RESUMEN
Understanding the importance of the gut microbiota (GM) in non-alcoholic fatty liver disease (NAFLD) has raised the hope for therapeutic microbes. We have shown that high hepatic fat content associated with low abundance of Faecalibacterium prausnitzii in humans and, further, the administration of F. prausnitzii prevented NAFLD in mice. Here, we aimed at targeting F. prausnitzii by prebiotic xylo-oligosaccharides (XOS) to treat NAFLD. First, the effect of XOS on F. prausnitzii growth was assessed in vitro. Then, XOS was supplemented or not with high (HFD, 60% of energy from fat) or low (LFD) fat diet for 12 weeks in Wistar rats (n = 10/group). XOS increased F. prausnitzii growth, having only a minor impact on the GM composition. When supplemented with HFD, XOS ameliorated hepatic steatosis. The underlying mechanisms involved enhanced hepatic ß-oxidation and mitochondrial respiration. Nuclear magnetic resonance (1H-NMR) analysis of cecal metabolites showed that, compared to the HFD, the LFD group had a healthier cecal short-chain fatty acid profile and on the HFD, XOS reduced cecal isovalerate and tyrosine, metabolites previously linked to NAFLD. Cecal branched-chain fatty acids associated positively and butyrate negatively with hepatic triglycerides. In conclusion, XOS supplementation can ameliorate NAFLD by improving hepatic oxidative metabolism and affecting GM.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Glucuronatos/administración & dosificación , Enfermedad del Hígado Graso no Alcohólico/dietoterapia , Oligosacáridos/administración & dosificación , Prebióticos/administración & dosificación , Animales , Composición Corporal , Ciego/metabolismo , Ciego/microbiología , Dieta con Restricción de Grasas , Ingestión de Energía , Metabolismo Energético , Faecalibacterium prausnitzii/crecimiento & desarrollo , Ácidos Grasos/metabolismo , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Glucosa/metabolismo , Glucuronatos/metabolismo , Glucuronatos/farmacología , Metabolismo de los Lípidos , Hígado/metabolismo , Masculino , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/microbiología , Oligosacáridos/metabolismo , Oligosacáridos/farmacología , Oxidación-Reducción , Ratas , Ratas Wistar , Triglicéridos/metabolismoRESUMEN
In some mammals, halogenated aromatic hydrocarbon (HAH) exposure causes wasting syndrome, defined as significant weight loss associated with lethal outcomes. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD), which exerts its toxic effects through the aryl hydrocarbon receptor (AHR). Since TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, it was hypothesized that wasting syndrome is a result of to TCDD-induced dysregulation of genes involved in regulation of food-intake. As the hypothalamus is the central nervous systems' regulatory center for food-intake and energy balance. Therefore, mRNA abundances in hypothalamic tissue from two rat strains with widely differing sensitivities to TCDD-induced wasting syndrome: TCDD-sensitive Long-Evans rats and TCDD-resistant Han/Wistar rats, 23h after exposure to TCDD (100µg/kg) or corn oil vehicle. TCDD exposure caused minimal transcriptional dysregulation in the hypothalamus, with only 6 genes significantly altered in Long-Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were Cyp1a1 and Nqo1, which are induced by TCDD across a wide range of tissues and are considered sensitive markers of TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting. TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Hipotálamo/efectos de los fármacos , Análisis de Secuencia por Matrices de Oligonucleótidos , Dibenzodioxinas Policloradas/toxicidad , Toxicogenética/métodos , Transcripción Genética/efectos de los fármacos , Síndrome Debilitante/inducido químicamente , Síndrome Debilitante/genética , Animales , Citocromo P-450 CYP1A1/genética , Regulación de la Expresión Génica/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , NAD(P)H Deshidrogenasa (Quinona)/genética , ARN Mensajero/metabolismo , Ratas Long-Evans , Ratas Wistar , Especificidad de la Especie , Factores de TiempoRESUMEN
An acutely toxic dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to a drastically and permanently reduced feed intake and wasting by an unknown mechanism. We focused on the possible interference of TCDD with hypothalamic factors known to take part in the regulation of eating and metabolism, utilizing the over 1000-fold TCDD-sensitivity difference between Long-Evans (Turku/AB; L-E) and Han/Wistar (Kuopio) rats. The mRNA expression of 18 hypothalamic factors (including NPY, AgRP, and CART) was measured by quantitative RT-PCR at 6, 24 and 96 h after TCDD administration. The effects of TCDD were compared with those of leptin and with feed restriction employing a TCDD dose that elicited a severe reduction of feed intake in L-E rats. TCDD mainly modified expression of orexigenic factors causing an initial suppression followed by reversal to enhanced expression by 96 h. The latter was also seen in feed-restricted controls. In contrast, leptin altered both orexigenic and anorexigenic factor mRNAs in a more even manner and its effects were clustered at 6 h. The transient nature of feeding-promoting factor suppression does not strongly support a key role for this phenomenon in TCDD-induced wasting syndrome. However, the fact that TCDD mainly affected orexigenic factors and the temporal differences in response found between the rat strains warrant further research.