Abstract
Aims/hypothesisDespite the current pandemic of metabolic diseases, our understanding of the diverse nature of the development of metabolic alterations in people who eat a high-fat diet (HFD) is still poor. We recently demonstrated a cardio-metabolic adaptation in mice fed an HFD, which was characterised by a specific gut and periodontal microbiota profile. Since the severity of hepatic disease is characterised by specific microRNA (miRNA) signatures and the gut microbiota is a key driver of both hepatic disease and miRNA expression, we analysed the expression of three hepatic miRNA and studied their correlation with hepatic triacylglycerol content and gut microbiota.MethodsTwo cohorts of C57BL/6 4-week-old wild-type (WT) male mice (n = 62 and n = 96) were fed an HFD for 3 months to provide a model of metabolic adaptation. Additionally 8-week-old C57BL/6 mice, either WT or of different genotypes, with diverse gut microbiota (ob/ob, Nod1, Cd14 knockout [Cd14KO] and Nod2) or without gut microbiota (axenic mice) were fed a normal chow diet. Following which, glycaemic index, body weight, blood glucose levels and hepatic triacylglycerol levels were measured. Gut (caecum) microbiota taxa were analysed by pyrosequencing. To analyse hepatic miRNA expression, real-time PCR was performed on total extracted miRNA samples. Data were analysed using two-way ANOVA followed by the Dunnett’s post hoc test, or by the unpaired Student’s t test. A cluster analysis and multivariate analyses were also performed.ResultsOur results demonstrated that the expression of miR-181a, miR-666 and miR-21 in primary murine hepatocytes is controlled by lipopolysaccharide in a dose-dependent manner. Of the gut microbiota, Firmicutes were positively correlated and Proteobacteria and Bacteroides acidifaciens were negatively correlated with liver triacylglycerol levels. Furthermore, the relative abundance of Firmicutes was negatively correlated with hepatic expression of miR-666 and miR-21. In contrast, the relative abundance of B. acidifaciens was positively correlated with miR-21.Conclusions/interpretationWe propose the involvement of hepatic miRNA, liver triacylglycerols and gut microbiota as a new triad that underlies the molecular mechanisms by which gut microbiota governs hepatic pathophysiology during metabolic adaptation to HFD.
Highlights
The current pandemic of metabolic diseases, such as obesity and type 2 diabetes, cannot be completely explained by genetic alterations and the growing consumption of a Western diet [1, 2]
Conclusions/interpretation We propose the involvement of hepatic miRNA, liver triacylglycerols and gut microbiota as a new triad that underlies the molecular mechanisms by which gut microbiota governs hepatic pathophysiology during metabolic adaptation to high-fat diet (HFD)
Liver triacylglycerol content showed high interindividual variation, which is typical of this animal model and suggests that liver triacylglycerol levels are dependent on the metabolic response of each mouse to HFD feeding (Fig. 1)
Summary
The current pandemic of metabolic diseases, such as obesity and type 2 diabetes, cannot be completely explained by genetic alterations and the growing consumption of a Western diet [1, 2]. Obesity is not an inevitable consequence of a fat-rich diet, since both people and mice consuming a high-fat diet (HFD) can display the opposite metabolic outcome, suggesting the existence of metabolic adaptations in some individuals [3, 4]. We previously found that adaptation to obesity in terms of insulin sensitivity was characterised by a specific gut microbiota profile in insulin-resistant vs insulin-sensitive obese individuals [10]. We showed that divergent gut microbiota profiles characterise the different metabolic phenotypes developed during metabolic adaptation to an HFD in mice [3, 4]. We reported that the periodontal microbiota profile correlates with cardio-metabolic adaptations to an HFD in mice [11]
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