RESUMEN
Recent advances in next-generation sequencing (NGS) technologies have opened the door to a wellspring of information regarding the composition of the gut microbiota. Leveraging NGS technology, early metagenomic studies revealed that several diseases, such as Alzheimer's disease, Parkinson's disease, autism, and myalgic encephalomyelitis, are characterized by alterations in the diversity of gut-associated microbes. More recently, interest has shifted toward understanding how these microbes impact their host, with a special emphasis on their interactions with the brain. Such interactions typically occur either systemically, through the production of small molecules in the gut that are released into circulation, or through signaling via the vagus nerves which directly connect the enteric nervous system to the central nervous system. Collectively, this system of communication is now commonly referred to as the gut-microbiota-brain axis. While equally important, little attention has focused on the causes of the alterations in the composition of gut microbiota. Although several factors can contribute, mucosal immunity plays a significant role in shaping the microbiota in both healthy individuals and in association with several diseases. The purpose of this review is to provide a brief overview of the components of mucosal immunity that impact the gut microbiota and then discuss how altered immunological conditions may shape the gut microbiota and consequently affect neuroimmune diseases, using a select group of common neuroimmune diseases as examples.
Asunto(s)
Sistema Nervioso Entérico , Microbioma Gastrointestinal , Enfermedad de Parkinson , Humanos , Inmunidad Mucosa , Microbioma Gastrointestinal/fisiología , Sistema Nervioso Entérico/fisiología , Encéfalo/fisiologíaRESUMEN
BACKGROUND/OBJECTIVES: Obesity is an important risk factor for the development of diseases such as diabetes mellitus, hypertension, and dyslipidemia; however, a small number of individuals with long-standing obesity do not present with these cardiometabolic diseases. Such individuals are referred to as metabolically healthy obese (MHO) and potentially represent a subgroup of the general population with a protective genetic predisposition to obesity-related diseases. We hypothesized that individuals who were metabolically healthy, but significantly obese (BMI ≥ 35 kg/m2) would represent a highly homogenous subgroup, with which to investigate potential genetic associations to obesity. We further hypothesized that such a cohort may lend itself well to investigate potential genotypes that are protective with respect to the development of cardiometabolic disease. SUBJECTS/METHODS: In the present study, we implemented this novel selection strategy by screening 892 individuals diagnosed as Class 2 or Class 3 obese and identified 38 who presented no manifestations of cardiometabolic disease. We then assessed these subjects for single-nucleotide polymorphisms (SNPs) that associated with this phenotype. RESULTS: Our analysis identified 89 SNPs that reach statistical significance (p < 1 × 10-5), some of which are associated with genes of biological pathways that influences dietary behavior; others are associated with genes previously linked to obesity and cardiometabolic disease as well as neuroimmune disease. This study, to the best of our knowledge, represents the first genetic screening of a cardiometabolically healthy, but significantly obese population.
Asunto(s)
Enfermedades Cardiovasculares , Síndrome Metabólico , Obesidad , Polimorfismo de Nucleótido Simple/genética , Adulto , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Síndrome Metabólico/complicaciones , Síndrome Metabólico/epidemiología , Síndrome Metabólico/genética , Obesidad/complicaciones , Obesidad/epidemiología , Obesidad/genéticaRESUMEN
BACKGROUND: Myalgic encephalomyelitis (ME) is a complex and debilitating disease that often initially presents with flu-like symptoms, accompanied by incapacitating fatigue. Currently, there are no objective biomarkers or laboratory tests that can be used to unequivocally diagnosis ME; therefore, a diagnosis is made when a patient meets series of a costly and subjective inclusion and exclusion criteria. The purpose of the present study was to evaluate the utility of four clinical parameters in diagnosing ME. METHODS: In the present study, we utilized logistic regression and classification and regression tree analysis to conduct a retrospective investigation of four clinical laboratory in 140 ME cases and 140 healthy controls. RESULTS: Correlations between the covariates ranged between [- 0.26, 0.61]. The best model included the serum levels of the soluble form of CD14 (sCD14), serum levels of prostaglandin E2 (PGE2), and serum levels of interleukin 8, with coefficients 0.002, 0.249, and 0.005, respectively, and p-values of 3 × 10-7, 1 × 10-5, and 3 × 10-3, respectively. CONCLUSIONS: Our findings show that these parameters may help physicians in their diagnosis of ME and may additionally shed light on the pathophysiology of this disease.
Asunto(s)
Técnicas de Laboratorio Clínico/métodos , Síndrome de Fatiga Crónica/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Adulto JovenRESUMEN
The gut-brain axis refers to the bidirectional communication between the enteric nervous system and the central nervous system. Mounting evidence supports the premise that the intestinal microbiota plays a pivotal role in its function and has led to the more common and perhaps more accurate term gut-microbiota-brain axis. Numerous studies have identified associations between an altered microbiome and neuroimmune and neuroinflammatory diseases. In most cases, it is unknown if these associations are cause or effect; notwithstanding, maintaining or restoring homeostasis of the microbiota may represent future opportunities when treating or preventing these diseases. In recent years, several studies have identified the diet as a primary contributing factor in shaping the composition of the gut microbiota and, in turn, the mucosal and systemic immune systems. In this review, we will discuss the potential opportunities and challenges with respect to modifying and shaping the microbiota through diet and nutrition in order to treat or prevent neuroimmune and neuroinflammatory disease.
Asunto(s)
Encéfalo/fisiología , Microbioma Gastrointestinal/fisiología , Inflamación/prevención & control , Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/terapia , Animales , Encéfalo/patología , Dieta , Sistema Nervioso Entérico/fisiología , Síndrome de Fatiga Crónica/terapia , Humanos , Inmunidad Mucosa/fisiología , Inflamación/patología , Inflamación/terapia , Factores de Crecimiento Nervioso/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Polifenoles/farmacología , Prebióticos , Probióticos/farmacología , Esquizofrenia/terapia , Vitaminas/farmacologíaRESUMEN
Myalgic encephalomyelitis (ME) is a complex, heterogeneous illness of unknown etiology. The search for biomarkers that can delineate cases from controls is one of the most active areas of ME research; however, little progress has been made in achieving this goal. In contrast to identifying biomarkers that are directly involved in the pathological process, an immunosignature identifies antibodies raised to proteins expressed during, and potentially involved in, the pathological process. Although these proteins might be unknown, it is possible to detect antibodies that react to these proteins using random peptide arrays. In the present study, we probe a custom 125,000 random 12-mer peptide microarray with sera from 21 ME cases and 21 controls from the USA and Europe and used these data to develop a diagnostic signature. We further used these peptide sequences to potentially uncover the naturally occurring candidate antigens to which these antibodies may specifically react with in vivo. Our analysis revealed a subset of 25 peptides that distinguished cases and controls with high specificity and sensitivity. Additionally, Basic Local Alignment Search Tool (BLAST) searches suggest that these peptides primarily represent human self-antigens and endogenous retroviral sequences and, to a minor extent, viral and bacterial pathogens.
Asunto(s)
Síndrome de Fatiga Crónica/inmunología , Inmunidad Humoral , Péptidos/metabolismo , Análisis por Matrices de Proteínas , Algoritmos , Secuencia de Aminoácidos , Estudios de Casos y Controles , Humanos , Péptidos/química , Sensibilidad y Especificidad , Alineación de SecuenciaRESUMEN
The marked depletion of dendritic cells (DCs) in skin cancers, as well as preneoplastic and neoplastic cervical epithelium, suggests a central role for DCs in productive human papillomavirus (HPV) infection and cancer promotion. It has been suggested that HPV may facilitate tumor development by reducing DC density, contributing to a decrease in local immune surveillance. In this study, we have examined the response of human DCs transfected with a construct containing the HPV18 genome and their subsequent expression of papilloma virus proteins. Transfected cells expressed the L1 major capsid protein and upregulated E6 and E7 oncoprotein transcripts as detected by RT-PCR. Transfection of DCs also resulted in a significant increase in cytokine production. Finally, we observed that HPV18 transfection decreased the migratory activity of DCs. Our data indicate that HPV transfection of DCs leads to changes in migratory activity and cytokine production, which potentially can suppress or delay immune responses to viral antigens. Additionally, changes in cytokine production by HPV-transformed human fibroblasts and human cervical epithelial cells revealed that the migratory and antigen-presenting functions of DCs may be impaired by the suppressive effects of cytokines produced by HPV-infected epithelial and stromal cells.
Asunto(s)
Transformación Celular Viral , Cuello del Útero/inmunología , Citocinas/metabolismo , Células Dendríticas/inmunología , Fibroblastos/inmunología , Prepucio/inmunología , Infecciones por Papillomavirus/inmunología , Apoptosis , Northern Blotting , Southern Blotting , Western Blotting , Proliferación Celular , Células Cultivadas , Cuello del Útero/patología , Cuello del Útero/virología , Células Dendríticas/patología , Células Dendríticas/virología , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibroblastos/patología , Fibroblastos/virología , Prepucio/patología , Prepucio/virología , Papillomavirus Humano 18/fisiología , Humanos , Inmunoprecipitación , Masculino , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
Myalgic encephalomyelitis (ME) is a debilitating illness of unknown etiology characterized by neurocognitive dysfunction, inflammation, immune abnormalities and gastrointestinal distress. An increasing body of evidence suggests that disruptions in the gut may contribute to the induction of neuroinflammation. Therefore, reports of human endogenous retroviral (HERV) expression in association with neuroinflammatory diseases prompted us to investigate the gut of individuals with ME for the presence of HERV proteins. In eight out of 12 individuals with ME, immunoreactivity to HERV proteins was observed in duodenal biopsies. In contrast, no immunoreactivity was detected in any of the eight controls. Immunoreactivity to HERV Gag and Env proteins was uniquely co-localized in hematopoietic cells expressing the C-type lectin receptor CLEC4C (CD303/BDCA2), the co-stimulatory marker CD86 and the class II major histocompatibility complex HLA-DR, consistent with plasmacytoid dendritic cells (pDCs). Although the significance of HERVs present in the pDCs of individuals with ME has yet to be determined, these data raise the possibility of an involvment of pDCs and HERVs in ME pathology. To our knowledge, this report describes the first direct association between pDCs and HERVs in human disease.
Asunto(s)
Anticuerpos Antivirales/sangre , Células Dendríticas/inmunología , Duodeno/inmunología , Síndrome de Fatiga Crónica/inmunología , Células Plasmáticas/inmunología , Proteínas de los Retroviridae/inmunología , Anticuerpos Antivirales/inmunología , Células Dendríticas/patología , Duodeno/patología , Síndrome de Fatiga Crónica/patología , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Células Plasmáticas/patologíaRESUMEN
Patients with chronic fatigue syndrome (CFS) are affected by symptoms of cognitive dysfunction and neurological impairment, the cause of which has yet to be elucidated. However, these symptoms are strikingly similar to those of patients presented with D-lactic acidosis. A significant increase of Gram positive facultative anaerobic faecal microorganisms in 108 CFS patients as compared to 177 control subjects (p<0.01) is presented in this report. The viable count of D-lactic acid producing Enterococcus and Streptococcus spp. in the faecal samples from the CFS group (3.5 x 10(7) cfu/L and 9.8 x 10(7) cfu/L respectively) were significantly higher than those for the control group (5.0 x 10(6) cfu/L and 8.9 x 10(4) cfu/L respectively). Analysis of exometabolic profiles of Enterococcus faecalis and Streptococcus sanguinis, representatives of Enterococcus and Streptococcus spp. respectively, by NMR and HPLC showed that these organisms produced significantly more lactic acid (p<0.01) from (13)C-labeled glucose, than the Gram negative Escherichia coli. Further, both E. faecalis and S. sanguinis secrete more D-lactic acid than E. coli. This study suggests a probable link between intestinal colonization of Gram positive facultative anaerobic D-lactic acid bacteria and symptom expressions in a subgroup of patients with CFS. Given the fact that this might explain not only neurocognitive dysfunction in CFS patients but also mitochondrial dysfunction, these findings may have important clinical implications.
Asunto(s)
Síndrome de Fatiga Crónica/metabolismo , Síndrome de Fatiga Crónica/microbiología , Intestinos/microbiología , Ácido Láctico/metabolismo , Isótopos de Carbono , Cromatografía Líquida de Alta Presión , Enterococcus faecalis/metabolismo , Escherichia coli/metabolismo , Heces/microbiología , Bacterias Anaerobias Gramnegativas/metabolismo , Humanos , Resonancia Magnética Nuclear Biomolecular , Estudios Retrospectivos , Streptococcus sanguis/metabolismoRESUMEN
The interferon-inducible, double-stranded (ds)RNA-dependent protein kinase (PKR) plays a major role in antiviral defense mechanisms where it down-regulates translation via phosphorylation of eukaryotic translation initiation factor 2alpha. PKR is also involved in the activation of nuclear factor kappaB (NFkappaB) through activation of the IkappaB kinase complex. Activation of PKR can occur in the absence of dsRNA and in such case is controlled by intracellular regulators like the PKR-activating protein (PACT), the PKR inhibitor p58(IPK), or heat-shock proteins (Hsp). These regulators are activated by stress stimuli, supporting a role for PKR in response to stress; however the final outcome of PKR activation in stress situations is unclear. We present here evidence that expression and activation of PKR contributes to an increased cellular resistance to mercury cytotoxicity. In two cell lines constitutively expressing PKR (THP-1 and Molt-3), treatment with the PKR inhibitor 2-aminopurine increases their sensitivity to mercury. In contrast, Ramos cells, which do not constitutively express PKR, present an increased resistance to mercury when PKR expression is induced by polyIC or interferon-beta treatment. This protective effect is inhibited by 2-aminopurine. We also show that exposure of Ramos cells to mercury leads to the induction of Hsp70. Treatment of cells with Hsp70 or NFkappaB inhibitors suppresses the PKR-dependent protection. We propose a model where PKR, modulated by Hsp70, activates a NFkappaB-mediated protective pathway. Because the cytotoxicity of mercury is primarily due to the generation of reactive oxygen species, our results suggest a more general function of PKR in the mechanisms of cellular response to oxidative stress.