The gut microbiota promotes hepatic fatty acid desaturation and elongation in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Josef Ecker
PROVIDER: E-MTAB-6079 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Interactions between the gut microbial ecosystem and host lipid homeostasis are highly relevant to host physiology and metabolic diseases. We present a comprehensive multi-omics view of the effect of intestinal microbial colonization on hepatic lipid metabolism, integrating transcriptomic, proteomic, phosphoproteomic, and lipidomic analyses of liver and plasma samples from germfree and specific pathogen-free mice. Microbes induced monounsaturated fatty acid generation by stearoyl-CoA desaturase 1 and polyunsaturated fatty acid elongation by fatty acid elongase 5, leading to significant alterations in glycerophospholipid acyl-chain profiles. Germfree mice contained more abundant saturated and poly-unsaturated lipids, whereas colonized mice primarily contained mono-unsaturated lipids. A composite classification score calculated from the observed alterations in fatty acid profiles in germfree mice clearly differentiated antibiotic-treated mice from untreated controls with high sensitivity. Mechanistic investigations revealed that acetate originating from gut microbial degradation of dietary fiber serves as precursor for hepatic synthesis of C16 and C18 fatty acids and their related glycerophospholipid species that are also released into the circulation.
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Project description:2,4-dinitrotoluene (2,4-DNT), a nitroaromatic used in industrial and explosive manufacturing processes, is known to contaminate artillery ranges, demilitarization areas and munitions manufacturing facilities. Previous transcriptomic and lipidomic studies identified energy metabolism as a principle biochemical process affected by 2,4-DNT where up-stream effects on PPAR? signaling were hypothesized as themolecular initiating event for these effects. Here, the validity of this hypothetical adverse outcome pathway (AOP) was assessed by testing the hypothesis that 2,4-DNT-induced perturbations in PPAR? signaling and resultant downstream deficits in energy metabolism, especially from lipids, would result in organism-level impacts on exercise endurance. PPAR? knock-out (-/-) and wild-type (WT) mice were exposed for 14 days to vehicle or 2,4-DNT at a dose (134 mg/kg/day) that did not exhibit overt systemic toxicity. Mice performed an exercise challenge (forced swim) 1 day after the last dose. 2,4-DNT decreased swim times in WT and PPAR? (-/-) mice, but the effect was significantly less in PPAR? (-/-) mice indicating the critical of PPAR? in mediating 2,4-DNT-induced energy metabolism deficits. 2,4-DNT caused down-regulation of transcripts involved in fatty acid metabolism, gluconeogenesis, triacylglycerol catabolism, and the pentose phosphate pathway, and 2,4-DNT treated wild-type mice had decreased serum trigylcerides and increased serum glucose versus 2,4-DNT treated PPAR? (-/-) mice. Our results support the hypothesis that 2,4-DNT perturbs PPAR? signaling as a molecular initiating event therefore impacting energy metabolism, especially lipid metabolism, producing reduced exercise endurance in mice. RNA was isolated from liver tissue of vehicle or 2,4-DNT treated wild-type or PPAR? (-/-) mice (n=6) and RT-PCR performed to analyze genes involved in fatty acid metabolism
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Project description:in the present study, we evaluated whether microbiota modulation is able to restore hepatic steatosis induced by n-3 PUFA depletion in mice. For this purpose, mice were fed during three months with a n-3 PUFA-depleted diet (presenting a high n-6/n-3 PUFA ratio), and then supplemented with fructooligosaccharides (FOS, 0.25g/day/mice), a prebiotic, during the last ten days of the experiment (DEF/FOS). In the same time, some n-3 PUFA-depleted mice were returned on a control diet during the last 10 days of treatment (DEF/CT) to compare the effect of FOS supplementation to a restored intake in n-3 PUFA. Microarray analyses were performed to identify the molecular targets modified by FOS supplementation in the liver of n-3 PUFA depleted mice. These mice were compared to control mice (fed a control diet during the 112 days of experiment) and to n-3 PUFA-depleted mice (fed a n-3 PUFA-depleted diet during the 112 days of experiment) for which the results have been previously published (Pachikian B.D. et al. PLoS One. 2011;6(8):e23365, accession number GSE26986) Male C57Bl/6J mice (9 weeks old; Charles River, Brussels, Belgium) were housed in groups of 4 mice per cage at 22°C in a 12 h light/dark cycle and given free access to diet and water. After an acclimatisation period of 1 week, mice were fed a control (CT) (D08041805, Research Diets, New Brunswick, USA) or an n-3 PUFA-depleted diet (DEF) (D08041806, Research Diets, New Brunswick, USA) for 112 days ad libitum. The CT diet contained the following (percent w/w): casein 20, total carbohydrate 72.4 (including corn starch 44.2, sucrose 10, maltodextrin 13.2, cellulose 5), soybean oil 5, mineral mix 3.5 and vitamin mix 1. The depletion was induced by replacing the soybean oil with sunflower oil, which exhibited a higher n-6/n-3 PUFA ratio. The n-6/n-3 PUFA ratio was 6.9 and 127.2 for the CT diet and the DEF diet, respectively. Ten days before the end of the experiment, DEF mice were divided into three groups: DEF, DEF/FOS and DEF/CT mice. The DEF mice were still fed with the n-3 PUFA depleted diet (DEF). The DEF/FOS mice were still fed the DEF diet and were supplemented for 10 days with fructooligosaccharides (DEF/FOS). FOS (Beneo P95 gift from Orafti; Tienen, Belgium) was added to tap water in a concentration adequate to reach an intake of 0.25g of FOS per day. For DEF/CT mice, the DEF diet was replaced by the CT diet during the last 10 days of treatment. At the end of the study period, mice fed the CT (n=4), DEF (n=7), DEF/CT (n=8) or DEF/FOS diet (n=8) were anaesthetised (ketamine/xylazine i.p., 100 and 10 mg/kg of body weight, respectively). The liver tissue was immediately clamped in liquid N2 and kept at -80°C until analysis. All mice experiments were approved by the local animal ethics committee and the housing conditions were as specified by the Belgian Law of April 6, 2010 on the protection of laboratory animals (agreement n° LA 1230314).
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Project description:A growing body of evidence highlights the relevance of free fatty acids (FFA) for human health, and their role in the cross talk between the metabolic status and immune system. Altered serum FFA profiles are related to several metabolic conditions, although the underlying mechanisms remain unclear. Recent studies have highlighted the link between gut microbiota and host metabolism. However, although most of the studies have focused on different clinical conditions, evidence on the role of these mediators in healthy populations is lacking. Therefore, we have addressed the analysis of the relationship among gut microbial populations, short-chain fatty acid (SCFA) production, FFA levels, and immune mediators (IFNγ, IL-6, and MCP-1) in 101 human adults from the general Spanish population. Levels of selected microbial groups, representing the major phylogenetic types present in the human intestinal microbiota, were determined by quantitative PCR. Our results showed that the intestinal abundance of Akkermansia was the main predictor of total FFA serum levels, displaying a negative association with total FFA and the pro-inflammatory cytokine IL-6. Similarly, an altered FFA profile, identified by cluster analysis, was related to imbalanced levels of Akkermansia and Lactobacillus as well as increased fecal SCFA, enhanced IL-6 serum levels, and higher prevalence of subclinical metabolic alterations. Although no differences in nutritional intakes were observed, divergent patterns in the associations between nutrient intakes with intestinal microbial populations and SCFA were denoted. Overall, these findings provide new insights on the gut microbiota-host lipid metabolism axis and its potential relevance for human health, where FFA and SCFA seem to play an important role.
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