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Inflammatory bowel diseases (IBD) are gastrointestinal disorders characterized by a breakdown in intestinal homeostasis by inflammatory immune responses to luminal antigens. Novel strategies for ameliorating IBD have been proposed in many studies using animal models. Our group has demonstrated that administration of Lactococcus lactis NCDO 2118 can improve clinical parameters of colitis induced by oral administration of dextran sulphate sodium (DSS). However, it is not clear whether other strains of L. lactis can yield the same effect. The objective of present study was to analyze the effects of three different L. lactis strains (NCDO2118, IL1403 and MG1363) in the development of DSS-induced colitis in C57BL/6 mice. Acute colitis was induced in C57/BL6 mice by the administration of 2% DSS during 7 consecutive days. Body weight loss and shortening of colon length were observed in DSS-treated mice, and none of L. lactis strains had an impact in these clinical signs of colitis. On the other hand, all strains improved the global macroscopical disease index and prevented goblet cells depletion as well as the increase of intestinal permeability. TNF-α production was reduced in gut mucosa of L. lactis DSS-treated mice indicating a modulation of a critical pro-inflammatory response by all strains tested. However, only L. lactis NCDO2118 and MG1363 induced a higher frequency of CD11c+CD11b-CD103+ tolerogenic dendritic cells in lymphoid organs of mice at steady state. We conclude that all tested strains of L. lactis improved the clinical scores and parameters of colitis, which confirm their anti-inflammatory properties in this model of colitis.
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Colite , Doenças Inflamatórias Intestinais , Lactococcus lactis , Animais , Camundongos , Lactococcus lactis/genética , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Doenças Inflamatórias Intestinais/induzido quimicamente , Imunidade , Modelos Animais de DoençasRESUMO
Several antigens can act as allergens eliciting IgE-mediated food allergy reactions when fed to sensitized animals. One of them is ovalbumin (OVA) which is the main allergen in egg white. Allergic mice develop aversion to OVA consumption. This aversive behavior is associated with anxiety, and it can be transferred to non-sensitized mice by injection of serum of allergic mice. However, it is yet to be determined whether altered behavior is a general component of food allergy or whether it is specific for some types of allergens. Cow's milk allergy is the most prevalent food allergy that usually begins early in life and ß-lactoglobulin (BLG) is the milk component with the highest allergenicity. In this study, we investigated behavioral and neuroimmune circuits triggered by allergic sensitization to BLG. A neuroimmune conflict between aversion and reward was observed in a model of food allergy induced by BLG intake. Mice sensitized to BLG did not present aversive behavior when BLG was used for sensitization and oral challenge. Mice allergic to BLG preferred to drink the allergen-containing solution over water even though they had high levels of specific IgE, inflammatory cells in the intestinal mucosa and significant weight loss. When sensitized to OVA and challenged with the same antigen, mice had increased levels of neuron activation in the amygdala, a brain area related to anxiety. On the other hand, when mice were sensitized to OVA and received a mixture of BLG and OVA in the oral challenge, mice preferred to drink this mixture, despite their aversion to OVA, which was associated with neuron activation in the nucleus accumbens, an area related to reward behavior. Thus, the aversive behavior observed in food allergy to OVA does not apply to all antigens and some allergens may activate the brain reward system rather than anxiety and aversion. Our study provides novel insights into the neuroimmune conflicts regarding preference and avoidance to a common antigen associated with food allergy.
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Oral tolerance is the physiological process that enables the immune system to differentiate between harmless dietary and microbiota antigens from pathogen derived antigens. It develops at the mucosal surfaces and can result in local and systemic regulatory and anti-inflammatory effects. Translation of these benefits to the clinical practice faces limitations involving specificity and doses of antigen as well as regimens of feeding. To circumvent these problems, we developed a recombinant Hsp65 delivered by the acid lactic bacteria Lactococcus lactis NCDO 2118 directy in the intestinal mucosa. Hsp65 is a ubiquitous protein overexpressed in inflamed tissues and capable of inducing immunoregulatory mechanisms. L. lactis has probiotic properties and is commonly and safely used in dairy products. In this study, we showed that continuous delivery of HSP65 in the gut mucosa by L. lactis is a potent tolerogenic stimulus inducing regulatory CD4+LAP+ T cells that prevented collagen-induced and methylated bovine serum albumin-induced arthritis in mice. Clinical and histological signs of arthritis were inhibited as well as levels of inflammatory cytokines such as IL-17 and IFN-γ, serum titers of anti-collagen antibodies and rheumatoid factor. Oral administration of L. lactis induced alterations in microbiota composition toward an increased abundance of anaerobic bacteria such as Bifidobacterium and Lactobacillus. Tolerance to HSP65 and arthritis prevention induced by the recombinant L. lactis was associated with increase in IL-10 production by B cells and it was dependent on LAP+ T cells, IL-10 and TLR2 signaling. Therefore, HSP65-producing treatment induced effective tolerance and prevented arthritis development suggesting it can be used as a therapeutic tool for autoimmune diseases.
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Artrite/induzido quimicamente , Artrite/prevenção & controle , Proteínas de Bactérias/metabolismo , Colágeno/efeitos adversos , Proteínas de Choque Térmico/metabolismo , Lactococcus lactis/metabolismo , Soroalbumina Bovina/efeitos adversos , Administração Oral , Animais , Artrite/imunologia , Doenças Autoimunes/prevenção & controle , Proteínas de Bactérias/genética , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Microbioma Gastrointestinal , Proteínas de Choque Térmico/genética , Tolerância Imunológica , Mucosa Intestinal/imunologia , Lactococcus lactis/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Probióticos/administração & dosagem , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUNDS AND AIMS: Inflammatory Bowel Diseases (IBD), including Ulcerative Colitis (UC), coincide with alterations in the gut microbiota. Consumption of immunomodulatory strains of probiotic bacteria may induce or prolong remission in UC patients. Fermented foods, including cheeses, constitute major vectors for bacteria consumption. New evidences revealed anti-inflammatory effects in selected strains of Propionibacterium freudenreichii. We thus hypothesized that consumption of a functional cheese, fermented by such a strain, may exert a positive effect on IBD. METHODS: We investigated the impact of cheese fermented by P. freudenreichii on gut inflammation. We developed an experimental single-strain cheese solely fermented by a selected immunomodulatory strain of P. freudenreichii, CIRM-BIA 129. We moreover produced, in industrial conditions, an Emmental cheese using the same strain, in combination with Lactobacillus delbrueckii CNRZ327 and Streptococcus thermophilus LMD-9, as starters. Consumption of both cheeses was investigated with respect to prevention of Dextran Sodium Sulphate (DSS)-induced colitis in mice. RESULTS: Consumption of the single-strain experimental cheese, or of the industrial Emmental, both fermented by P. freudenreichii CIRM-BIA 129, reduced severity of subsequent DSS-induced colitis, weight loss, disease activity index and histological score. Both treatments, in a preventive way, reduced small bowel Immunoglobulin A (IgA) secretion, restored occludin gene expression and prevented induction of Tumor Necrosis Factor α (TNFα), Interferon γ (IFNγ) and Interleukin-17 (IL-17). CONCLUSIONS: A combination of immunomodulatory strains of starter bacteria can be used to manufacture an anti-inflammatory cheese, as revealed in an animal model of colitis. This opens new perspectives for personalised nutrition in the context of IBD.
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BACKGROUND: Food allergy is an abnormal immune response to antigens introduced into the body through food. Its prevalence has increased in developed and developing countries. Natural products are traditionally used to alleviate and treat diseases, and diet can play a role in both the prevention and management of food allergy. The effects of capsaicin as an anti-oxidant, anticarcinogenic, and anti-inflammatory in the energy expenditure and suppression of fat accumulation have been demonstrated. This study evaluated the effect of oral supplementation with capsaicin on a food allergy model. METHODS: OVA-sensitized mice received ovalbumin solution, and they were fed with chow supplemented with capsaicin for 7 days. The control group received AIN-93 chow with no supplementation. IgE anti-ova, inflammatory infiltration, oxidative stress and metabolic analysis were performed. RESULTS: The results showed that capsaicin supplementation is not able to reduce characteristic signs of food allergy, such as production of IgE and weight loss. However, macrophages infiltration and IL-33 in proximal jejunum was reduced in OVA capsaicin group. In addition, hepatic triglycerides and intestinal hydroperoxides were reduced in both capsaicin groups. CONCLUSION: Oral supplementation with capsaicin attenuated important factors associated to food allergy such as inflammation and oxidative stress, suggesting better prognosis and evolution of the disease.
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Alterations in the composition of the intestinal microbiota have been associated with development of type 1 diabetes (T1D), but little is known about changes in intestinal homeostasis that contribute to disease pathogenesis. Here, we analyzed oral tolerance induction, components of the intestinal barrier, fecal microbiota, and immune cell phenotypes in non-obese diabetic (NOD) mice during disease progression compared to non-obese diabetes resistant (NOR) mice. NOD mice failed to develop oral tolerance and had defective protective/regulatory mechanisms in the intestinal mucosa, including decreased numbers of goblet cells, diminished mucus production, and lower levels of total and bacteria-bound secretory IgA, as well as an altered IEL profile. These disturbances correlated with bacteria translocation to the pancreatic lymph node possibly contributing to T1D onset. The composition of the fecal microbiota was altered in pre-diabetic NOD mice, and cross-fostering of NOD mice by NOR mothers corrected their defect in mucus production, indicating a role for NOD microbiota in gut barrier dysfunction. NOD mice had a reduction of CD103+ dendritic cells (DCs) in the MLNs, together with an increase of effector Th17 cells and ILC3, as well as a decrease of Th2 cells, ILC2, and Treg cells in the small intestine. Importantly, most of these gut alterations precede the onset of insulitis. Disorders in the intestinal mucosa of NOD mice can potentially interfere with the development of T1D due the close relationship between the gut and the pancreas. Understanding these early alterations is important for the design of novel therapeutic strategies for T1D prevention.
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Diabetes Mellitus Tipo 1/patologia , Mucosa Intestinal/anormalidades , Animais , Citocinas/metabolismo , Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Disbiose/patologia , Feminino , Microbioma Gastrointestinal , Tolerância Imunológica , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/patologia , Linfonodos/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Muco/metabolismo , Pâncreas/metabolismo , Pâncreas/patologiaRESUMO
Dietary supplementation with conjugated linoleic acid (CLA) has been proposed for weight management and to prevent gut inflammation. However, some animal studies suggest that supplementation with CLA leads to the development of nonalcoholic fatty liver disease. The aims of this study were to test the efficiency of CLA in preventing dextran sulfate sodium (DSS)-induced colitis, to analyze the effects of CLA in the liver function, and to access putative liver alterations upon CLA supplementation during colitis. So, C57BL/6 mice were supplemented for 3 weeks with either control diet (AIN-G) or 1% CLA-supplemented diet. CLA content in the diet and in the liver of mice fed CLA containing diet were accessed by gas chromatography. On the first day of the third week of dietary treatment, mice received ad libitum a 1.5%-2.5% DSS solution for 7 days. Disease activity index score was evaluated; colon and liver samples were stained by hematoxylin and eosin for histopathology analysis and lamina propria cells were extracted to access the profile of innate cell infiltrate. Metabolic alterations before and after colitis induction were accessed by an open calorimetric circuit. Serum glucose, cholesterol, triglycerides and alanine aminotransaminase were measured; the content of fat in liver and feces was also accessed. CLA prevented weight loss, histopathologic and macroscopic signs of colitis, and inflammatory infiltration. Mice fed CLA-supplemented without colitis induction diet developed steatosis, which was prevented in mice with colitis probably due to the higher lipid consumption as energy during gut inflammation. This result suggests that CLA is safe for use during gut inflammation but not at steady-state conditions.
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Colite/dietoterapia , Ácidos Linoleicos Conjugados/farmacologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Alanina Transaminase/sangue , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Colite/induzido quimicamente , Colite/prevenção & controle , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Sulfato de Dextrana/toxicidade , Suplementos Nutricionais , Feminino , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/fisiologia , Ácido Linoleico/metabolismo , Ácidos Linoleicos Conjugados/efeitos adversos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE AND DESIGN: The aim of this study was to investigate the contribution of IL-33/ST2 axis in the onset and progression of acute liver injury using a mice model of drug-induced liver injury (DILI). MATERIAL AND TREATMENTS: DILI was induced by overdose administration of acetaminophen (APAP) by oral gavage in wild-type BALB/c, ST2-deficient mice and in different bone marrow chimeras. Neutrophils were depleted by anti-Ly6G and macrophages with clodronate liposomes (CLL). METHODS: Blood and liver were collected for biochemical, immunologic and genetic analyses. Mice were imaged by confocal intravital microscopy and liver non-parenchymal cells and hepatocytes were isolated for flow cytometry, genetic and immunofluorescence studies. RESULTS: Acetaminophen overdose caused a massive necrosis and accumulation of immune cells within the liver, concomitantly with IL-33 and chemokine release. Liver non-parenchymal cells were the major sensors for IL-33, and amongst them, neutrophils were the major players in amplification of the inflammatory response triggered by IL-33/ST2 signalling pathway. CONCLUSION: Blockage of IL-33/ST2 axis reduces APAP-mediated organ injury by dampening liver chemokine release and activation of resident and infiltrating liver non-parenchymal cells.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Interleucina-33/imunologia , Fígado/imunologia , Acetaminofen/toxicidade , Analgésicos não Narcóticos/toxicidade , Animais , Transplante de Medula Óssea , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/terapia , DNA/metabolismo , Feminino , Hepatócitos/imunologia , Inflamação/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/sangue , Interleucina-33/genética , Fígado/citologia , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neutrófilos/imunologia , Transdução de SinaisRESUMO
Dietary proteins can influence the maturation of the immune system, particularly the gut-associated lymphoid tissue, when consumed from weaning to adulthood. Moreover, replacement of dietary proteins by amino acids at weaning has been shown to impair the generation of regulatory T cells in the gut as well as immune activities such as protective response to infection, induction of oral and nasal tolerance as well as allergic responses. Polymeric and elemental diets are used in the clinical practice, but the specific role of intact proteins and free amino acids during the intestinal inflammation are not known. It is plausible that these two dietary nitrogen sources would yield distinct immunological outcomes since proteins are recognized by the immune system as antigens and amino acids do not bind to antigen-recognition receptors but instead to intracellular receptors such as mammalian target of rapamycin (mTOR). In this study, our aim was to evaluate the effects of consumption of an amino acid-containing diet (AA diet) versus a control protein-containing diet in adult mice at steady state and during colitis development. We showed that consumption of a AA diet by adult mature mice lead to various immunological changes including decrease in the production of serum IgG as well as increase in the levels of IL-6, IL-17A, TGF-ß, and IL-10 in the small and large intestines. It also led to changes in the intestinal morphology, to increase in intestinal permeability, in the number of total and activated CD4+ T cells in the small intestine as well as in the frequency of proliferating cells in the colon. Moreover, consumption of AA diet during and prior to development of dextran sodium sulfate-induced colitis exacerbated gut inflammation. Administration of rapamycin during AA diet consumption prevented colitis exacerbation suggesting that mTOR activation was involved in the effects triggered by the AA diet. Therefore, our study suggests that different outcomes can result from the use of diets containing either intact proteins or free amino acids such as elemental, semielemental, and polymeric diets during intestinal inflammation. These results may contribute to the design of nutritional therapeutic intervention for inflammatory bowel diseases.
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Heat shock proteins (Hsps) are highly expressed at all sites of inflammation. As they are ubiquitous and immunodominant antigens, these molecules represent good candidates for the therapeutic use of oral tolerance in autoimmune and chronic inflammatory diseases. Evidences from human and animal studies indicate that inflammatory bowel disease (IBD) results from uncontrolled inflammatory responses to intestinal microbiota. Hsps are immunodominant proteins expressed by several immune cells and by commensal bacteria. Using an IBD mouse model, we showed that oral pretreatment with genetically modified Lactococcus lactis that produces and releases Mycobacterium Hsp65, completely prevented DSS-induced colitis in C57BL/6 mice. Protection was associated with reduced pro-inflammatory cytokines, such as IFN-γ, IL-6, and TNF-α; increased IL-10 production in colonic tissue; and expansion of CD4+Foxp3+ and CD4+LAP+ regulatory T cells in spleen and mesenteric lymph nodes. This effect was dependent on IL-10 and toll-like receptor 2. Thus, this approach may open alternative options for long-term management of IBD.
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Excess intake of sodium is often associated with high risk for cardiovascular disease. More recently, some studies on the effects of high-salt diets (HSDs) have also demonstrated that they are able to activate Th17 cells and increase severity of autoimmune diseases. The purpose of the present study was to evaluate the effects of a diet supplemented with NaCl in the colonic mucosa at steady state and during inflammation. We showed that consumption of HSD by mice triggered a gut inflammatory reaction associated with IL-23 production, recruitment of neutrophils, and increased frequency of the IL-17-producing type 3 innate lymphoid cells (ILC3) in the colon. Moreover, gut inflammation was not observed in IL-17-/- mice but it was present, although at lower grade, in RAG-/- mice suggesting that the inflammatory effects of HSD was dependent on IL-17 but only partially on Th17 cells. Expression of SGK1, a kinase involved in sodium homeostasis, increased 90 min after ingestion of 50% NaCl solution and decreased 3 weeks after HSD consumption. Colitis induced by oral administration of either dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid was exacerbated by HSD consumption and this effect was associated with increased frequencies of RORγt+ CD4+ T cells and neutrophils in the colon. Therefore, our results demonstrated that consumption of HSD per se triggered a histologically detectable inflammation in the colon and also exacerbated chemically induced models of colitis in mice by a mechanism dependent on IL-17 production most likely by both ILC3 and Th17 cells.
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Platelet-activating factor (PAF) is known to be an important mediator of anaphylaxis. However, there is a lack of information in the literature about the role of PAF in food allergy. The aim of this work was to elucidate the participation of PAF during food allergy development and the consequent adipose tissue inflammation along with its alterations. Our data demonstrated that, both before oral challenge and after 7 days receiving ovalbumin (OVA) diet, OVA-sensitized mice lacking the PAF receptor (PAFR) showed a decreased level of anti-OVA IgE associated with attenuated allergic markers in comparison to wild type (WT) mice. Moreover, there was less body weight and adipose tissue loss in PAFR-deficient mice. However, some features of inflamed adipose tissue presented by sensitized PAFR-deficient and WT mice after oral challenge were similar, such as a higher rate of rolling leukocytes in this tissue and lower circulating levels of adipokines (resistin and adiponectin) in comparison to nonsensitized mice. Therefore, PAF signaling through PAFR is important for the allergic response to OVA but not for the adipokine alterations caused by this inflammatory process. Our work clarifies some effects of PAF during food allergy along with its role on the metabolic consequences of this inflammatory process.
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Adipocinas/sangue , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/metabolismo , Glicoproteínas da Membrana de Plaquetas/imunologia , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptores Acoplados a Proteínas G/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Ração Animal , Animais , Biomarcadores/sangue , Peso Corporal/imunologia , Dieta , Hipersensibilidade Alimentar/sangue , Imunoglobulina E/imunologia , Inflamação/sangue , Inflamação/imunologia , Inflamação/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Ovalbumina/imunologiaRESUMO
BACKGROUND: Mucositis is a common complication in patients undergoing radiotherapy and chemotherapy. It is associated with pain, poor quality of life, and malnutrition, leading to an increased number of hospital admissions and prolonged hospitalization. The use of immunonutrients may be an alternative treatment option, which may help to improve patient outcome. OBJECTIVE: Here we assessed the impact of L-citrulline (CIT) on a murine model of 5-fluorouracil (5FU)-induced mucositis. METHODS: Swiss male mice were randomized into 4 groups: control, CIT, 5FU, and 5FU+CIT. Mice were fed with commercial chow and supplemented with an oral solution of alanine (control and 5FU groups) or CIT (CIT and 5FU+CIT groups). On the seventh day, mice received intraperitoneal phosphate-buffered saline or 5FU (200 mg/kg, single dose) to induce mucositis. On the 10th day, mice were euthanized, and the blood and small intestines were harvested. Body weight, morphology, histopathology score (hematoxylin and eosin) of the small intestine (from 0-12), myeloperoxidase activity, oxidative stress level, and intestinal permeability were assessed. RESULTS: We observed significant weight loss after the administration of 5FU in both treated and control animals. CIT administration contributed to a partial recovery of the mucosal architecture as well as an intermediate reduction of the histopathologic score, and functional intestinal permeability was partially rescued. CONCLUSIONS: CIT administration attenuated 5FU-mediated damage to the mucosal architecture of the small intestine, decreasing the size of the injured areas and promoting decreased intestinal permeability.
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Citrulina/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosite/tratamento farmacológico , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Fluoruracila/efeitos adversos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Mucosite/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , PermeabilidadeRESUMO
OBJECTIVE: Allergic mice show a reduction in body weight and adiposity with a higher inflammatory response in the adipose tissue similar to obese fat tissue. This study aimed to evaluate whether the low-grade inflammatory milieu of mice with diet-induced mild obesity interferes with the allergic response induced by ovalbumin (OVA). METHODS: BALB/c mice were divided into four groups: 1) non-allergic (OVA-) mice fed chow diet, 2) allergic (OVA+) mice fed chow diet, 3) OVA- mice fed high-refined carbohydrate-containing (HC) diet, and 4) OVA+ mice fed HC diet. After 5 wk, allergic groups were sensitized with OVA and received a booster 14 d later. All groups received an oral OVA challenge 7 d after the booster. RESULTS: Allergic groups showed increased serum levels of total IgE, anti-OVA IgE, and IgG1; a high disease activity index score; aversion to OVA; and increased intestinal eosinophil infiltration. Non-allergic mild-obese mice also showed aversion to OVA and an increased number of eosinophils in the proximal jejunum. After the allergic challenge, OVA+ mice fed chow diet showed weight loss and lower adiposity in several adipose tissue depots. OVA+ mice fed HC diet showed a loss of fat mass only in the mesenteric adipose tissue. Furthermore, increased levels of TNF, IL-6, and IL-10 were observed in this tissue. CONCLUSIONS: Our data show that mild-obese allergic mice do not present severe pathologic features of food allergy similar to those exhibited by lean allergic mice. Mild obesity promoted by HC diet ingestion causes important intestinal disorders that appear to modulate the inflammatory response during the antigen challenge.
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Dieta , Carboidratos da Dieta/administração & dosagem , Hipersensibilidade Alimentar/imunologia , Tecido Adiposo/metabolismo , Adiposidade , Animais , Peso Corporal , Hipersensibilidade Alimentar/sangue , Teste de Tolerância a Glucose , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Inflamação/sangue , Inflamação/imunologia , Resistência à Insulina , Interleucina-10/sangue , Interleucina-6/sangue , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Contagem de Leucócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Obesidade/metabolismo , Ovalbumina/imunologiaRESUMO
Food allergy is an adverse immune response to dietary proteins. Hydrolysates are frequently used for children with milk allergy. However, hydrolysates effects afterwards are poorly studied. The aim of this study was to investigate the immunological consequences of hydrolyzed whey protein in allergic mice. For that, we developed a novel model of food allergy in BALB/c mice sensitized with alum-adsorbed ß-lactoglobulin. These mice were orally challenged with either whey protein or whey hydrolysate. Whey-challenged mice had elevated levels of specific IgE and lost weight. They also presented gut inflammation, enhanced levels of SIgA and IL-5 as well as decreased production of IL-4 and IL-10 in the intestinal mucosa. Conversely, mice challenged with hydrolyzate maintained normal levels of IgE, IL-4 and IL-5 and showed no sign of gut inflammation probably due to increased IL-12 production in the gut. Thus, consumption of hydrolysate prevented the development of clinical signs of food allergy in mice.
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Mucosa Intestinal/imunologia , Lactoglobulinas/imunologia , Hipersensibilidade a Leite/imunologia , Hidrolisados de Proteína/imunologia , Proteínas do Soro do Leite/imunologia , Animais , Modelos Animais de Doenças , Hipersensibilidade Alimentar/imunologia , Imunoglobulina A Secretora/imunologia , Imunoglobulina A Secretora/metabolismo , Imunoglobulina E/sangue , Inflamação/imunologia , Interleucina-10/metabolismo , Subunidade p35 da Interleucina-12/biossíntese , Subunidade p35 da Interleucina-12/imunologia , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Hidrolisados de Proteína/administração & dosagem , Soro do Leite/imunologia , Proteínas do Soro do Leite/farmacologiaRESUMO
As antimicrobials are introduced into the environment, microorganisms may respond in different ways, sometimes displaying alterations in cellular physiology. Considering the clinical relevance of the Bacteroides fragilis, strains were selected to investigate bacterial response after exposure to subinhibitory concentrations (SIC) of ampicillin (AMP), ampicillin-sulbactam (AMS), clindamycin (CLI), chloramphenicol (CHL), and its relationship to a host model (BALB/c mice) after experimental challenge. Morphological alterations, and biochemical-physiological and genetic profiles were evaluated among drug-selected bacteria. Histopathological evaluation of the liver and spleen, and inflammatory cytokines were determined after bacterial infection in mice. AMP and AMS exposure were related to most significant cellular alterations. Decreased sensitivity to all antimicrobials was observed for all drug-selected bacteria. Down regulation in adherence properties were also observed. Spleen and liver alterations were observed in different patterns. Increased levels of TNF-α, IL-6 and IFN-γ were also observed. Our results show that SICs of AMP, AMS, CLI and CHL may be related to alterations in cell physiology in B. fragilis with implications to the host-bacteria relationship. The data emphasizes the risks of inappropriate chemotherapy, and the concerns regarding ecological consequences lead by SICs of antimicrobials in resident microbiota.
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Antibacterianos/farmacologia , Infecções por Bacteroides/microbiologia , Bacteroides fragilis/efeitos dos fármacos , Bacteroides fragilis/crescimento & desenvolvimento , Animais , Infecções por Bacteroides/genética , Infecções por Bacteroides/metabolismo , Bacteroides fragilis/patogenicidade , Feminino , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Virulência/efeitos dos fármacosRESUMO
BACKGROUND: Many probiotic bacteria have been described as promising tools for the treatment and prevention of inflammatory bowel diseases (IBDs). Most of these bacteria are lactic acid bacteria, which are part of the healthy human microbiota. However, little is known about the effects of transient bacteria present in normal diets, including Lactococcus lactis. METHODS: In the present study, we analysed the immunomodulatory effects of three L. lactis strains in vitro using intestinal epithelial cells. L. lactis NCDO 2118 was administered for 4 days to C57BL/6 mice during the remission period of colitis induced by dextran sodium sulphate (DSS). RESULTS: Only one strain, L. lactis NCDO 2118, was able to reduce IL-1ß-induced IL-8 secretion in Caco-2 cells, suggesting a potential anti-inflammatory effect. Oral treatment using L. lactis NCDO 2118 resulted in a milder form of recurrent colitis than that observed in control diseased mice. This protective effect was not attributable to changes in secretory IgA (sIgA); however, NCDO 2118 administration was associated with an early increase in IL-6 production and sustained IL-10 production in colonic tissue. Mice fed L. lactis NCDO 2118 had an increased number of regulatory CD4(+) T cells (Tregs) bearing surface TGF-ß in its latent form (Latency-associated peptide-LAP) in the mesenteric lymph nodes and spleen. CONCLUSIONS: Here, we identified a new probiotic strain with a potential role in the treatment of IBD, and we elucidated some of the mechanisms underlying its anti-inflammatory effect.
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OBJECTIVE: Interleukin-4 (IL-4) is a multifunctional cytokine involved in many diseases such as autoimmune hepatitis and idiosyncratic drug reactions. However, its role in acetaminophen (APAP)-induced liver injury remains unclear. Our objective was to evaluate the contribution of IL-4 to the pathogenesis of APAP-induced liver injury. METHODS: Balb/C (WT) and IL-4 knockout (IL-4(-/-)) mice were orally overdosed with APAP. After 24 h, survival percentage, biochemical and morphological markers of liver injury, and tissue inflammation were assessed. RESULTS: IL-4(-/-) mice were protected from APAP toxicity. Intravital confocal microscopy, tissue histology and serum ALT levels showed significantly less liver injury and inflammation than in the WT group, which may explain the increased survival rate of IL-4(-/-) mice. In addition, IL-4(-/-) mice had decreased production of tumor necrosis factor α, CXCL1 and interleukin-1ß in the liver, but not in a remote site such as the lungs. Hepatic macrophage activation was markedly reduced in IL-4-deficient mice. In addition, glutathione depletion-a primary cause of APAP-mediated injury-was significantly attenuated in IL-4(-/-) mice. CONCLUSIONS: Taken together, our data demonstrate that IL-4(-/-) mice are protected from APAP-induced liver injury due to reduced depletion of glutathione, which prevented liver damage and tissue inflammation.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Glutationa/imunologia , Interleucina-4/imunologia , Acetaminofen , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Quimiocina CXCL1/imunologia , Inflamação/imunologia , Interleucina-4/genética , Fígado/imunologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Concomitant chronic diseases are a common finding in clinics and may consist in a major issue in therapeutics. Here, we investigated whether prolonged ingestion of ovalbumin (Ova) by sensitized mice would reduce the severity of an associated concurrent immunomediated condition such as antigen-induced arthritis (AIA). AIA was induced by administration of methylated bovine albumin (mBSA) into the knee joints of previously immunized mice, and evaluated by articular leukocyte trafficking and levels of cytokines (TNF-α, IL-1ß) and chemokine (CXCL-1) in the periarticular tissue. Continuous Ova feeding by Ova sensitized mice decreased serum levels of anti-Ova IgE, and led to a significant suppression of leukocyte adhesion and infiltration into synovial tissue and cavity. Also, a marked cytokine reduction was observed, suggesting that prolonged ingestion of ovalbumin by sensitized mice suppresses specific IgE production with concomitant reduction in peripheral T cells, which may impact in the pathogenesis of AIA, a non-related condition.
Assuntos
Artrite Experimental/dietoterapia , Artrite Experimental/imunologia , Artrite Reumatoide/dietoterapia , Artrite Reumatoide/imunologia , Ovalbumina/administração & dosagem , Membrana Sinovial/imunologia , Animais , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Quimiocina CXCL1/imunologia , Citometria de Fluxo , Histocitoquímica , Tolerância Imunológica/imunologia , Imunoglobulina E/análise , Imunoglobulina E/imunologia , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The intestinal mucosa is the major site of contact with antigens, and it houses the largest lymphoid tissue in the body. In physiological conditions, microbiota and dietary antigens are the natural sources of stimulation for the gut-associated lymphoid tissues (GALT) and for the immune system as a whole. Germ-free models have provided some insights on the immunological role of gut antigens. However, most of the GALT is not located in the large intestine, where gut microbiota is prominent. It is concentrated in the small intestine where protein absorption takes place. In this review, we will address the involvement of food components in the development and the function of the immune system. Studies in mice have already shown that dietary proteins are critical elements for the developmental shift of the immature neonatal immune profile into a fully developed immune system. The immunological effects of other food components (such as vitamins and lipids) will also be addressed. Most of the cells in the GALT are activated and local pro-inflammatory mediators are abundant. Regulatory elements are known to provide a delicate yet robust balance that maintains gut homeostasis. Usually antigenic contact in the gut induces two major immune responses, oral tolerance and production of secretory IgA. However, under pathological conditions mucosal homeostasis is disturbed resulting in inflammatory reactions such as food hypersensitivity. Food allergy development depends on many factors such as genetic predisposition, biochemical features of allergens, and a growing array of environmental elements. Neuroimmune interactions are also implicated in food allergy and they are examples of the high complexity of the phenomenon. Recent findings on the gut circuits triggered by food components will be reviewed to show that, far beyond their role as nutrients, they are critical players in the operation of the immune system in health and disease.