Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction

Abstract

ObjectiveTo investigate the beneficial role of prebiotics on endothelial dysfunction, an early key marker of cardiovascular diseases, in an original mouse model linking steatosis and endothelial dysfunction.DesignWe examined the contribution of the gut microbiota to vascular dysfunction observed in apolipoprotein E knockout (Apoe−/−) mice fed an n-3 polyunsaturated fatty acid (PUFA)-depleted diet for 12 weeks with or without inulin-type fructans (ITFs) supplementation for the last 15 days. Mesenteric and carotid arteries were isolated to evaluate endothelium-dependent relaxation ex vivo. Caecal microbiota composition (Illumina Sequencing of the 16S rRNA gene) and key pathways/mediators involved in the control of vascular function, including bile acid (BA) profiling, gut and liver key gene expression, nitric oxide and gut hormones production were also assessed.ResultsITF supplementation totally reverses endothelial dysfunction in mesenteric and carotid arteries of n-3 PUFA-depleted Apoe−/− mice via activation of the nitric oxide (NO) synthase/NO pathway. Gut microbiota changes induced by prebiotic treatment consist in increased NO-producing bacteria, replenishment of abundance in Akkermansia and decreased abundance in bacterial taxa involved in secondary BA synthesis. Changes in gut and liver gene expression also occur upon ITFs suggesting increased glucagon-like peptide 1 production and BA turnover as drivers of endothelium function preservation.ConclusionsWe demonstrate for the first time that ITF improve endothelial dysfunction, implicating a short-term adaptation of both gut microbiota and key gut peptides. If confirmed in humans, prebiotics could be proposed as a novel approach in the prevention of metabolic disorders-related cardiovascular diseases.

Endothelial dysfunction: what is the role of the microbiota?

“…In conclusion, the article by Catry et al describes an excellent study how endothelial dysfunction can be improved via a microbiota-mediated prebiotic intervention in apoE knockout mice and hence, this study opens interesting avenues for novel therapeutics to prevent cardiovascular disease 1. In our opinion, a clear mechanistic description of the host response towards the intervention has been provided, but the microbial counterpart is still hypothetical and needs further exploration.…”

“…In this issue, Catry et al described a study in which inulin-type fructans (ITF) improved endothelial dysfunction in mice 1. They demonstrated that the supplementation of ITF reverses endothelial dysfunction in mesenteric and carotid arteries of apolipoprotein E ( apoE ) gene knockout mice that were fed an n-3 polyunsaturated fatty acid-depleted diet.…”

“…The article by Catry et al showed that ITF improved endothelial dysfunction in apoE knockout mice and that this is mediated via the activation of the nitric oxide synthase/NO pathway that could be dependent on the increase in NO-producing bacteria 1. The authors based their mechanistic explanation on detailed host measurements complemented with 16S ribosomal RNA (rRNA) gene-based microbiota profiling.…”

Single-cell genomics of uncultured bacteria reveals dietary fiber responders in the mouse gut microbiota

“…Many studies have demonstrated that dietary fiber supplementation can modulate gut microbiota composition and promote SCFA production [3][4][5]. This dietary fiber metabolism is particularly important for non-digestible inulin-type fructans classified as prebiotics, which are substrates that promote the growth of beneficial microorganisms in the gut [6][7][8][9][10][11][12]. Thus, to enhance the benefits of dietary fiber to the host, it is important to identify inulin responders in the complex microbiome community of the host intestine, and characterize their mechanisms of inulin fermentation and potential for SCFA production.Recently developed metagenomic approaches can provide comprehensive microbial profiling and putative functions using 16S rRNA gene amplicon sequencing and shotgun metagenome sequencing.…”

Distal versus proximal intestinal short-chain fatty acid release in man

“…Catry and colleagues1 demonstrated that inulin-type fructans improve endothelial dysfunction, and Roager et al 2 showed that a whole grain-rich diet reduced body weight and inflammation. Li et al 3 reported that butyrate administration reduced appetite and activated brown adipose tissue in mice, and Chambers and colleagues4 showed that targeted propionate delivery to the human colon reduced energy intake and body weight gain.…”