and a decrease in inflammatory gene expression in the liver. Lastly, SCFA supplementation during influenza tended to reduce the translocation of the enteric pathogen Salmonella enterica serovar Typhimurium and to enhance the survival of doubly infected animals. Collectively, influenza virus infection can remotely impair the gut's barrier properties and trigger secondary enteric infections. The latter phenomenon can be partially countered by SCFA supplementation.
Assuntos
Infecções por Enterobacteriaceae/etiologia , Ácidos Graxos Voláteis/biossíntese , Interações Hospedeiro-Patógeno , Vírus da Influenza A/fisiologia , Influenza Humana/complicações , Influenza Humana/virologia , Mucosa Intestinal/metabolismo , Interações Microbianas , Suscetibilidade a Doenças , Disbiose , Infecções por Enterobacteriaceae/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Influenza Humana/metabolismo , Mucosa Intestinal/imunologiaRESUMO
Brucella abortus is a Gram-negative bacterium responsible for a worldwide zoonotic infection-Brucellosis, which has been associated with high morbidity rate in humans and severe economic losses in infected livestock. The natural route of infection is through oral and nasal mucosa but the invasion process through host gut mucosa is yet to be understood. Studies have examined the role of NLRP6 (NOD-like receptor family pyrin domain-containing-6 protein) in gut homeostasis and defense against pathogens. Here, we investigated the impact of gut microbiota and NLRP6 in a murine model of Ba oral infection. Nlrp6-/- and wild-type (WT) mice were infected by oral gavage with Ba and tissues samples were collected at different time points. Our results suggest that Ba oral infection leads to significant alterations in gut microbiota. Moreover, Nlrp6-/- mice were more resistant to infection, with decreased CFU in the liver and reduction in gut permeability when compared to the control group. Fecal microbiota transplantation from WT and Nlrp6-/- into germ-free mice reflected the gut permeability phenotype from the donors. Additionally, depletion of gut microbiota by broad-spectrum-antibiotic treatment prevented Ba replication in WT while favoring bacterial growth in Nlrp6-/-. Finally, we observed higher eosinophils in the gut and leukocytes in the blood of infected Nlrp6-/- compared to WT-infected mice, which might be associated to the Nlrp6-/- resistance phenotype. Altogether, these results indicated that gut microbiota composition is the major factor involved in the initial stages of pathogen host replication and partially also by the resistance phenotype observed in Nlrp6 -/- mice regulating host inflammation against Ba infection.
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Brucelose/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Intestinos/microbiologia , Intestinos/fisiopatologia , Administração Oral , Animais , Antibacterianos/administração & dosagem , Brucella abortus , Brucelose/microbiologia , Transplante de Microbiota Fecal , Interações Hospedeiro-Patógeno , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Permeabilidade , Receptores de Superfície Celular/genética , Organismos Livres de Patógenos EspecíficosRESUMO
INTRODUCTION: Asthma is a heterogeneous disease with complex multifactorial causes. It is possible to subclassify asthma into different phenotypes that have distinct immunological features. Eosinophilic asthma is a well-known phenotype of severe asthma; however, a large body of clinical and experimental evidence strongly associates persistent airway inflammation, including the accumulation of neutrophils in the bronchial mucosa, and resistance to corticosteroid therapy and non-Type-2 immune responses with severe asthma. Importantly, mainstay therapies are often ineffective in severe asthma and effective alternatives are urgently needed. AREAS COVERED: Here, we discussed recently developed mouse models of severe asthma that recapitulates key features of the disease in humans. We also provide findings from clinically relevant experimental models that have identified potential therapeutic targets for severe asthma. The most relevant publications on the topic of interest were selected from PubMed. EXPERT COMMENTARY: Increasing the understanding of disease-causing mechanisms in severe asthma may lead to the identification of novel therapeutic targets and the development of more effective therapies. Intense research interest into investigating the pathophysiological mechanisms of severe asthma has driven the development and interrogation of a myriad of mouse models that aim to replicate hallmark features of severe asthma in humans.
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Asma/terapia , Modelos Animais de Doenças , Terapia de Alvo Molecular , Animais , Asma/imunologia , Asma/fisiopatologia , Humanos , Camundongos , Índice de Gravidade de DoençaRESUMO
The ST2 receptor plays an important role in the gut such as permeability regulation, epithelium regeneration, and promoting intestinal immune modulation. Here, we studied the role of ST2 receptor in a murine model of oral infection with Brucella abortus, its influence on gut homeostasis and control of bacterial replication. Balb/c (wild-type, WT) and ST2 deficient mice (ST2-/-) were infected by oral gavage and the results were obtained at 3 and 14 days post infection (dpi). Our results suggest that ST2-/- are more resistant to B. abortus infection, as a lower bacterial colony-forming unit (CFU) was detected in the livers and spleens of knockout mice, when compared to WT. Additionally, we observed an increase in intestinal permeability in WT-infected mice, compared to ST2-/- animals. Breakage of the intestinal epithelial barrier and bacterial dissemination might be associated with the presence of the ST2 receptor; since, in the knockout mice no change in intestinal permeability was observed after infection. Together with enhanced resistance to infection, ST2-/- produced greater levels of IFN-γ and TNF-α in the small intestine, compared to WT mice. Nevertheless, in the systemic model of infection ST2 plays no role in controlling Brucella replication in vivo. Our results suggest that the ST2 receptor is involved in the invasion process of B. abortus by the mucosa in the oral infection model.
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Secondary bacterial infections often complicate viral respiratory infections. We hypothesize that perturbation of the gut microbiota during influenza A virus (IAV) infection might favor respiratory bacterial superinfection. Sublethal infection with influenza transiently alters the composition and fermentative activity of the gut microbiota in mice. These changes are attributed in part to reduced food consumption. Fecal transfer experiments demonstrate that the IAV-conditioned microbiota compromises lung defenses against pneumococcal infection. In mechanistic terms, reduced production of the predominant short-chain fatty acid (SCFA) acetate affects the bactericidal activity of alveolar macrophages. Following treatment with acetate, mice colonized with the IAV-conditioned microbiota display reduced bacterial loads. In the context of influenza infection, acetate supplementation reduces, in a free fatty acid receptor 2 (FFAR2)-dependent manner, local and systemic bacterial loads. This translates into reduced lung pathology and improved survival rates of double-infected mice. Lastly, pharmacological activation of the SCFA receptor FFAR2 during influenza reduces bacterial superinfection.
Assuntos
Disbiose/microbiologia , Ácidos Graxos Voláteis/biossíntese , Trato Gastrointestinal/microbiologia , Influenza Humana/microbiologia , Pulmão/microbiologia , Infecções Pneumocócicas/complicações , Superinfecção/complicações , Superinfecção/microbiologia , Acetatos/farmacologia , Animais , Disbiose/complicações , Disbiose/virologia , Comportamento Alimentar , Microbioma Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/microbiologia , Macrófagos Alveolares/patologia , Camundongos Endogâmicos C57BL , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/virologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Infecções Respiratórias/microbiologiaRESUMO
Brucella spp. infection is frequently acquired through contaminated aerosols. The role of interleukin-1 beta (IL-1ß) in the early pulmonary response to respiratory Brucella infection is unknown. As shown here, IL-1ß levels in lung homogenates and bronchoalveolar lavage fluid (BALF) of mice intratracheally inoculated with B. abortus were increased at 3 and 7 days p.i. At 7 days p.i., pulmonary CFU numbers were higher in IL-1 receptor (IL-1R) knockout (KO) mice than in wild type (WT) mice. At different times p.i. CFU in lungs and BALF were higher in mice lacking some inflammasome components (caspase-1, AIM2, NLRP3) than in WT mice. At 2 days p.i. pulmonary levels of IL-1ß and CXCL1 (neutrophils chemoattractant) were lower in caspase-1/11 KO mice. At day 3 p.i., neutrophils counts in BALF were lower in caspase-1/11 KO mice than in WT mice. During in vitro infections, IL-1ß secretion was lower in alveolar macrophages from caspase-1/11, NLRP3 or AIM2 KO mice than in WT controls. Similarly, IL-1ß production by B. abortus-infected alveolar epithelial cells was reduced by pretreatment with a specific caspase-1 inhibitor. This study shows that IL-1R, probably through IL-1ß action, and the NLRP3 and AIM2 inflammasomes are involved in pulmonary innate immune protective mechanisms against respiratory B. abortus infection.
Assuntos
Brucella abortus/imunologia , Brucelose/imunologia , Inflamassomos/metabolismo , Pulmão/imunologia , Receptores de Interleucina-1/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Brucella abortus/patogenicidade , Caspase 1/metabolismo , Caspases/genética , Caspases/metabolismo , Caspases Iniciadoras , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Imunidade Inata , Inflamassomos/farmacologia , Interleucina-1beta/metabolismo , Macrófagos Alveolares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Substâncias Protetoras/farmacologia , Serpinas/metabolismo , Proteínas Virais/metabolismoRESUMO
Mucositis is a clinically important gastrointestinal inflammatory infirmity, generated by antineoplastic drugs cytotoxic effects. The inflammatory process caused by this disease frequently leads to derangements in the alimentary tract and great malaise for the patient. Novel strategies are necessary for its prevention or treatment, as currently available treatments of mucositis have several limitations in relieving its symptoms. In this context, several research groups have investigated the use of probiotic bacteria, and in particular dairy bacterial strains. Compelling evidences reveal that milk fermented by certain probiotic bacteria has the capacity to ameliorate intestinal inflammatory disorders. In addition, innovative probiotic delivery strategies, based on probiotics incorporation into protective matrices, such as whey proteins, were able to increase the therapeutic effect of probiotic strains by providing extra protection for bacteria against environmental stresses. Therefore, in this study, we evaluated the role of the whey protein isolate (WPI), when added to skim milk fermented by Lactobacillus casei BL23 (L. casei BL23) or by Propionibacterium freudenreichii CIRM-BIA138 (P. freudenreichii 138), as a protective matrix against in vitro stress challenges. In addition, we investigated the therapeutic effect of these fermented beverages in a murine model of mucositis induced by 5-Fluorouracil (5-FU). Our results demonstrated that milk supplementation with 30% (w/v) of WPI increases the survival rate of both strains when challenged with acid, bile salts, high temperature and cold storage stresses, compared to fermented skim milk without the addition of WPI. Moreover, treatment with the probiotic beverages prevented weight loss and intestinal damages in mice receiving 5-FU. We conclude that the presence of WPI maximizes the anti-inflammatory effects of L. casei BL23, but not for P. freudenreichii 138, suggesting that whey protein enhancement of probiotic activity might be strain-dependent.
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Pneumonia is one of the leading causes of death and mortality worldwide. The inflammatory responses that follow respiratory infections are protective leading to pathogen clearance but can also be deleterious if unregulated. The microbiota is known to be an important protective barrier against infections, mediating both direct inhibitory effects against the potential pathogen and also regulating the immune responses contributing to a proper clearance of the pathogen and return to homeostasis. GPR43 is one receptor for acetate, a microbiota metabolite shown to induce and to regulate important immune functions. Here, we addressed the role of GPR43 signaling during pulmonary bacterial infections. We have shown for the first time that the absence of GPR43 leads to increased susceptibility to Klebsiella pneumoniae infection, which was associated to both uncontrolled proliferation of bacteria and to increased inflammatory response. Mechanistically, we showed that GPR43 expression especially in neutrophils and alveolar macrophages is important for bacterial phagocytosis and killing. In addition, treatment with the GPR43 ligand, acetate, is protective during bacterial lung infection. This was associated to reduction in the number of bacteria in the airways and to the control of the inflammatory responses. Altogether, GPR43 plays an important role in the "gut-lung axis" as a sensor of the host gut microbiota activity through acetate binding promoting a proper immune response in the lungs.
Assuntos
Infecções por Klebsiella/imunologia , Klebsiella pneumoniae , Receptores Acoplados a Proteínas G/imunologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Macrófagos Alveolares/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Fagocitose , Receptores Acoplados a Proteínas G/genéticaRESUMO
Protease inhibitors have important function during homeostasis, inflammation and tissue injury. In this study, we described the role of Schistosoma mansoni SmKI-1 serine protease inhibitor in parasite development and as a molecule capable of regulating different models of inflammatory diseases. First, we determine that recombinant (r) SmKI-1 and its Kunitz domain but not the C-terminal region possess inhibitory activity against trypsin and neutrophil elastase (NE). To better understand the molecular basis of NE inhibition by SmKI-1, molecular docking studies were also conducted. Docking results suggest a complete blockage of NE active site by SmKI-1 Kunitz domain. Additionally, rSmKI-1 markedly inhibited the capacity of NE to kill schistosomes. In order to further investigate the role of SmKI-1 in the parasite, we designed specific siRNA to knockdown SmKI-1 in S. mansoni. SmKI-1 gene suppression in larval stage of S. mansoni robustly impact in parasite development in vitro and in vivo. To determine the ability of SmKI-1 to interfere with neutrophil migration and function, we tested SmKI-1 anti-inflammatory potential in different murine models of inflammatory diseases. Treatment with SmKI-1 rescued acetaminophen (APAP)-mediated liver damage, with a significant reduction in both neutrophil recruitment and elastase activity. In the model of gout arthritis, this protein reduced neutrophil accumulation, IL-1ß secretion, hypernociception, and overall pathological score. Finally, we demonstrated the ability of SmKI-1 to inhibit early events that trigger neutrophil recruitment in pleural cavities of mice in response to carrageenan. In conclusion, SmKI-1 is a key protein in S. mansoni survival and it has the ability to inhibit neutrophil function as a promising therapeutic molecule against inflammatory diseases.
Assuntos
Inflamação/metabolismo , Elastase de Leucócito/metabolismo , Neutrófilos/efeitos dos fármacos , Schistosoma mansoni , Inibidores de Serina Proteinase/metabolismo , Inibidores de Serina Proteinase/farmacologia , Animais , Células Cultivadas , Feminino , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , Neutrófilos/fisiologia , Ligação Proteica , Schistosoma mansoni/imunologia , Schistosoma mansoni/metabolismo , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/metabolismoRESUMO
The clinical pathogen Klebsiella pneumoniae is a relevant cause of nosocomial infections, and resistance to current treatment with carbapenem antibiotics is becoming a significant problem. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) used for controlling plasma cholesterol levels. There is clinical evidence showing other effects of statins, including decrease of lung inflammation. In the current study, we show that pretreatment with atorvastatin markedly attenuated lung injury, which was correlated with a reduction in the cellular influx into the alveolar space and lungs and downmodulation of the production of proinflammatory mediators in the initial phase of infection in C57BL/6 mice with K. pneumoniae However, atorvastatin did not alter the number of bacteria in the lungs and blood of infected mice, despite decreasing local inflammatory response. Interestingly, mice that received combined treatment with atorvastatin and imipenem displayed better survival than mice treated with vehicle, atorvastatin, or imipenem alone. These findings suggest that atorvastatin could be an adjuvant in host-directed therapies for multidrug-resistant K. pneumoniae, based on its powerful pleiotropic immunomodulatory effects. Together with antimicrobial approaches, combination therapy with anti-inflammatory compounds could improve the efficiency of therapy during acute lung infections.
Assuntos
Antibacterianos/uso terapêutico , Atorvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imipenem/uso terapêutico , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Pneumonia Bacteriana/tratamento farmacológico , Animais , Carga Bacteriana/efeitos dos fármacos , Quimiocinas/análise , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Feminino , Inflamação/tratamento farmacológico , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Pneumonia Bacteriana/microbiologiaRESUMO
Sex differences in gut microbiota are acknowledged, and evidence suggests that gut microbiota may have a role in higher incidence and/or severity of autoimmune diseases in females. Additionally, it has been suggested that oral, vaginal, and gut microbiota composition can be regulated by estrogen levels. The association of vaginal microbiota with vulvovaginal atrophy at menopause is well described in the literature. However, the relevance of oral and gut microbiota modulation in the immune system during estrogen deficiency and its effect on inflammatory diseases is not well explored. Estrogen deficiency is a condition that occurs in menopausal women, and it can last approximately 30 years of a woman's life. The purpose of this mini- review is to highlight the importance of alterations in the oral and gut microbiota during estrogen deficiency and their effect on oral and inflammatory diseases that are associated with menopause. Considering that hormone replacement therapy is not always recommended or sufficient to prevent or treat menopause-related disease, we will also discuss the use of probiotics and prebiotics as an option for the prevention or treatment of these diseases.
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The indigenous intestinal microbiota is frequently considered an additional major organ of the human body and exerts profound immunomodulating activities. Germ-free (GF) mice display a significantly different inflammatory responsiveness pattern compared with conventional (CV) mice, and this was dubbed a "hyporesponsive phenotype." Taking into account that the deposition of immune complexes is a major event in acute inflammation and that GF mice have a distinct Ig repertoire and B cell activity, we aimed to evaluate whether this altered Ig repertoire interferes with the inflammatory responsiveness of GF mice. We found that serum transfer from CV naive mice was capable of reversing the inflammatory hyporesponsiveness of GF mice in sterile inflammatory injury induced by intestinal ischemia and reperfusion, as well as in a model of lung infection by Klebsiella pneumoniae Transferring serum from Ig-deficient mice to GF animals did not alter their response to inflammatory insult; however, injecting purified Abs from CV animals restored inflammatory responsiveness in GF mice, suggesting that natural Abs present in serum were responsible for altering GF responsiveness. Mechanistically, injection of serum and Ig from CV mice into GF animals restored IgG deposition, leukocyte influx, NF-κB activation, and proinflammatory gene expression in inflamed tissues and concomitantly downregulated annexin-1 and IL-10 production. Thus, our data show that microbiota-induced natural Abs are pivotal for host inflammatory responsiveness to sterile and infectious insults.
Assuntos
Anticorpos/imunologia , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes , Inflamação/imunologia , Intestinos/imunologia , Animais , Anexinas/imunologia , Anticorpos/administração & dosagem , Linfócitos B/imunologia , Regulação da Expressão Gênica , Humanos , Interleucina-10/imunologia , Intestinos/microbiologia , Intestinos/patologia , Isquemia , Infecções por Klebsiella/imunologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Camundongos , NF-kappa B/genéticaRESUMO
Gout is a disease characterized by the deposition of monosodium urate (MSU) crystals in the joints. Continuous gout episodes may lead to unresolved inflammatory responses and tissue damage. We investigated the effects of a high-fiber diet and acetate, a short-chain fatty acid (SCFA) resulting from the metabolism of fiber by gut microbiota, on the inflammatory response in an experimental model of gout in mice. Injection of MSU crystals into the knee joint of mice induced neutrophil influx and inflammatory hypernociception. The onset of inflammatory response induced by MSU crystals was not altered in animals given a high-fiber diet, but the high-fiber diet induced faster resolution of the inflammatory response. Similar results were obtained in animals given the SCFA acetate. Acetate was effective, even when given after injection of MSU crystals at the peak of the inflammatory response and induced caspase-dependent apoptosis of neutrophils that accounted for the resolution of inflammation. Resolution of neutrophilic inflammation was associated with decreased NF-κB activity and enhanced production of anti-inflammatory mediators, including IL-10, TGF-ß, and annexin A1. Acetate treatment or intake of a high-fiber diet enhanced efferocytosis, an effect also observed in vitro with neutrophils treated with acetate. In conclusion, a high-fiber diet or one of its metabolic products, acetate, controls the inflammatory response to MSU crystals by favoring the resolution of the inflammatory response. Our studies suggest that what we eat plays a determinant role in our capacity to fine tune the inflammatory response.
Assuntos
Acetatos/farmacologia , Fibras na Dieta/farmacologia , Gota/patologia , Inflamação/patologia , Neutrófilos/patologia , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Cristalização , Dieta Hiperlipídica , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fagocitose/efeitos dos fármacos , Ácido ÚricoRESUMO
Alcoholism is a multifactorial and complex disorder responsible for 5.9% of deaths worldwide. Excessive consumption of ethanol (Et-OH) induces alcoholic liver disease (ALD), a condition comprising a spectrum of clinical signs and morphological changes, ranging from fatty liver (steatosis) to more severe forms of chronic liver injury. Secondary cofactors, such as nutritional and hepatotoxic comorbid conditions, can also contribute to liver disease development. Here we investigated the effects in the progression of ALD following short-term exposure to diet high in refined carbohydrates (HC), a high-sugar and -butter (HSB) hypercaloric diet and acute Et-OH consumption. HSB diet increased the body weight (BW) and adiposity independently of acute Et-OH consumption. HC diet did not affect BW but increased the adiposity, while acute Et-OH alone did not affect BW and adiposity. All groups of mice developed steatosis except the control group. Exposure to acute Et-OH and HSB diet increased the number of neutrophils and macrophages, and apoptosis in the liver. This combination also increased the number of circulating neutrophils and reduced mononuclear cells in the blood. Thus, short-term exposure to HSB diet and acute Et-OH intake is linked to increased liver injury. These findings offer important clues to understand the hepatic injuries associated with short exposure to hypercaloric diets and acute Et-OH.