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1.
J Microbiol ; 59(9): 861-870, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34382146

RESUMO

Salmonella Typhimurium (ST313) has caused an epidemic of invasive disease in sub-Saharan Africa and has been recently identified in Brazil. As the virulence of this ST is poorly understood, the present study aimed to (i) perform the RNA-seq in vitro of S. Typhimurium STm30 (ST313) grown in Luria-Bertani medium at 37°C; (ii) compare it with the RNA-seq of the S. Typhimurium SL1344 (ST19) and S. Typhimurium STm11 (ST19) strains under the same growing conditions; and (iii) examine the colonization capacity and expression of virulence genes and cytokines in murine colon. The STm30 (ST313) strain exhibited stronger virulence and was associated with a more inflammatory profile than the strains SL1344 (ST19) and STm11 (ST19), as demonstrated by transcriptome and in vivo assay. The expression levels of the hilA, sopD2, pipB, and ssaS virulence genes, other Salmonella pathogenicity islands SPI-1 and SPI-2 genes or effectors, and genes of the cytokines IL-1ß, IFN-γ, TNF-α, IL-6, IL-17, IL-22, and IL-12 were increased during ST313 infection in C57BL/6J mice. In conclusion, S. Typhimurium STm30 (ST313) isolated from human feces in Brazil express higher levels of pathogenesis-related genes at 37°C and has stronger colonization and invasion capacity in murine colon due to its high expression levels of virulence genes, when compared with the S. Typhimurium SL1344 (ST19) and STm11 (ST19) strains. STm30 (ST313) also induces stronger expression of pro-inflammatory cytokines in this organ, suggesting that it causes more extensive tissue damage.


Assuntos
Colo/microbiologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Salmonella typhimurium/patogenicidade , Animais , Brasil , Colo/imunologia , Citocinas/genética , Citocinas/imunologia , Fezes/microbiologia , Ilhas Genômicas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Salmonella/genética , Salmonella typhimurium/genética , Salmonella typhimurium/isolamento & purificação , Salmonella typhimurium/fisiologia , Virulência
2.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361102

RESUMO

Interactions between the intestinal microbiota, immune system and nervous system are essential for homeostasis in the gut. Inflammasomes contribute to innate immunity and brain-gut interactions, but their role in microbiota-neuro-immune interactions is not clear. Therefore, we investigated the effect of the inflammasome on visceral pain and local and systemic neuroimmune responses after antibiotic-induced changes to the microbiota. Wild-type (WT) and caspase-1/11 deficient (Casp1 KO) mice were orally treated for 2 weeks with an antibiotic cocktail (Abx, Bacitracin A and Neomycin), followed by quantification of representative fecal commensals (by qPCR), cecal short chain fatty acids (by HPLC), pathways implicated in the gut-neuro-immune axis (by RT-qPCR, immunofluorescence staining, and flow cytometry) in addition to capsaicin-induced visceral pain responses. Abx-treatment in WT-mice resulted in an increase in colonic macrophages, central neuro-immune interactions, colonic inflammasome and nociceptive receptor gene expression and a reduction in capsaicin-induced visceral pain. In contrast, these responses were attenuated in Abx-treated Casp1 KO mice. Collectively, the data indicate an important role for the inflammasome pathway in functional and inflammatory gastrointestinal conditions where pain and alterations in microbiota composition are prominent.


Assuntos
Caspase 1/fisiologia , Microbioma Gastrointestinal , Inflamassomos/imunologia , Inflamação/complicações , Neuroimunomodulação , Dor Visceral/patologia , Animais , Antibacterianos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/microbiologia , Encéfalo/patologia , Capsaicina/toxicidade , Colo/efeitos dos fármacos , Colo/imunologia , Colo/microbiologia , Colo/patologia , Feminino , Inflamassomos/efeitos dos fármacos , Inflamação/imunologia , Inflamação/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Dor Visceral/etiologia , Dor Visceral/metabolismo
3.
Medicine (Baltimore) ; 100(32): e26843, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397890

RESUMO

INTRODUCTION: Secondary amyloidosis is a rare complication of rheumatoid arthritis (RA) that is histologically characterized by the deposition of amyloid fibrils in target organs, such as the kidneys and gastrointestinal tract. Controlling the inflammatory response is essential to prevent organ dysfunction in amyloid A (AA) amyloidosis secondary to RA, and no clear treatment strategy exists. PATIENT CONCERNS AND DIAGNOSIS: A 66-year-old woman with RA, who had been treated with disease-modifying anti-rheumatic drugs for 1 year, presented with recurrent abdominal pain and prolonged diarrhea. Endoscopy showed chronic inflammation, and colon tissue histology confirmed AA amyloidosis. INTERVENTIONS AND OUTCOMES: After tocilizumab therapy was begun, her diarrhea and abdominal pain subsided, and articular symptoms improved. Biologic drugs for RA have been used in patients with secondary AA amyloidosis, including tumor necrosis factor and Janus kinase inhibitors, interleukin 6 blockers, and a T cell modulator. Here, we systematically review existing case reports and compare the outcomes of RA-related AA amyloidosis after treatment with various drugs. CONCLUSION: The data indicate that biologic drugs like tocilizumab might be treatments of choice for AA amyloidosis secondary to RA.


Assuntos
Amiloidose , Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Reumatoide , Terapia Biológica/métodos , Colo , Proteína Amiloide A Sérica/análise , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Idoso , Amiloidose/etiologia , Amiloidose/imunologia , Amiloidose/fisiopatologia , Amiloidose/terapia , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Produtos Biológicos/administração & dosagem , Colo/imunologia , Colo/patologia , Diarreia/diagnóstico , Diarreia/etiologia , Feminino , Humanos , Interleucina-6/antagonistas & inibidores , Resultado do Tratamento
4.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203196

RESUMO

Background: Concerns are emerging that a high-fat diet rich in n-6 PUFA (n-6HFD) may alter gut microbiome and increase the risk of intestinal disorders. Research is needed to model the relationships between consumption of an n-6HFD starting at weaning and development of gut dysbiosis and colonic inflammation in adulthood. We used a C57BL/6J mouse model to compare the effects of exposure to a typical American Western diet (WD) providing 58.4%, 27.8%, and 13.7% energy (%E) from carbohydrates, fat, and protein, respectively, with those of an isocaloric and isoproteic soybean oil-rich n-6HFD providing 50%E and 35.9%E from total fat and carbohydrates, respectively on gut inflammation and microbiome profile. Methods: At weaning, male offspring were assigned to either the WD or n-6HFD through 10-16 weeks of age. The WD included fat exclusively from palm oil whereas the n-6HFD contained fat exclusively from soybean oil. We recorded changes in body weight, cyclooxygenase-2 (COX-2) expression, colon histopathology, and gut microbiome profile. Results: Compared to the WD, the n-6HFD increased plasma levels of n-6 fatty acids; colonic expression of COX-2; and the number of colonic inflammatory and hyperplastic lesions. At 16 weeks of age, the n-6HFD caused a marked reduction in the gut presence of Firmicutes, Clostridia, and Lachnospiraceae, and induced growth of Bacteroidetes and Deferribacteraceae. At the species level, the n-6HFD sustains the gut growth of proinflammatory Mucispirillum schaedleri and Lactobacillus murinus. Conclusions: An n-6HFD consumed from weaning to adulthood induces a shift in gut bacterial profile associated with colonic inflammation.


Assuntos
Colo/imunologia , Colo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Disbiose/etiologia , Disbiose/microbiologia , Microbioma Gastrointestinal/fisiologia , Animais , Western Blotting , Masculino , Camundongos , Camundongos Endogâmicos C57BL
5.
Immunity ; 54(6): 1123-1136.e8, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34107271

RESUMO

Neutrophils migrate rapidly to damaged tissue and play critical roles in host defense and tissue homeostasis. Here we investigated the mechanisms whereby neutrophils participate in tissue repair. In an intestinal epithelia injury model, neutrophil depletion exacerbated colitis and associated with reduced interleukin (IL)-22 and limited activation of type 3 innate lymphoid cells (ILC3s). Co-culture with neutrophils activated ILC3s in a manner dependent on neutrophil apoptosis. Metabolomic analyses revealed that lysophosphatidylserine (LysoPS) from apoptotic neutrophils directly stimulated ILC3 activation. ILC3-specific deletion of Gpr34, encoding the LysoPS receptor GPR34, or inhibition of downstream PI3K-AKT or ERK suppressed IL-22 production in response to apoptotic neutrophils. Gpr34-/- mice exhibited compromised ILC3 activation and tissue repair during colon injury, and neutrophil depletion abrogated these defects. GPR34 deficiency in ILC3s limited IL-22 production and tissue repair in vivo in settings of colon and skin injury. Thus, GPR34 is an ILC3-expressed damage-sensing receptor that triggers tissue repair upon recognition of dying neutrophils.


Assuntos
Apoptose/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Lisofosfolipídeos/imunologia , Neutrófilos/imunologia , Receptores de Lisofosfolipídeos/imunologia , Animais , Células Cultivadas , Colite/imunologia , Colo/imunologia , Homeostase/imunologia , Humanos , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol 3-Quinases/imunologia
6.
Immunity ; 54(5): 1022-1036.e8, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33932356

RESUMO

The sympathetic nervous system is composed of an endocrine arm, regulating blood adrenaline and noradrenaline, and a local arm, a network of fibers innervating immune organs. Here, we investigated the impact of the local arm of the SNS in an inflammatory response in the colon. Intra-rectal insertion of an optogenetic probe in mice engineered to express channelrhodopsin-2 in tyrosine hydroxylase cells activated colonic sympathetic fibers. In contrast to systemic application of noradrenaline, local activation of sympathetic fibers attenuated experimental colitis and reduced immune cell abundance. Gene expression profiling showed decreased endothelial expression of the adhesion molecule MAdCAM-1 upon optogenetic stimulation; this decrease was sensitive to adrenergic blockers and 6-hydroxydopamine. Antibody blockade of MAdCAM-1 abrogated the optogenetic effect on immune cell extravasation into the colon and the pathology. Thus, sympathetic fibers control colonic inflammation by regulating immune cell extravasation from circulation, a mechanism likely relevant in multiple organs.


Assuntos
Colite/imunologia , Colo/imunologia , Colo/inervação , Organogênese/imunologia , Sistema Nervoso Simpático/imunologia , Animais , Molécula 1 de Adesão Intercelular/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Optogenética/métodos
7.
Nat Immunol ; 22(6): 699-710, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34040226

RESUMO

It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes are unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic but not bone marrow-derived macrophages, which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early-life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later-life susceptibility or resistance to iNKT cell-associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota, and they reveal an important postnatal function of macrophages that emerge in fetal life.


Assuntos
Colite/imunologia , Mucosa Intestinal/imunologia , Listeriose/imunologia , Macrófagos/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Animais , Proliferação de Células/genética , Colite/microbiologia , Colite/patologia , Colo/citologia , Colo/embriologia , Colo/imunologia , Colo/patologia , Citocinas/metabolismo , Toxina Diftérica/administração & dosagem , Toxina Diftérica/imunologia , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Vida Livre de Germes , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/embriologia , Mucosa Intestinal/patologia , Listeriose/microbiologia , Listeriose/patologia , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , RNA-Seq , Transdução de Sinais/genética , Transdução de Sinais/imunologia
8.
Food Funct ; 12(9): 3831-3841, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977958

RESUMO

The aim of the present study was to determine the inhibitory effects and the potential underlying mechanisms of a novel Pleurotus eryngii ß-type glycosidic polysaccharide (WPEP) on colitis. To achieve this, sixty CD-1 (ICR) mice were divided into six groups including healthy and colitic mice treated with or without WPEP at two different doses (n = 10). The results showed that WPEP displayed a significant inhibitory effect on colitis as indicated by the lowered disease activity index in the treated colitic mice compared to the untreated colitic mice (2.78 ± 0.50 to 1.80 ± 0.17). A decrease in pro-inflammatory cytokine concentrations and pro-inflammatory protein expressions and an increase in the colon length (9.31 ± 0.59 cm to 10.89 ± 1.20 cm) along with histological improvements were also observed in the treated colitic mice compared to the untreated colitic mice in the present study. Flow cytometry and western blotting analysis revealed that these anti-colitis effects were associated with decreased accumulation of CD45+ immune cells, CD45 + F4/80+ macrophages and CD45 + Gr1+ neutrophils. Moreover, the 16s rRNA sequencing analysis of the gut microbiota revealed that WPEP partially reversed gut microbiota dysbiosis in the colitic mice including the decreased abundance of Akkermansia muciniphila (35.80 ± 9.10% to 18.24 ± 6.23%) and Clostridium cocleatum (2.34 ± 1.78% to 0.011 ± 0.003%) and the increased abundance of Bifidobacterium pseudolongum (3.48 ± 2.72% to 9.65 ± 3.74%), Lactobacillus reuteri (0.007 ± 0.002% to 0.21 ± 0.12%), Lactobacillus salivarius (1.23 ± 0.87% to 2.22 ± 1.53%) and Ruminococcus bromii (0.009 ± 0.001% to 3.83 ± 1.98%). In summary, our results demonstrated that WPEP could be utilized as a functional food component in colitis management as well as a potential prebiotic agent to improve inflammation-related disorders.


Assuntos
Colite/dietoterapia , Colo , Suplementos Nutricionais , Glicosídeos/administração & dosagem , Pleurotus/química , Animais , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colo/imunologia , Colo/metabolismo , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Microbioma Gastrointestinal , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas/metabolismo
9.
Food Funct ; 12(9): 4142-4151, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977961

RESUMO

Irritable bowel syndrome (IBS) is a common chronic functional bowel disease, associated with a high risk of depression and anxiety. The brain-gut axis plays an important role in the pathophysiological changes involved in IBS; however, an effective treatment for the same is lacking. The natural compound costunolide (COS) has been shown to exert gastroprotective, enteroprotective, and neuroprotective effects, but its therapeutic effects in IBS are unclear. Our study explored the effect of COS on intestinal dysfunction and depressive behaviour in stress-induced IBS mice. Mice were subjected to chronic unpredictable mild stress to trigger IBS, and some were administered COS. Behavioural tests, histochemical assays, western blotting, and measurement of 5-hydroxytryptamine (5-HT) levels in the colon and hippocampus were applied to monitor the physiological and molecular consequences of COS treatment in IBS mice. COS administration relieved intestinal dysfunction and depression-like behaviours in IBS mice. Improvements in low-grade colon inflammation and intestinal mucosal permeability, inhibition of the activation of mast cells, upregulation of colonic Occludin expression, and downregulation of Claudin 2 expression were also observed. COS was also found to upregulate GluN2A, BDNF, p-ERK1/2, and p-CREB expression and 5-HT levels in hippocampal cells but inhibited 5-HT metabolism. Molecular docking showed that COS could form hydrogen bonds with the serotonin transporter (SERT) to affect the reuptake of 5-HT in the intercellular space. In conclusion, COS alleviates intestinal dysfunction and depressive behaviour in stress-induced IBS mice by inhibiting mast cell activation in the colon and regulating 5-HT metabolism in the central nervous system.


Assuntos
Transtorno Depressivo/tratamento farmacológico , Intestinos/fisiopatologia , Síndrome do Intestino Irritável/fisiopatologia , Síndrome do Intestino Irritável/psicologia , Mastócitos/imunologia , Serotonina/metabolismo , Sesquiterpenos/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Colo/imunologia , Hipocampo/metabolismo , Mucosa Intestinal/fisiopatologia , Síndrome do Intestino Irritável/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Receptores de N-Metil-D-Aspartato/metabolismo , Sesquiterpenos/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico
10.
Ecotoxicol Environ Saf ; 220: 112340, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34015635

RESUMO

Microplastics are plastic fragments widely distributed in the environment and accumulate in the organisms. However, the research on microplastics effects in mammals is limited. Polyethylene is the main kind of microplastics in the environment. We hypothesized that polyethylene exposure disrupts host intestine metabolism by modifying intestine microflora composition and then lipopolysaccharide (LPS) pathway. Female mice were orally exposed to 0, 0.002 and 0.2 µg/g/d polyethylene microplastics (PE MPs) for 30 days. Colon mucin density was quantized after AB-PAS staining. Mucin 2 (MUC2), inflammatory factors (IL-1ß, IL-6, IL-8 and IL-10), short-chain fatty acid receptors (GPR41 and GPR43), LPS receptors (TLR4 and MyD88) and LPS pathway downstream genes (ERK1 and NF-κB) mRNA levels in colon were measured. Feces were collected on the 15th day of exposure for gut microflora analysis. Blood biochemical analysis was performed. Results showed that 0.2 µg/g/d PE MPs exposure significantly decreased colon mucin expression (p < 0.05), decreased IL-1ß (p < 0.05) and increased IL-8 and IL-10 levels (p < 0.01 and p < 0.001 respectively). Microflora data showed that in 0.2 µg/g/d PE MPs group the number of Firmicutes decreased and the number of Bacteroides increased (both p < 0.01). Predicted KEGG metabolic pathways by piecrust method indicated that PE MPs enhanced amino acids metabolism in microflora. ERK1 and NF-κB mRNA were significantly lower in 0.2 µg/g/d PE MPs group (both p < 0.001). Blood total protein, albumin and globulin levels significantly increased after 0.2 µg/g/d PE MPs exposure (p < 0.01, p < 0.01 and p < 0.05 respectively). These results indicate that PE MPs exposure induced decreased mucin production, a slight immune response and increased the microflora amino acid metabolism in the mice colon by modifying colon microflora composition. SUMMARY: Polyethylene microplastics exposure decreased colon mucin release and increased amino acid metabolism by modifying colon microflora composition.


Assuntos
Bactérias/efeitos dos fármacos , Colo/imunologia , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/imunologia , Microplásticos/efeitos adversos , Mucinas/metabolismo , Polietileno/efeitos adversos , Administração Oral , Animais , Bactérias/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Relação Dose-Resposta a Droga , Feminino , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos ICR
11.
Front Immunol ; 12: 627605, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33927713

RESUMO

Several reports have described a beneficial effect of Mesenchymal Stromal Cells (MSCs) and of their secreted extracellular vesicles (EVs) in mice with experimental colitis. However, the effects of the two treatments have not been thoroughly compared in this model. Here, we compared the effects of MSCs and of MSC-EV administration in mice with colitis induced by dextran sulfate sodium (DSS). Since cytokine conditioning was reported to enhance the immune modulatory activity of MSCs, the cells were kept either under standard culture conditions (naïve, nMSCs) or primed with a cocktail of pro-inflammatory cytokines, including IL1ß, IL6 and TNFα (induced, iMSCs). In our experimental conditions, nMSCs and iMSCs administration resulted in both clinical and histological worsening and was associated with pro-inflammatory polarization of intestinal macrophages. However, mice treated with iEVs showed clinico-pathological improvement, decreased intestinal fibrosis and angiogenesis and a striking increase in intestinal expression of Mucin 5ac, suggesting improved epithelial function. Moreover, treatment with iEVs resulted in the polarization of intestinal macrophages towards and anti-inflammatory phenotype and in an increased Treg/Teff ratio at the level of the intestinal lymph node. Collectively, these data confirm that MSCs can behave either as anti- or as pro-inflammatory agents depending on the host environment. In contrast, EVs showed a beneficial effect, suggesting a more predictable behavior, a safer therapeutic profile and a higher therapeutic efficacy with respect to their cells of origin.


Assuntos
Colite/cirurgia , Colo/metabolismo , Vesículas Extracelulares/transplante , Mucosa Intestinal/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Animais , Linhagem da Célula , Colite/induzido quimicamente , Colite/imunologia , Colite/metabolismo , Colo/imunologia , Colo/patologia , Citocinas/farmacologia , Sulfato de Dextrana , Modelos Animais de Doenças , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/metabolismo , Fibrose , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mucina-5AC/metabolismo , Neovascularização Patológica , Fenótipo , Células RAW 264.7 , Nicho de Células-Tronco
12.
Immunity ; 54(4): 673-686.e4, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33852831

RESUMO

The interleukin (IL)-17 family, consisting of six members, promotes host defense but can in some context promote the development of autoimmune disease. Here, we examined the role of IL-17D, a poorly understood member in the IL-17 family. IL-17D was expressed primarily by colonic epithelial cells. Il17d-/- mice were more susceptible to acute colitis, bacterial infection and experimentally induced colon cancer than their wildtype counterparts. Il17d deficiency impaired IL-22 production by group 3 innate lymphoid cells (ILC3s) and reduced expression of IL-22-dependent antimicrobial peptides, RegIIIß and RegIIIγ, in colon tissue at steady state and in colitis; this was associated with changes in microbial composition and dysbiosis. Protein purification studies revealed that IL-17D bound not canonical IL-17 receptors, but rather CD93, a glycoprotein expressed on mature ILC3s. Mice lacking Cd93 in ILC3s exhibited impaired IL-22 production and aggravated colonic inflammation in experimental colitis. Thus, an IL-17D-CD93 axis regulates ILC3 function to preserve intestinal homeostasis.


Assuntos
Imunidade Inata/imunologia , Interleucina-27/imunologia , Linfócitos/imunologia , Glicoproteínas de Membrana/imunologia , Animais , Linhagem Celular , Colite/imunologia , Colo/imunologia , Células Epiteliais/imunologia , Interleucinas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7
13.
Molecules ; 26(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808793

RESUMO

Inflammasomes are multiprotein complexes formed to regulate the maturation of pro-inflammatory caspases, in response to intracellular or extracellular stimulants. Accumulating studies showed that the inflammasomes are implicated in the pathogenesis of inflammatory bowel disease (IBD), although their activation is not a decisive factor for the development of IBD. Inflammasomes and related cytokines play an important role in the maintenance of gut immune homeostasis, while its overactivation might induce excess immune responses and consequently cause tissue damage in the gut. Emerging studies provide evidence that some genetic abnormalities might induce enhanced NLRP3 inflammasome activation and cause colitis. In these cases, the colonic inflammation can be ameliorated by blocking NLRP3 activation or its downstream cytokine IL-1ß. A number of natural products were shown to play a role in preventing colon inflammation in various experimental colitis models. On the other hand, lack of inflammasome function also causes intestinal abnormalities. Thus, an appropriate regulation of inflammasomes might be a promising therapeutic strategy for IBD intervention. This review aims at summarizing the main findings in these studies and provide an outline for further studies that might contribute to our understanding of the role of inflammasomes in the pathogenesis and therapeutic treatment of IBD.


Assuntos
Colo/imunologia , Inflamassomos/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-1beta/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Colo/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/patologia
14.
Nat Commun ; 12(1): 2281, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863879

RESUMO

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generate Il11 reporter mice. IL-11+ cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11+ cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11+ fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11+ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.


Assuntos
Adenoma/imunologia , Colite/patologia , Neoplasias Colorretais/imunologia , Fibroblastos/imunologia , Interleucina-11/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Adenoma/genética , Adenoma/mortalidade , Adenoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/imunologia , Colo/citologia , Colo/imunologia , Colo/patologia , Colo/cirurgia , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Intervalo Livre de Doença , Feminino , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Genes Reporter , Proteínas de Fluorescência Verde/genética , Humanos , Interleucina-11/genética , Subunidade alfa de Receptor de Interleucina-11/genética , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Organoides , Cultura Primária de Células , Estudos Retrospectivos , Transcriptoma/imunologia , Microambiente Tumoral/imunologia
15.
Food Funct ; 12(8): 3476-3492, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33900330

RESUMO

Bifidobacterium longum (B. longum) species are widely used to prevent and treat ulcerative colitis (UC). In this study, phylogenetic and pan-genomic characterization of 122 B. longum strains was performed on the basis of 936 core genes; among these, four strains from different branches of the phylogenetic tree were selected for an evaluation of anti-inflammatory and immune modulatory activities in a DSS-induced colitis mouse model. Among the tested B. longum strains (B. longum FBJ20M1, B. longum FGDLZ8M1, B. longum FGSZY16M3, and B. longum FJSWXJ2M1), B. longum FGDLZ8M1 was found to most effectively alleviate colitis by reducing the expression of pro-inflammatory cytokines, restoring the colon length, and maintaining the mucosal integrity. The anti-inflammatory mechanisms of B. longum FGDLZ8M1 were related to the inhibition of NF-κB signaling. Genomic analysis indicated that these protective effects of B. longum FGDLZ8M1 may be related to specific genes associated with carbohydrate transport and metabolism and defense mechanisms (e.g., tolerance to bile salts and acids). Correlation analysis indicated that gastrointestinal transit tolerance was the most strongly associated factor. Our findings may contribute to the rapid screening of lactic acid bacterial strains with UC-alleviating effects.


Assuntos
Bifidobacterium longum/fisiologia , Colite Ulcerativa/terapia , Animais , Anti-Inflamatórios , Bifidobacterium longum/classificação , Bifidobacterium longum/genética , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/imunologia , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Microbioma Gastrointestinal , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Filogenia
16.
Genome Med ; 13(1): 64, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879239

RESUMO

BACKGROUND: Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. METHODS: To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-ß) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. RESULTS: We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. CONCLUSIONS: Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.


Assuntos
COVID-19/imunologia , Citocinas/imunologia , Macrófagos/imunologia , SARS-CoV-2 , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/genética , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colo/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Pulmão/imunologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Fenótipo , RNA-Seq
17.
Methods Mol Biol ; 2285: 349-373, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33928564

RESUMO

Inflammatory bowel disease (IBD) is a group of severe chronic inflammatory conditions of the human gastrointestinal tract. Murine models of colitis have been invaluable tools to improve the understanding of IBD development and pathogenesis. While the disease etiology of IBD is complex and multifactorial, CD4+ T helper cells have been shown to strongly contribute to the disease pathogenesis of IBD. Here, we present a detailed protocol of the preclinical model of T-cell transfer colitis, which can easily be utilized in the laboratory to study T helper cell functions in intestinal inflammation.


Assuntos
Transferência Adotiva , Separação Celular , Colite/imunologia , Colo/imunologia , Citometria de Fluxo , Linfócitos T Auxiliares-Indutores/transplante , Animais , Colite/metabolismo , Colite/patologia , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Proteínas de Homeodomínio/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Projetos de Pesquisa , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Fluxo de Trabalho
18.
Clin Transl Gastroenterol ; 12(3): e00320, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33704099

RESUMO

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) is a membrane-bound glycoprotein that acts as a receptor but also exists in a soluble form. It has been recognized as a mediator of inflammation and considered a biomarker in inflammatory bowel disease (IBD). METHODS: We evaluated a prospectively recruited cohort, consisting of 101 patients with IBD, using validated clinical indexes; 22 patients with ulcerative colitis (UC) underwent endoscopic evaluation. Fecal DPP-4 (fDPP-4) levels were analyzed and correlated with clinical scores, Mayo endoscopic score (in UC patients), serum DPP-4, C-reactive protein, and fecal calprotectin. Immunohistochemical staining for DPP-4 in intestinal biopsies was also performed. RESULTS: When compared with remitters, median fDPP-4 levels were higher in patients with ileal Crohn's disease (CD) (7,584 [1,464-7,816] vs 2,104 [630-2,676] ng/mL, P = 0.015) and lower in patients with UC exhibiting clinical activity (1,213 [559-1,682] vs 7,814 [2,555-7,985] ng/mL, P < 0.001). Patients with UC presenting endoscopic activity also had lower levels than remitters (939 [559-1,420] vs 7,544 [4,531-7,940] ng/mL, P = 0.006). Fecal DPP-4 discriminated clinical activity from remission with areas under the curve of 0.76 (95% confidence interval [CI] 0.58-0.94, P = 0.015) and 0.80 (95% CI 0.68-0.93, P < 0.001) in CD and UC, respectively; it allowed to differentiate endoscopic activity in patients with UC, with areas under the curve of 0.84 (95% CI 0.63-1.00, P = 0.009). Immunohistochemical analysis revealed higher DPP-4 apical expression in UC remitters, but no statistically significant differences were revealed between patients with ileal CD. DISCUSSION: Our results suggest that fDPP-4 can be used as a biomarker of IBD activity, particularly in UC. The expression profiles in intestinal tissue might represent a functional compartmentalization of DPP-4 expression.


Assuntos
Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Dipeptidil Peptidase 4/análise , Adulto , Biomarcadores/análise , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Colite Ulcerativa/imunologia , Colo/diagnóstico por imagem , Colo/imunologia , Doença de Crohn/imunologia , Dipeptidil Peptidase 4/metabolismo , Endoscopia Gastrointestinal , Fezes/química , Feminino , Humanos , Íleo/diagnóstico por imagem , Íleo/imunologia , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/imunologia , Complexo Antígeno L1 Leucocitário/análise , Complexo Antígeno L1 Leucocitário/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transdução de Sinais/imunologia , Adulto Jovem
19.
Pharmacol Res ; 167: 105548, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33722710

RESUMO

Acute Respiratory Distress Syndrome (ARDS) is triggered by a variety of agents, including Staphylococcal Enterotoxin B (SEB). Interestingly, a significant proportion of patients with COVID-19, also develop ARDS. In the absence of effective treatments, ARDS results in almost 40% mortality. Previous studies from our laboratory demonstrated that resveratrol (RES), a stilbenoid, with potent anti-inflammatory properties can attenuate SEB-induced ARDS. In the current study, we investigated the role of RES-induced alterations in the gut and lung microbiota in the regulation of ARDS. Our studies revealed that SEB administration induced inflammatory cytokines, ARDS, and 100% mortality in C3H/HeJ mice. Additionally, SEB caused a significant increase in pathogenic Proteobacteria phylum and Propionibacterium acnes species in the lungs. In contrast, RES treatment attenuated SEB-mediated ARDS and mortality in mice, and significantly increased probiotic Actinobacteria phylum, Tenericutes phylum, and Lactobacillus reuteri species in both the colon and lungs. Colonic Microbiota Transplantation (CMT) from SEB-injected mice that were treated with RES as well as the transfer of L. reuteri into recipient mice inhibited the production of SEB-mediated induction of pro-inflammatory cytokines such as IFN-γ and IL-17 but increased that of anti-inflammatory IL-10. Additionally, such CMT and L. reuteri recipient mice exposed to SEB, showed a decrease in lung-infiltrating mononuclear cells, cytotoxic CD8+ T cells, NKT cells, Th1 cells, and Th17 cells, but an increase in the population of regulatory T cells (Tregs) and Th3 cells, and increase in the survival of mice from SEB-mediated ARDS. Together, the current study demonstrates that ARDS induced by SEB triggers dysbiosis in the lungs and gut and that attenuation of ARDS by RES may be mediated, at least in part, by alterations in microbiota in the lungs and the gut, especially through the induction of beneficial bacteria such as L. reuteri.


Assuntos
Anti-Inflamatórios/farmacologia , Colo/efeitos dos fármacos , Enterotoxinas , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Síndrome do Desconforto Respiratório/prevenção & controle , Resveratrol/farmacologia , Superantígenos , Animais , Linhagem Celular , Colo/imunologia , Colo/metabolismo , Colo/microbiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Disbiose , Feminino , Mediadores da Inflamação/metabolismo , Lactobacillus reuteri/efeitos dos fármacos , Lactobacillus reuteri/crescimento & desenvolvimento , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Camundongos Endogâmicos C3H , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/microbiologia
20.
Medicine (Baltimore) ; 100(10): e24925, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33725853

RESUMO

ABSTRACT: Ileocolonoscopy is currently recognized as the gold standard for evaluating mucosal healing in patients with Crohn disease (CD). However, the ideal noninvasive marker to assess mucosal healing instead of invasive ileocolonoscopy is not available. This study aimed to determine the correlations between the mucosal healing and serological optimizing markers in CD.This retrospective study consecutively included 62 CD patients with 137 hospitalizations between March 2014 and March 2020. On the basis of the Simple Endoscopic Score for Crohn's disease (SES-CD), the CD patients were divided into mucosal healing group (SES-CD ≤ 2) and nonmucosal healing group (SES-CD > 2). We collected the results of ileocolonoscopy examination and inflammatory markers and then serological optimizing markers, including C-reactive protein/albumin ratio (CRP/ALB), platelet/albumin ratio (PLT/ALB), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) were calculated. The control group consisted of 50 healthy volunteers in the corresponding period.We found that CRP/ALB, PLT/ALB, NLR, and PLR were correlated with the mucosal healing of CD, and the correlation of CRP/ALB with the mucosal healing was the highest (r = -0.64). Receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) of CRP/ALB (0.87) was higher than NLR (0.69), PLR (0.72), and PLT/ALB (0.81). In the efficacy of assessing the mucosal healing in CD, the sensitivity of CRP/ALB, NLR, PLR, and PLT/ALB were 91.1%, 83.9%, 73.2%, and 73.2%, respectively, and the specificity was 76.5%, 46.9%, 64.2%, and 75.3%, respectively.CRP/ALB was the most appropriate marker to assess CD mucosal healing among the serological optimizing markers.


Assuntos
Proteína C-Reativa/análise , Doença de Crohn/diagnóstico , Mucosa Intestinal/imunologia , Albumina Sérica Humana/análise , Adulto , Biomarcadores/sangue , Proteína C-Reativa/imunologia , Colo/diagnóstico por imagem , Colo/imunologia , Colonoscopia , Doença de Crohn/sangue , Doença de Crohn/imunologia , Feminino , Humanos , Íleo/diagnóstico por imagem , Íleo/imunologia , Mucosa Intestinal/diagnóstico por imagem , Masculino , Estudos Retrospectivos , Albumina Sérica Humana/imunologia , Índice de Gravidade de Doença , Adulto Jovem
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