Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
J Immunol ; 207(7): 1719-1724, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34544814

RESUMO

Metabolic diseases are common worldwide and include diseases of overnutrition, such as obesity, or undernutrition, such as kwashiorkor. Both the immune system and the microbiota contribute to a variety of metabolic diseases; however, these two processes have largely been studied independently of one another in this context. The gastrointestinal system houses the greatest density of microbes but also houses one of the largest collections of immune molecules, especially Abs. The IgA isotype dominates the Ab landscape at mucosal sites, and a number of studies have demonstrated the importance of this Ab to the stability of the microbiota. In this article, we review the literature that demonstrates how homeostatic Ab responses control microbiota composition and function to influence metabolic disease. We propose that many metabolic diseases may arise from disruptions to homeostatic immune control of gut commensals and that further understanding this interaction can offer a novel opportunity for therapeutic interventions.


Assuntos
Disbiose/imunologia , Imunoglobulina A/metabolismo , Doenças Metabólicas/imunologia , Microbiota/imunologia , Mucosa/imunologia , Animais , Disbiose/microbiologia , Interações entre Hospedeiro e Microrganismos , Humanos , Imunidade nas Mucosas , Imunomodulação , Doenças Metabólicas/microbiologia , Mucosa/microbiologia
2.
J Neuroinflammation ; 17(1): 291, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023618

RESUMO

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects 2.5 million people worldwide. Growing evidence suggests that perturbation of the gut microbiota, the dense collection of microorganisms that colonize the gastrointestinal tract, plays a functional role in MS. Indeed, specific gut-resident bacteria are altered in patients with MS compared to healthy individuals, and colonization of gnotobiotic mice with MS-associated microbiota exacerbates preclinical models of MS. However, defining the molecular mechanisms by which gut commensals can remotely affect the neuroinflammatory process remains a critical gap in the field. METHODS: We utilized monophasic experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice and relapse-remitting EAE in SJL/J mice to test the effects of the products from a human gut-derived commensal strain of Lactobacillus paracasei (Lb). RESULTS: We report that Lb can ameliorate preclinical murine models of MS with both prophylactic and therapeutic administrations. Lb ameliorates disease through a Toll-like receptor 2-dependent mechanism via its microbe-associated molecular patterns that can be detected in the systemic circulation, are sufficient to downregulate chemokine production, and can reduce immune cell infiltration into the central nervous system (CNS). In addition, alterations in the gut microbiota mediated by Lb-associated molecular patterns are sufficient to provide partial protection against neuroinflammatory diseases. CONCLUSIONS: Local Lb modulation of the gut microbiota and the shedding of Lb-associated molecular patterns into the circulation may be important physiological signals to prevent aberrant peripheral immune cell infiltration into the CNS and have relevance to the development of new therapeutic strategies for MS.


Assuntos
Sistema Nervoso Central/imunologia , Microbioma Gastrointestinal/imunologia , Lacticaseibacillus paracasei/imunologia , Leucócitos/imunologia , Animais , Sistema Nervoso Central/patologia , Feminino , Humanos , Leucócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
3.
Plant Physiol ; 178(3): 1154-1169, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30206104

RESUMO

Plant intracellular Ras-group leucine-rich repeat (LRR) proteins (PIRLs) are related to Ras-interacting animal LRR proteins that participate in developmental cell signaling. Systematic knockout analysis has implicated some members of the Arabidopsis (Arabidopsis thaliana) PIRL family in pollen development. However, for PIRL6, no bona fide knockout alleles have been recovered, suggesting that it may have an essential function in both male and female gametophytes. To test this hypothesis, we investigated PIRL6 expression and induced knockdown by RNA interference. Knockdown triggered defects in gametogenesis, resulting in abnormal pollen and early developmental arrest in the embryo sac. Consistent with this, PIRL6 was expressed in gametophytes: functional transcripts were detected in wild-type flowers but not in sporocyteless (spl) mutant flowers, which do not produce gametophytes. A genomic PIRL6-GFP fusion construct confirmed expression in both pollen and the embryo sac. Interestingly, PIRL6 is part of a convergent overlapping gene pair, a scenario associated with an increased likelihood of alternative splicing. We detected multiple alternative PIRL6 mRNAs in vegetative organs and spl mutant flowers, tissues that lacked the functionally spliced transcript. cDNA sequencing revealed that all contained intron sequences and premature termination codons. These alternative mRNAs accumulated in the nonsense-mediated decay mutant upf3, indicating that they are normally subjected to degradation. Together, these results demonstrate that PIRL6 is required in both male and female gametogenesis and suggest that sporophytic expression is negatively regulated by unproductive alternative splicing. This posttranscriptional mechanism may function to minimize PIRL6 protein expression in sporophyte tissues while allowing the overlapping adjacent gene to remain widely transcribed.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Processamento Alternativo/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Gametogênese Vegetal/genética , Óvulo Vegetal/genética , Pólen/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Arabidopsis/fisiologia , Arabidopsis/ultraestrutura , Proteínas de Arabidopsis/genética , Códon sem Sentido/genética , DNA Complementar/genética , Técnicas de Inativação de Genes , Genes Reporter , Proteínas de Repetições Ricas em Leucina , Mutação , Especificidade de Órgãos , Óvulo Vegetal/fisiologia , Óvulo Vegetal/ultraestrutura , Plantas Geneticamente Modificadas , Pólen/fisiologia , Pólen/ultraestrutura , Proteínas , RNA Mensageiro/genética
4.
Hum Mol Genet ; 25(R1): R2-8, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26443596

RESUMO

Achondroplasia (ACH) is the prototype and most common of the human chondrodysplasias. It results from gain-of-function mutations that exaggerate the signal output of the fibroblast growth factor receptor 3 (FGFR3), a receptor tyrosine kinase that negatively regulates growth plate activity and linear bone growth. Several approaches to reduce FGFR3 signaling by blocking receptor activation or inhibiting downstream signals have been proposed. Five show promise in preclinical mouse studies. Two candidate therapies target the extracellular domain of FGFR3. The first is a decoy receptor that competes for activating ligands. The second is a synthetic blocking peptide that prevents ligands from binding and activating FGFR3. Two established drugs, statins and meclozine, improve growth of ACH mice. The strongest candidate therapy employs an analog of C-type natriuretic peptide (CNP), which antagonizes the mitogen-activated-protein (MAP) kinase pathway downstream of the FGFR3 receptor and may also act independently in the growth plate. Only the CNP analog has reached clinical trials. Preliminary results of Phase 2 studies show a substantial increase in growth rate of ACH children after six months of therapy with no serious adverse effects. A challenge for drug therapy in ACH is targeting agents to the avascular growth plate. The application of gene therapy in osteoarthritis offers insights because it faces similar technical obstacles. Major advances in gene therapy include the emergence of recombinant adeno-associated virus as the vector of choice, capsid engineering to target vectors to specific tissues, and development of methods to direct vectors to articular chondrocytes.


Assuntos
Acondroplasia/terapia , Osteoartrite/terapia , Animais , Terapia Genética , Humanos , Camundongos
5.
Microbiol Resour Announc ; 13(8): e0038524, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-38967489

RESUMO

Turicibacter is a common mammalian gut commensal; however, very few genomes have been sequenced, and little is understood regarding its importance for host health. Here, we add a complete Turicibacter sp. genome isolated from a spore-forming community in mice.

6.
Microbiol Resour Announc ; 13(7): e0035124, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-38899922

RESUMO

Clostridia are common mammalian gut commensals with emerging roles in human health. Here, we describe 10 Clostridia genomes from a consortium of spore forming bacteria, shown to protect mice from metabolic syndrome. These genomes will provide valuable insight on the beneficial role of spore forming bacteria in the gut.

7.
Nutrients ; 16(12)2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38931165

RESUMO

Iron deficiency is the number one nutritional problem worldwide. Iron uptake is regulated at the intestine and is highly influenced by the gut microbiome. Blood from the intestines drains directly into the liver, informing iron status and gut microbiota status. Changes in either iron or the microbiome are tightly correlated with the development of metabolic dysfunction-associated steatotic liver disease (MASLD). To investigate the underlying mechanisms of the development of MASLD that connect altered iron metabolism and gut microbiota, we compared specific pathogen free (SPF) or germ-free (GF) mice, fed a normal or low-iron diet. SPF mice on a low-iron diet showed reduced serum triglycerides and MASLD. In contrast, GF low-iron diet-fed mice showed increased serum triglycerides and did not develop hepatic steatosis. SPF mice showed significant changes in liver lipid metabolism and increased insulin resistance that was dependent upon the presence of the gut microbiota. We report that total body loss of mitochondrial iron importer Mitoferrin2 (Mfrn2-/-) exacerbated the development of MASLD on a low-iron diet with significant lipid metabolism alterations. Our study demonstrates a clear contribution of the gut microbiome, dietary iron, and Mfrn2 in the development of MASLD and metabolic syndrome.


Assuntos
Microbioma Gastrointestinal , Fígado , Animais , Feminino , Masculino , Camundongos , Fígado Gorduroso/etiologia , Resistência à Insulina , Ferro/metabolismo , Deficiências de Ferro , Ferro da Dieta/administração & dosagem , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Triglicerídeos/sangue
8.
Nat Commun ; 15(1): 2769, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38553486

RESUMO

Multiple neurological disorders are associated with gastrointestinal (GI) symptoms, including autism spectrum disorder (ASD). However, it is unclear whether GI distress itself can modify aspects of behavior. Here, we show that mice that experience repeated colitis have impaired active social engagement, as measured by interactions with a foreign mouse, even though signs of colitis were no longer present. We then tested the hypothesis that individuals with ASD harbor a microbiota that might differentially influence GI health by performing microbiota transplantation studies into male germfree animals, followed by induction of colitis. Animals that harbor a microbiota from ASD individuals have worsened gut phenotypes when compared to animals colonized with microbiotas from familial neurotypical (NT) controls. We identify the enrichment of Blautia species in all familial NT controls and observe an association between elevated abundance of Bacteroides uniformis and reductions in intestinal injury. Oral treatment with either of these microbes reduces colon injury in mice. Finally, provision of a Blautia isolate from a NT control ameliorates gut injury-associated active social engagement in mice. Collectively, our data demonstrate that past intestinal distress is associated with changes in active social behavior in mice that can be ameliorated by supplementation of members of the human microbiota.


Assuntos
Transtorno do Espectro Autista , Colite , Gastroenteropatias , Microbiota , Humanos , Masculino , Camundongos , Animais , Transtorno do Espectro Autista/terapia , Participação Social , Colite/terapia , Suplementos Nutricionais
9.
bioRxiv ; 2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36993296

RESUMO

Regulation of the microbiota is critical to intestinal health yet the mechanisms employed by innate immunity remain unclear. Here we show that mice deficient in the C-Type-lectin receptor, Clec12a developed severe colitis, which was dependent on the microbiota. Fecal-microbiota-transplantation (FMT) studies into germfree mice revealed a colitogenic microbiota formed within Clec12a -/- mice that was marked by expansion of the gram-positive organism, Faecalibaculum rodentium . Treatment with F. rodentium was sufficient to worsen colitis in wild-type mice. Macrophages within the gut express the highest levels of Clec12a. Cytokine and sequencing analysis in Clec12a -/- macrophages revealed heighten inflammation but marked reduction in genes associated with phagocytosis. Indeed, Clec12a -/- macrophages are impaired in their ability to uptake F. rodentium. Purified Clec12a had higher binding to gram-positive organisms such as F. rodentium . Thus, our data identifies Clec12a as an innate immune surveillance mechanism to control expansion of potentially harmful commensals without overt inflammation.

10.
JCI Insight ; 7(19)2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-36214220

RESUMO

Intercellular communication is critical for homeostasis in mammalian systems, including the gastrointestinal (GI) tract. Exosomes are nanoscale lipid extracellular vesicles that mediate communication between many cell types. Notably, the roles of immune cell exosomes in regulating GI homeostasis and inflammation are largely uncharacterized. By generating mouse strains deficient in cell-specific exosome production, we demonstrate deletion of the small GTPase Rab27A in CD11c+ cells exacerbated murine colitis, which was reversible through administration of DC-derived exosomes. Profiling RNAs within colon exosomes revealed a distinct subset of miRNAs carried by colon- and DC-derived exosomes. Among antiinflammatory exosomal miRNAs, miR-146a was transferred from gut immune cells to myeloid and T cells through a Rab27-dependent mechanism, targeting Traf6, IRAK-1, and NLRP3 in macrophages. Further, we have identified a potentially novel mode of exosome-mediated DC and macrophage crosstalk that is capable of skewing gut macrophages toward an antiinflammatory phenotype. Assessing clinical samples, RAB27A, select miRNAs, and RNA-binding proteins that load exosomal miRNAs were dysregulated in ulcerative colitis patient samples, consistent with our preclinical mouse model findings. Together, our work reveals an exosome-mediated regulatory mechanism underlying gut inflammation and paves the way for potential use of miRNA-containing exosomes as a novel therapeutic for inflammatory bowel disease.


Assuntos
Antígenos CD11 , Colite , Exossomos , Inflamação , Células Mieloides , Animais , Antígenos CD11/genética , Antígenos CD11/imunologia , Colite/genética , Colite/imunologia , Exossomos/genética , Exossomos/imunologia , Inflamação/genética , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Intestinos/imunologia , Lipídeos , Mamíferos/genética , Mamíferos/imunologia , Camundongos , MicroRNAs/imunologia , Proteínas Monoméricas de Ligação ao GTP/imunologia , Células Mieloides/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fator 6 Associado a Receptor de TNF/imunologia
11.
Curr Biol ; 30(20): R1271-R1272, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33080200

RESUMO

In a recent issue of Cell, Winkler et al. provide a comprehensive analysis of how secondary bile acids produced by unique members of the microbiota regulate plasmacytoid dendritic cells and monocytes via TLR7 and MyD88 signaling to protect from alphavirus dissemination.


Assuntos
Infecções por Alphavirus , Microbioma Gastrointestinal , Microbiota , Bile/metabolismo , Ácidos e Sais Biliares , Células Dendríticas/metabolismo , Humanos , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 7 Toll-Like/metabolismo
12.
Science ; 365(6451)2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31346040

RESUMO

The microbiota influences obesity, yet organisms that protect from disease remain unknown. During studies interrogating host-microbiota interactions, we observed the development of age-associated metabolic syndrome (MetS). Expansion of Desulfovibrio and loss of Clostridia were key features associated with obesity in this model and are present in humans with MetS. T cell-dependent events were required to prevent disease, and replacement of Clostridia rescued obesity. Inappropriate immunoglobulin A targeting of Clostridia and increased Desulfovibrio antagonized the colonization of beneficial Clostridia. Transcriptional and metabolic analysis revealed enhanced lipid absorption in the obese host. Colonization of germ-free mice with Clostridia, but not Desulfovibrio, down-regulated genes that control lipid absorption and reduced adiposity. Thus, immune control of the microbiota maintains beneficial microbial populations that constrain lipid metabolism to prevent MetS.


Assuntos
Clostridium/imunologia , Desulfovibrio/imunologia , Microbiota/imunologia , Obesidade/imunologia , Obesidade/microbiologia , Linfócitos T Reguladores/imunologia , Animais , Antibiose , Interações entre Hospedeiro e Microrganismos , Absorção Intestinal , Metabolismo dos Lipídeos , Síndrome Metabólica/imunologia , Síndrome Metabólica/microbiologia , Camundongos , Camundongos Mutantes , Fator 88 de Diferenciação Mieloide/genética
13.
Plants (Basel) ; 2(3): 507-20, 2013 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-27137390

RESUMO

Arabidopsis thaliana has proven a powerful system for developmental genetics, but identification of gametophytic genes with developmental mutants can be complicated by factors such as gametophyte-lethality, functional redundancy, or poor penetrance. These issues are exemplified by the Plant Intracellular Ras-group LRR (PIRL) genes, a family of nine genes encoding a class of leucine-rich repeat proteins structurally related to animal and fungal LRR proteins involved in developmental signaling. Previous analysis of T-DNA insertion mutants showed that two of these genes, PIRL1 and PIRL9, have an essential function in pollen formation but are functionally redundant. Here, we present evidence implicating three more PIRLs in gametophyte development. Scanning electron microscopy revealed that disruption of either PIRL2 or PIRL3 results in a low frequency of pollen morphological abnormalities. In addition, molecular analysis of putative pirl6 insertion mutants indicated that knockout alleles of this gene are not represented in current Arabidopsis mutant populations, suggesting gametophyte lethality may hinder mutant recovery. Consistent with this, available microarray and RNA-seq data have documented strongest PIRL6 expression in developing pollen. Taken together, these results now implicate five PIRLs in gametophyte development. Systematic reverse genetic analysis of this novel LRR family has therefore identified gametophytically active genes that otherwise would likely be missed by forward genetic screens.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA