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WESTERN-TYPE DIET OVERRULES THE PROTECTIVE EFFECT OF COMMENSAL BACTERIA IN ATHEROGENESIS
Abstract
Background and Aims
Studies have shown that atherosclerosis is associated with an altered gut microbiota composition (dysbiosis). However, studies have shown contradictory findings and the mechanistic effects are lacking.
Methods
To study the role of gut microbiota in atherosclerosis, male and female germ-free (GF) low-density lipoprotein knockout (Ldlr-/-) mice were conventionalized (CONV) with fecal microbiota from sex-matched Ldlr-/- donor mice or remained GF. Mice (n=12/group) were fed a chow or western-type diet (WD) for 12 weeks.
Results
Atherosclerotic plaque size was significantly reduced in chow-fed CONV mice compared to GF mice, with females displaying larger plaque sizes than males (p<0.05). In males, this athero-protective effect was independent of plasma cholesterol and systemic inflammation, whereas plasma cholesterol was reduced in female CONV mice compared to their GF counterparts (p<0.05). In contrast, the athero-protective effect was lost in WD-fed mice as plaque size was similar in CONV and GF mice, independent of gender. To investigate whether the microbiota could explain this atherosclerosis phenotype, we analyzed gut microbiota composition and function. 16S rRNA sequencing revealed a different microbial composition between chow-fed male and female mice, however, a sex difference was not found in WD-fed mice. Moreover, an increase in the Firmicutes:Bacteroidetes ratio was observed in WD-fed mice compared to chow-fed mice, indicative of microbial dysbiosis. Cecal SCFAs and plasma BA were similarly affected by chow and WD in CONV compared to GF mice, excluding an athero-protective role of these metabolites.
Conclusions
WD overrules the protective effect of commensal bacteria in atherogenesis, which is independent of BA- and SCFA metabolism.