RESUMO
Microbe-host communication is essential to maintain vital functions of a healthy host, and its disruption has been associated with several diseases, including Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD). Although individual members of the intestinal microbiota have been associated with experimental IBD, identifying microorganisms that affect disease susceptibility and phenotypes in humans remains a considerable challenge. Currently, the lack of a definition between what is healthy and what is a dysbiotic gut microbiome limits research. Nevertheless, although clear proof-of-concept of causality is still lacking, there is an increasingly evident need to understand the microbial basis of IBD at the microbial strain, genomic, epigenomic, and functional levels and in specific clinical contexts. Recent information on the role of diet and novel environmental risk factors affecting the gut microbiome has direct implications for the immune response that impacts the development of IBD. The complexity of IBD pathogenesis, involving multiple distinct elements, suggests the need for an integrative approach, likely utilizing computational modeling of molecular datasets to identify more specific therapeutic targets.
Assuntos
Colite Ulcerativa , Doença de Crohn , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Disbiose , Microbioma Gastrointestinal/fisiologia , Humanos , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/terapiaRESUMO
Phenolic compounds (PCs) present in foods are associated with a decreased risk of developing inflammatory diseases. The aim of this study was to extract and characterize PCs from craft beer powder and evaluate their potential benefits in an experimental model of inflammatory bowel disease (IBD). PCs were extracted and quantified from pure beer samples. BALB/c mice received either the beer phenolic extract (BPE) or beer powder fortified with phenolic extract (BPFPE) of PCs daily for 20 days by gavage. Colon samples were collected for histopathological and immunohistochemical analyses. Dextran sodium sulfate (DSS)-induced mice lost more weight, had reduced colon length, and developed more inflammatory changes compared with DSS-induced mice treated with either BPE or BPFPE. In addition, in DSS-induced mice, the densities of CD4- and CD11b-positive cells, apoptotic rates, and activation of NF-κB and p-ERK1/2 MAPK intracellular signaling pathways were higher in those treated with BPE and BPFPE than in those not treated. Pretreatment with the phenolic extract and BPFPE remarkably attenuated DSS-induced colitis. The protective effect of PCs supports further investigation and development of therapies for human IBD.
Assuntos
Cerveja , Colite , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pós , Dodecilsulfato de Sódio/toxicidadeRESUMO
Dramatic changes in the environment and human lifestyle have been associated with the rise of various chronic complex diseases, such as inflammatory bowel disease (IBD). A dysbiotic gut microbiota has been proposed as a crucial pathogenic element, contributing to immune imbalances and fostering a proinflammatory milieu, which may be associated with disease relapses or even the initiation of IBD. In addition to representing important regulators of the mucosal immunity and the composition of the gut microbiota, food components have been shown to be potential environmental triggers of epigenetic modifications. In the context of chronic intestinal inflammation, dietary habits and specific food components have been implicated as important modulators of epigenetic mechanisms, including DNA methylation, which may predispose a person to the increased risk of the initiation and evolution of IBD. This review provides novel insights about how dietary factors may interact with the intestinal mucosa and modulate immune homeostasis by shaping the intestinal ecosystem, as well as the potential influence of diet in the etiopathogenesis and management of IBD.
Assuntos
Dieta/efeitos adversos , Comportamento Alimentar , Doenças Inflamatórias Intestinais/etiologia , Estilo de Vida , Animais , Dieta Saudável , Disbiose , Epigênese Genética , Microbioma Gastrointestinal , Interação Gene-Ambiente , Interações Hospedeiro-Patógeno , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Intestinos/microbiologia , Prognóstico , Fatores de Proteção , Medição de Risco , Fatores de Risco , Comportamento de Redução do RiscoRESUMO
The purpose of the present study was to investigate the geographical distribution and time trends of the incidence and lethality of esophageal cancer (EC) in Brazil. The present study conducted an ecological study of EC using records from January 2005 to December 2015 in the Health Informatics Department of the Brazilian Ministry of Health (DATASUS) registry. In addition to demographical data on the population, EC incidence and lethality rates were estimated from hospitalizations and in-hospital mortalities and were adjusted by total available hospital beds. The adjusted EC rates per 100,000 increased from 9.1 in 2005 to 12.1 in 2015. The prevalence among males increased from 69 to 78%, while the female rates remained stable over the same period. Although EC was the most common in South and Southeast Brazil, the rates increased proportionately more in the other regions of the country, especially among males. Geographical analysis revealed higher rates of EC in more urbanized areas, with a coast-to-inland gradient. While rates increased in people older than 50 years, they decreased among people below this age. However, the lethality rates remained stable and high during the study period, overlapping with hospital admission rates. The recent increasing trend in the EC incidence, with shifts from the south towards the north and from more urbanized towards rural areas, suggests that environmental factors are crucial in EC pathogenesis. The concentration of EC in South Brazil may reflect the presence of major environmental factors in association with a possible genetic predisposition. The unchanging high mortality associated with EC in the rapidly aging population suggests that EC will continue to impose a significant social and economic burden in the future.
RESUMO
Background and aims: Mice orally infected with T. gondii develop Crohn's disease (CD)-like enteritis associated with severe mucosal damage and a systemic inflammatory response, resulting in high morbidity and mortality. Previously, helminthic infections have shown therapeutic potential in experimental colitis. However, the role of S. mansoni in T. gondii-induced CD-like enteritis has not been elucidated. Our study investigated the mechanisms underlying T. gondii-induced ileitis and the potential therapeutic effect of S. mansoni coinfection. Methods: C57BL/6 mice were infected by subcutaneous injection of cercariae of the BH strain of S. mansoni, and 7-9 weeks later, they were orally infected with cysts of the ME49 strain of T. gondii. After euthanasia, the ileum was removed for histopathological analysis; staining for goblet cells; immunohistochemistry characterizing mononuclear cells, lysozyme expression, apoptotic cells, and intracellular pathway activation; and measuring gene expression levels by real-time PCR. Cytokine concentrations were measured in the serial serum samples and culture supernatants of the ileal explants, in addition to myeloperoxidase (MPO) activity. Results:T. gondii-monoinfected mice presented dense inflammatory cell infiltrates and ulcerations in the terminal ileum, with abundant cell extrusion, apoptotic bodies, and necrosis; these effects were absent in S. mansoni-infected or coinfected animals. Coinfection preserved goblet cells and Paneth cells, remarkably depleted in T. gondii-infected mice. Densities of CD4- and CD11b-positive cells were increased in T. gondii- compared to S. mansoni-infected mice and controls. MPO was significantly increased among T. gondii-mice, while attenuated in coinfected animals. In T. gondii-infected mice, the culture supernatants of the explants showed increased concentrations of TNF-alpha, IFN-gamma, and IL-17, and the ileal tissue revealed increased expression of the mRNA transcripts for IL-1 beta, NOS2, HMOX1, MMP3, and MMP9 and activation of NF-kappa B and p38 MAPK signaling, all of which were counterregulated by S. mansoni coinfection. Conclusion:S. mansoni coinfection attenuates T. gondii-induced ileitis by preserving mucosal integrity and downregulating the local inflammatory response based on the activation of NF-kappa B and MAPK. The protective function of prior S. mansoni infection suggests the involvement of innate immune mechanisms and supports a conceptually new approach to the treatment of chronic inflammatory diseases, including CD.
Assuntos
Coinfecção/imunologia , Ileíte/prevenção & controle , Mucosa Intestinal/fisiopatologia , Esquistossomose mansoni/imunologia , Terapia com Helmintos , Toxoplasmose Animal/terapia , Animais , Apoptose , Doença de Crohn/terapia , Citocinas/sangue , Modelos Animais de Doenças , Regulação para Baixo , Epitélio/fisiologia , Perfilação da Expressão Gênica , Ileíte/etiologia , Ileíte/imunologia , Ileíte/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Peroxidase/sangue , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Toxoplasmose Animal/complicações , Toxoplasmose Animal/imunologiaRESUMO
Despite unquestionable progress in the management of inflammatory bowel disease (IBD) and the much improved clinical results achievable today in Crohn's disease (CD) and ulcerative colitis (UC) patients, the overall therapeutic outcome remains far from optimal. The main reason of this partial success is that all current medications only block individual components of a highly complex disease process that results from the integration of multiple and incompletely identified pathogenic components. Thus, if further progress is to be achieved in IBD therapeutics and we want to move from the current success rate to nearly 100%, bold new ideas must be entertained and new approaches put into practice. Both are necessary because in IBD we are dealing with a prototypical complex disease superimposed to the background of the extreme biological diversity of humans in response to injury. An unresolved challenge mandates the adoption of new solutions specifically designed to address the unique features of that challenge. Translated to a disease condition, and IBD in particular, the unresolved challenges of CD and UC demand bold new thinking leading to the conception and implementation of totally innovative therapies. In this article, we propose that one such new thinking is the notion of network medicine for IBD, and that the development of brand new treatments should be based on the identification of the molecular structure of the IBD interactome with the purpose of targeting its controlling elements (central nodes or hubs). This specific targeting of the underlying molecular disease modules will lead to the disruption of the IBD interactome and foster the resolution of intestinal inflammatory process.
Assuntos
Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/terapia , Biologia de Sistemas/tendências , Colite Ulcerativa/genética , Colite Ulcerativa/terapia , Doença de Crohn/genética , Doença de Crohn/terapia , Epigenômica/tendências , Humanos , Metabolômica/tendênciasRESUMO
Crohn's disease and ulcerative colitis are prototypical complex diseases characterized by chronic and heterogeneous manifestations, induced by interacting environmental, genomic, microbial and immunological factors. These interactions result in an overwhelming complexity that cannot be tackled by studying the totality of each pathological component (an '-ome') in isolation without consideration of the interaction among all relevant -omes that yield an overall 'network effect'. The outcome of this effect is the 'IBD interactome', defined as a disease network in which dysregulation of individual -omes causes intestinal inflammation mediated by dysfunctional molecular modules. To define the IBD interactome, new concepts and tools are needed to implement a systems approach; an unbiased data-driven integration strategy that reveals key players of the system, pinpoints the central drivers of inflammation and enables development of targeted therapies. Powerful bioinformatics tools able to query and integrate multiple -omes are available, enabling the integration of genomic, epigenomic, transcriptomic, proteomic, metabolomic and microbiome information to build a comprehensive molecular map of IBD. This approach will enable identification of IBD molecular subtypes, correlations with clinical phenotypes and elucidation of the central hubs of the IBD interactome that will aid discovery of compounds that can specifically target the hubs that control the disease.
Assuntos
Doenças Inflamatórias Intestinais/etiologia , Descoberta de Drogas/métodos , Epigenômica , Fármacos Gastrointestinais/uso terapêutico , Microbioma Gastrointestinal , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Proteômica , Biologia de Sistemas/métodos , TranscriptomaRESUMO
PURPOSE OF REVIEW: Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), represent chronic diseases of unknown cause, and they are regarded as prototypical complex diseases. Despite all the recent advances, a complete appreciation of the pathogenesis of IBD is still limited. In this review, we present recent information contributing to a better understanding of mechanisms underlying IBD. RECENT FINDINGS: Here, we attempt to highlight novel environmental triggers, data on the gut microbiota, its interaction with the host, and the potential influence of diet and food components. We discuss recent findings on defective signaling pathways and the potential effects on the immune response, and we present new data on epigenetic changes, inflammasome, and damage-associated molecular patterns associated with IBD. SUMMARY: The continuing identification of several epigenetic, transcriptomic, proteomic, and metabolomic alterations in patients with IBD reflects the complex nature of the disease and suggests the need for innovative approaches such as systems biology for identifying novel relevant targets in IBD.
Assuntos
Dieta Ocidental/efeitos adversos , Microbioma Gastrointestinal/imunologia , Imunidade Inata/imunologia , Doenças Inflamatórias Intestinais/fisiopatologia , Epigenômica , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Imunidade Inata/genética , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Metabolômica , Proteômica , Fatores de Risco , Biologia de SistemasRESUMO
P2X7 receptor activation contributes to inflammation development in different pathologies. We previously reported that the P2X7 receptor is over-expressed in the gut mucosa of patients with inflammatory bowel disease, and that P2X7 inhibition protects against chemically induced colitis. Here, we investigated in detail the role of the P2X7 receptor in inflammatory bowel disease development, by treating P2X7 knockout (KO) and WT mice with two different (and established) colitis inductors. P2X7 KO mice were protected against gut inflammation induced by 2,4,6-trinitrobenzenesulfonic acid or oxazolone, with no weight loss or gut histological alterations after treatment. P2X7 receptor knockout induced regulatory T cell accumulation in the colon, as evaluated by qRT-PCR for FoxP3 expression and immunostaining for CD90/CD45RBlow. Flow cytometry analysis of mesenteric lymph node cells showed that P2X7 activation (by ATP) triggered regulatory T cell death. In addition, such cells from P2X7 KO mice expressed more CD103, suggesting increased migration of regulatory T cells to the colon (relative to the WT). Our results show that the P2X7 has a key role during inflammation development in inflammatory bowel disease, by triggering the death and retention in the mesenteric lymph nodes of regulatory T cells that would otherwise promote immune system tolerance in the gut.
Assuntos
Colite/imunologia , Imunidade nas Mucosas , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Receptores Purinérgicos P2X7/imunologia , Linfócitos T/imunologia , Animais , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Feminino , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Oxazolona/efeitos adversos , Oxazolona/farmacologia , Receptores Purinérgicos P2X7/genética , Linfócitos T/patologia , Ácido Trinitrobenzenossulfônico/toxicidadeRESUMO
IBD is a chronic inflammatory condition of the gastrointestinal tract encompassing two main clinical entities: Crohn's disease and ulcerative colitis. Although Crohn's disease and ulcerative colitis have historically been studied together because they share common features (such as symptoms, structural damage and therapy), it is now clear that they represent two distinct pathophysiological entities. Both Crohn's disease and ulcerative colitis are associated with multiple pathogenic factors including environmental changes, an array of susceptibility gene variants, a qualitatively and quantitatively abnormal gut microbiota and a broadly dysregulated immune response. In spite of this realization and the identification of seemingly pertinent environmental, genetic, microbial and immune factors, a full understanding of IBD pathogenesis is still out of reach and, consequently, treatment is far from optimal. An important reason for this unsatisfactory situation is the currently limited comprehension of what are the truly relevant components of IBD immunopathogenesis. This article will comprehensively review current knowledge of the classic immune components and will expand the concept of IBD immunopathogenesis to include various cells, mediators and pathways that have not been traditionally associated with disease mechanisms, but that profoundly affect the overall intestinal inflammatory process.