RESUMEN
Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.
Asunto(s)
Acetatos/metabolismo , Linfocitos B/inmunología , Butiratos/metabolismo , Colon/metabolismo , Diabetes Mellitus Tipo 1/dietoterapia , Disbiosis/dietoterapia , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad , Linfocitos B/microbiología , Células Cultivadas , Colon/patología , Dietoterapia , Microbioma Gastrointestinal , Interleucinas/sangre , Ratones , Ratones Endogámicos NOD , Linfocitos T Reguladores/microbiologíaRESUMEN
This corrects the article DOI: 10.1038/ni.3713.
RESUMEN
Targeting the BAFF/APRIL system has shown to be effective in preventing T-cell dependent autoimmune disease in the NOD mouse, a spontaneous model of type 1 diabetes. In this study we generated BAFF-deficient NOD mice to examine how BAFF availability would influence T-cell responses in vivo and the development of spontaneous diabetes. BAFF-deficient NOD mice which lack mature B cells, were protected from diabetes and showed delayed rejection of an allogeneic islet graft. Diabetes protection correlated with a failure to expand pathogenic IGRP-reactive CD8(+) T cells, which were maintained in the periphery at correspondingly low levels. Adoptive transfer of IGRP-reactive CD8(+) T cells with B cells into BAFF-deficient NOD mice enhanced IGRP-reactive CD8(+) T-cell expansion. Furthermore, when provoked with cyclophosphamide, or transferred to a secondary lymphopenic host, the latent pool of self-reactive T cells resident in BAFF-deficient NOD mice could elicit beta cell destruction. We conclude that lack of BAFF prevents the procurement of B-cell-dependent help necessary for the emergence of destructive diabetes. Indeed, treatment of NOD mice with the BAFF-blocking compound, BR3-Fc, resulted in a delayed onset and reduced incidence of diabetes.
Asunto(s)
Autoinmunidad/inmunología , Factor Activador de Células B/inmunología , Linfocitos B/inmunología , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , Animales , Autoinmunidad/genética , Factor Activador de Células B/genética , Factor Activador de Células B/metabolismo , Linfocitos B/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Citometría de Flujo , Glucosa-6-Fosfatasa/inmunología , Glucosa-6-Fosfatasa/metabolismo , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Supervivencia de Injerto/genética , Supervivencia de Injerto/inmunología , Inmunofenotipificación , Trasplante de Islotes Pancreáticos/métodos , Activación de Linfocitos/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Linfocitos T/metabolismo , Factores de TiempoRESUMEN
OBJECTIVES: During gastrointestinal infection, dysbiosis can result in decreased production of microbially derived short-chain fatty acids (SCFAs). In response to the presence of intestinal pathogens, we examined whether an engineered acetate- or butyrate-releasing diet can rectify the deficiency of SCFAs and lead to the resolution of enteric infection. METHODS: We tested whether a high acetate- or butyrate-producing diet (HAMSA or HAMSB, respectively) condition Citrobacter rodentium infection in mice and assess its impact on host-microbiota interactions. We analysed the adaptive and innate immune responses, changes in gut microbiome function, epithelial barrier function and the molecular mechanism via metabolite sensing G protein-coupled receptor 43 (GPR43) and IL-22 expression. RESULTS: HAMSA diet rectified the deficiency in acetate production and protected against enteric infection. Increased SCFAs affect the expression of pathogen virulence genes. HAMSA diet promoted compositional and functional changes in the gut microbiota during infection similar to healthy microbiota from non-infected mice. Bacterial changes were evidenced by the production of proteins involved in acetate utilisation, starch and sugar degradation, amino acid biosynthesis, carbohydrate transport and metabolism. HAMSA diet also induced changes in host proteins critical in glycolysis, wound healing such as GPX1 and epithelial architecture such as EZR1 and PFN1. Dietary acetate assisted in rapid epithelial repair, as shown by increased colonic Muc-2, Il-22, and anti-microbial peptides. We found that acetate increased numbers of colonic IL-22 producing TCRαß+CD8αß+ and TCRγδ+CD8αα+ intraepithelial lymphocytes expressing GPR43. CONCLUSION: HAMSA diet may be an effective therapeutic approach for fighting inflammation and enteric infections and offer a safe alternative that may impact on human health.
RESUMEN
Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.
Asunto(s)
Acetatos/sangre , Feto/inmunología , Preeclampsia/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Linfocitos T Reguladores/inmunología , Acetatos/administración & dosificación , Acetatos/inmunología , Acetatos/metabolismo , Adulto , Animales , Animales Recién Nacidos , Estudios de Casos y Controles , Desarrollo Infantil , Preescolar , Suplementos Dietéticos , Femenino , Feto/citología , Feto/diagnóstico por imagen , Microbioma Gastrointestinal/inmunología , Vida Libre de Gérmenes/inmunología , Humanos , Tolerancia Inmunológica/inmunología , Lactante , Recién Nacido , Estudios Longitudinales , Intercambio Materno-Fetal/inmunología , Ratones , Tamaño de los Órganos/inmunología , Preeclampsia/sangre , Preeclampsia/diagnóstico , Embarazo , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/prevención & control , Estudios Prospectivos , Timo/citología , Timo/diagnóstico por imagen , Timo/crecimiento & desarrollo , Timo/inmunología , Factores de Transcripción/inmunología , Factores de Transcripción/metabolismo , Ultrasonografía Prenatal , Adulto Joven , Proteína AIRERESUMEN
It is now convincingly clear that diet is one of the most influential lifestyle factors contributing to the rise of inflammatory diseases and autoimmunity in both developed and developing countries. In addition, the modern 'Western diet' has changed in recent years with increased caloric intake, and changes in the relative amounts of dietary components, including lower fibre and higher levels of fat and poor quality of carbohydrates. Diet shapes large-bowel microbial ecology, and this may be highly relevant to human diseases, as changes in the gut microbiota composition are associated with many inflammatory diseases. Recent studies have demonstrated a remarkable role for diet, the gut microbiota and their metabolites-the short-chain fatty acids (SCFAs)-in the pathogenesis of several inflammatory diseases, such as asthma, arthritis, inflammatory bowel disease, colon cancer and wound-healing. This review summarizes how diet, microbiota and gut microbial metabolites (particularly SCFAs) can modulate the progression of inflammatory diseases and autoimmunity, and reveal the molecular mechanisms (metabolite-sensing G protein-coupled receptor (GPCRs) and inhibition of histone deacetylases (HDACs)). Therefore, considerable benefit could be achieved simply through the use of diet, probiotics and metabolites for the prevention and treatment of inflammatory diseases and autoimmunity.