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1.
J Nutr Biochem ; 119: 109410, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37364793

RESUMO

The gut has been suggested as the first organ to be affected by unbalanced diets contributing to the obesogenic process. This study aimed to test a short time-course exposition model to a known pro- or anti-inflammatory enriched fatty diet to understand the early gut alterations. Male mice were exposed to the chow diet (CT), high-fat (HF) diet, or a high-fat diet partially replaced on flaxseed oil (FS), rich in omega-3 (ω3), for 14 days. HF and FS increased the total body weight mass compared with the CT group, but FS reduced the epididymal fat depot compared to HF. The bioinformatics from mice and human databases showed the Zo1-Ocln-Cldn7 tight junctions as the main protein-triad. In the ileum, the HF diet has increased IL1ß transcript and IL1ß, TNFα, and CD11b proteins, but reduced the tight junctions (Zo1, Ocln, and Cld7) compared to the CT group. Despite the FS diet being partially efficient in protecting the ileum against inflammation, the tight junctions were increased, compared to the HF group. The GPR120 and GPR40 receptors were unaffected by diets, but GPR120 was colocalized on the surface of ileum macrophages. The short period of a high-fat diet was enough to start the obesogenic process, ileum inflammation, and reduce the tight junctions. Flaxseed oil did not protect efficiently against dysmetabolism. Still, it increased the tight junctions, even without alteration on inflammatory parameters, suggesting the protection against gut permeability during early obesity development.


Assuntos
Ácidos Graxos Ômega-3 , Óleo de Semente do Linho , Humanos , Masculino , Animais , Camundongos , Óleo de Semente do Linho/farmacologia , Junções Íntimas/metabolismo , Ácidos Graxos Insaturados , Inflamação/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Ácidos Graxos
2.
Proc Natl Acad Sci U S A ; 119(35): e2200960119, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-35951647

RESUMO

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.


Assuntos
Encéfalo , COVID-19 , Viroses do Sistema Nervoso Central , SARS-CoV-2 , Astrócitos/patologia , Astrócitos/virologia , Encéfalo/patologia , Encéfalo/virologia , COVID-19/complicações , COVID-19/patologia , Viroses do Sistema Nervoso Central/etiologia , Viroses do Sistema Nervoso Central/patologia , Humanos , Síndrome de COVID-19 Pós-Aguda
3.
Cells ; 11(16)2022 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-36010648

RESUMO

Clinical and experimental data indicate that severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection is associated with significant changes in the composition and function of intestinal microbiota. However, the relevance of these effects for SARS-CoV-2 pathophysiology is unknown. In this study, we analyzed the impact of microbiota depletion after antibiotic treatment on the clinical and immunological responses of K18-hACE2 mice to SARS-CoV-2 infection. Mice were treated with a combination of antibiotics (kanamycin, gentamicin, metronidazole, vancomycin, and colistin, Abx) for 3 days, and 24 h later, they were infected with SARS-CoV-2 B lineage. Here, we show that more than 80% of mice succumbed to infection by day 11 post-infection. Treatment with Abx had no impact on mortality. However, Abx-treated mice presented better clinical symptoms, with similar weight loss between infected-treated and non-treated groups. We observed no differences in lung and colon histopathological scores or lung, colon, heart, brain and kidney viral load between groups on day 5 of infection. Despite some minor differences in the expression of antiviral and inflammatory markers in the lungs and colon, no robust change was observed in Abx-treated mice. Together, these findings indicate that microbiota depletion has no impact on SARS-CoV-2 infection in mice.


Assuntos
Tratamento Farmacológico da COVID-19 , Microbiota , Enzima de Conversão de Angiotensina 2 , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Modelos Animais de Doenças , Melfalan , Camundongos , Camundongos Transgênicos , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2 , gama-Globulinas
4.
Adv Exp Med Biol ; 1327: 93-106, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34279831

RESUMO

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, emerged last year in China and quickly spread to millions of people around the world. This virus infects cells in different tissues and causes pulmonary (e.g., pneumonia and acute respiratory distress syndrome), neurological, cardiovascular, and intestinal manifestations, which can be the result of a direct viral effect or secondary to endothelial, thrombotic, or immunological alterations. In this chapter, we discuss recent studies which highlighted the relevance of the intestinal microbiota for other infectious respiratory diseases. We present the "altered microbiota" (dysbiotic) as a point of connection between conditions that are risk factors for the development of severe forms of COVID-19. In addition, we describe the findings of recent studies reporting alterations of microbiota composition in COVID-19 patients and speculate on how this may impact in development of the disease.


Assuntos
COVID-19 , Microbioma Gastrointestinal , China , Disbiose , Humanos , SARS-CoV-2
5.
Gut Microbes ; 13(1): 1-9, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33550892

RESUMO

Microbiota-derived molecules called short-chain fatty acids (SCFAs) play a key role in the maintenance of the intestinal barrier and regulation of immune response during infectious conditions. Recent reports indicate that SARS-CoV-2 infection changes microbiota and SCFAs production. However, the relevance of this effect is unknown. In this study, we used human intestinal biopsies and intestinal epithelial cells to investigate the impact of SCFAs in the infection by SARS-CoV-2. SCFAs did not change the entry or replication of SARS-CoV-2 in intestinal cells. These metabolites had no effect on intestinal cells' permeability and presented only minor effects on the production of anti-viral and inflammatory mediators. Together our findings indicate that the changes in microbiota composition of patients with COVID-19 and, particularly, of SCFAs do not interfere with the SARS-CoV-2 infection in the intestine.


Assuntos
COVID-19/virologia , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal , Mucosa Intestinal/virologia , Adulto , Idoso , Células CACO-2 , Colo/virologia , Células Epiteliais/virologia , Feminino , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Carga Viral , Internalização do Vírus , Adulto Jovem
6.
Adv Exp Med Biol ; 1260: 85-105, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304031

RESUMO

Recent studies have indicated a prominent role of intestinal microbiota in regulation of several physiological aspects of the host including development and activation of the immune system and control of metabolism. In this review, we focused our discussion on bacterial metabolites produced from dietary fiber fermentation called short-chain fatty acids, which act as a link between the microbiota and host cells. Specifically, we described how modifications in their intestinal levels are associated with development of age-related pathologies including metabolic diseases and type 2 diabetes, hypertension, cardiovascular and neurodegenerative diseases. We also highlight their impact on the development of cancer.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Doença , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/fisiologia , Humanos , Intestinos/microbiologia
7.
J Exp Med ; 217(3)2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31876919

RESUMO

Antibiotic-induced dysbiosis is a key predisposing factor for Clostridium difficile infections (CDIs), which cause intestinal disease ranging from mild diarrhea to pseudomembranous colitis. Here, we examined the impact of a microbiota-derived metabolite, short-chain fatty acid acetate, on an acute mouse model of CDI. We found that administration of acetate is remarkably beneficial in ameliorating disease. Mechanistically, we show that acetate enhances innate immune responses by acting on both neutrophils and ILC3s through its cognate receptor free fatty acid receptor 2 (FFAR2). In neutrophils, acetate-FFAR2 signaling accelerates their recruitment to the inflammatory sites, facilitates inflammasome activation, and promotes the release of IL-1ß; in ILC3s, acetate-FFAR2 augments expression of the IL-1 receptor, which boosts IL-22 secretion in response to IL-1ß. We conclude that microbiota-derived acetate promotes host innate responses to C. difficile through coordinate action on neutrophils and ILC3s.


Assuntos
Acetatos/imunologia , Clostridioides difficile/imunologia , Infecções por Clostridium/imunologia , Enterocolite Pseudomembranosa/imunologia , Imunidade Inata/imunologia , Neutrófilos/imunologia , Receptores Acoplados a Proteínas G/imunologia , Animais , Inflamassomos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia
8.
J Nutr Biochem ; 66: 52-62, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30771734

RESUMO

GPR120 and GPR40 were recently reported as omega-3 (ω3) receptors with anti-inflammatory properties. Physical exercise could increase the expression of these receptors in the liver, improving hepatic metabolism in obesity and type 2 diabetes. Our aim was to investigate GPR120/40 in the liver of lean and obese mice after acute or chronic physical exercise, with or without the supplementation of ω3 rich flaxseed oil (FS), as well as assess the impact of exercise and FS on insulin signaling and inflammation. Mice were fed a high-fat diet (HF) for 4 weeks to induce obesity and subsequently subjected to exercise with or without FS, or FS alone. Insulin signaling, inflammatory markers and GPR120/40 and related cascades were measured. Chronic, but not acute, exercise and FS increased GPR120, but not GPR40, activating ß-arrestin-2 and decreasing the inflammatory response, as well as reducing fat depots in liver and adipose tissue. Exercise or a source of ω3 led to a higher tolerance to fatigue and an increased running distance and speed. The combination of physical exercise and ω3 food sources could provide a new strategy against obesity through the modulation of hepatic GPR120 and an increase in exercise performance.


Assuntos
Ácidos Graxos Insaturados/farmacologia , Óleo de Semente do Linho/química , Fígado/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Tecido Adiposo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Dieta Hiperlipídica/efeitos adversos , Teste de Tolerância a Glucose , Insulina/metabolismo , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Obesidade/dietoterapia , Obesidade/metabolismo , Condicionamento Físico Animal
9.
Sci Rep ; 8(1): 14318, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254287

RESUMO

The chronic and low-grade inflammation induced by obesity seem to be the "first hit" to retinopathy associated to diabetes type 2. Herein, we hypothesized that omega-3 fatty acids from flaxseed oil enriched diet disrupt the pro-inflammatory status in the retina, protecting against retinopathy development. For eight weeks under a high-fat diet (HF), several physiological parameters were monitored to follow the metabolic homeostasis disruption. After this period, mice were treated with a HF substituted in part of lard by flaxseed oil (FS) for another eight weeks. Food behavior, weight gain, glucose and insulin sensitivity, electroretinography, RT-qPCR and western blots were carried out. The HF was able to induce a pro-inflammatory background in the retina, changing IL1ß and TNFα. VEGF, a master piece of retinopathy, had early onset increased also induced by HF. The FS-diet was able to decrease inflammation and retinopathy and improved retinal electro stimuli compared to HF group. GPR120 and GPR40 (G Protein-Coupled Receptors 120 and 40), an omega-3 fatty acid receptors, were detected in the retina for the first time. FS-diet modulated the gene expression and protein content of these receptors. Thus, unsaturated fatty acids protect the retina from diabetes type 2 mice model from disease progression.


Assuntos
Retinopatia Diabética/metabolismo , Retinopatia Diabética/prevenção & controle , Ácidos Graxos Ômega-3/farmacologia , Óleo de Semente do Linho/química , Receptores Acoplados a Proteínas G/metabolismo , Animais , Retinopatia Diabética/patologia , Masculino , Camundongos , Camundongos Obesos , Retina/efeitos dos fármacos , Retina/patologia
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