RESUMEN
Altering the gut microbiome may be beneficial to the host and recently arose as a promising strategy to manage obesity. Here, we investigated the relative contribution of ω3 polyunsaturated fatty acid (PUFA)-mediated alterations in the microbiota to metabolic parameter changes in mice. Four groups were compared: male fat-1 transgenic mice (with constitutive production of ω3 PUFAs) and male wild-type (WT) littermates fed an obesogenic (high fat/high sucrose [HFHS]) or a control diet. Unlike WT mice, HFHS-fed fat-1 mice were protected against obesity, glucose intolerance, and hepatic steatosis. Unlike WT mice, fat-1 mice maintained a normal barrier function, resulting in a significantly lower metabolic endotoxemia. The fat-1 mice displayed greater phylogenic diversity in the cecum, and fecal microbiota transplantation from fat-1 to WT mice was able to reverse weight gain and to normalize glucose tolerance and intestinal permeability. We concluded that the ω3 PUFA-mediated alteration of gut microbiota contributed to the prevention of metabolic syndrome in fat-1 mice. It occurred independently of changes in the PUFA content of host tissues and may represent a promising strategy to prevent metabolic disease and preserve a lean phenotype.
Asunto(s)
Ácidos Grasos Omega-3/metabolismo , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Intolerancia a la Glucosa/prevención & control , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Obesidad/prevención & control , Animales , Cadherinas/genética , Cadherinas/metabolismo , Dieta de Carga de Carbohidratos/efectos adversos , Dieta Alta en Grasa/efectos adversos , Sacarosa en la Dieta/efectos adversos , Disbiosis/microbiología , Disbiosis/fisiopatología , Disbiosis/terapia , Endotoxemia/etiología , Endotoxemia/prevención & control , Trasplante de Microbiota Fecal/efectos adversos , Intolerancia a la Glucosa/microbiología , Intolerancia a la Glucosa/patología , Intolerancia a la Glucosa/fisiopatología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Mucosa Intestinal/fisiopatología , Intestinos/microbiología , Intestinos/patología , Intestinos/fisiopatología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Transgénicos , Músculo Esquelético/metabolismo , Enfermedad del Hígado Graso no Alcohólico/microbiología , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Obesidad/microbiología , Obesidad/patología , Obesidad/fisiopatología , Permeabilidad , FilogeniaRESUMEN
Overexpression of the tyrosine kinase receptor, ErbB2/HER2/Neu, occurs in 25-30% of invasive breast cancer (BC) with poor patient prognosis. Due to confounding factors, inconsistencies still remain regarding the protective effects of n-3 polyunsaturated fatty acids (PUFAs) on BC. We therefore evaluated whether fat-1 transgenic mice, endogenously synthesizing n-3 PUFAs from n-6 PUFAs, were protected against BC development, and we then aimed to study in vivo a mechanism potentially involved in such protection. E0771 BC cells were implanted into fat-1 and wild-type (WT) mice. After tumorigenesis examination, we analyzed the expression of proteins involved in the HER2 signaling pathway and lipidomic analyses were performed in tumor tissues and plasma. Our results showed that tumors totally disappeared by day 15 in fat-1 mice but continued to grow in WT mice. This prevention can be related in part to significant repression of the HER2/ß-catenin signaling pathway and formation of significant levels of n-3 PUFA-derived bioactive mediators (particularly 15-hydroxyeicosapentaenoic acid, 17-hydroxydocosahexaenoic acid, and prostaglandin E3) in the tumors of fat-1 mice compared with WT mice. All together these data demonstrate an anti-BC effect of n-3 PUFAs through, at least in part, HER2 signaling pathway downregulation, and highlight the importance of gene-diet interactions in BC.