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Endothelial dysfunction: what is the role of the microbiota?
  1. Erwin G Zoetendal,
  2. Hauke Smidt
  1. Laboratory of Microbiology, Wageningen University & Research, Wageningen, The Netherlands
  1. Correspondence to Dr Erwin G Zoetendal, Laboratory of Microbiology, Wageningen University & Research, Wageningen 6708 WE, The Netherlands; erwin.zoetendal{at}

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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. They further showed that improvement of endothelial dysfunction was accompanied with a change in microbiota composition and key gut peptides.

Endothelial dysfunction is a pathological state of the inner lining of the blood vessels which is characterised by a reduction in vasodilation in response to endothelial stimuli and considered an early key marker of cardiovascular disease.2 Impaired synthesis and release of nitric oxide (NO) by the endothelium is considered one of the important mechanisms associated with endothelial dysfunction.

A wide variety of risk factors associated with cardiovascular disease have been identified. These include general lifestyle factors such as the typical ‘Western diet’ and smoking, but also disorders, such as metabolic syndrome and type 2 diabetes as well as chronic inflammation. Increasing evidence indicates that the intestinal microbiota plays a key role in the latter risk factors for cardiovascular disease. A recent study demonstrated that the production of trimethylamine-N-oxide, a proatherosclerotic metabolite, from dietary phosphatidylcholine is dependent on microbial metabolism in the intestine.3 Hence, it is now generally acknowledged that the intestinal microbiota plays an important role in our health that extends beyond our intestine.

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. Such multidisciplinary studies, prompted by the introduction of high-throughput molecular approaches, have improved our insight into the complex interactions that exists in our intestinal ecosystem. In general, multidisciplinary intervention studies either in humans or other animals include detailed gene expression, histological and biochemical analyses of different host specimens that are frequently integrated to obtain detailed mechanistic insights into the host’s response to a certain intervention. Remarkably, analysis of the microbial response to these interventions is generally limited to 16S rRNA gene-based compositional profiling while conclusions about their role are generally at the same level of those concluded for the host. Although microbiota profiling studies give relevant information about the predominant groups of microbes in the intestine and their dynamics, the extrapolation to different functional roles should be taken with care.

First of all, it has to be realised that 16S rRNA profiling based on high-throughput next-generation technology sequencing results in a phylogenetic identification that in most cases does not go beyond the genus level. Although this phylogenetic level already provides a complex and diverse picture of the microbiota, this level is still very broad, considering that differences in functional capacity between microbes are already visible at species or even strain level. For example, the most famous species belonging to the genus Escherichia is Escherichia coli. Higher levels of this genus or even its corresponding phylum Proteobacteria in the intestine frequently result into a description of increase of potential pathogens. However, it has to be realised that a wide variety of E. coli strains have been described varying from pathogens to successfully marketed probiotics. Given the fact that the intestinal microbiota is already subject specific at genus level,4 the compositional differences between subjects at species and strain level will likely be higher, making a generalised interpretation even more complex. Moreover, it is evident that a considerable fraction of intestinal microbes, even from known genera, has not been obtained in culture yet, rendering their functional role in the ecosystem and whether they are beneficial, harmful or neutral to our health, unknown.

Second, as activity of human or animal cells cannot be extracted from DNA-based studies, the same holds for microbial activity. A recent study in which diets between African Americans and rural South Africans were switched resulted in very small shifts in microbiota composition but enormous alterations in metabolites in the faeces.5 This indicates that the activity of the microbiota can be drastically changed without major shifts in its community structure. As already known from pure cultures, bacteria are very versatile and can quickly respond to changes in their environment, including the availability of substrates for growth. This has also been nicely demonstrated in mice monoassociated with Bacteroides thetaiotaomicron.6 When mice were fed a diet rich in polysaccharides, B. thetaiotaomicron metabolism was dedicated to these. In contrast, host glycan metabolism was induced when mice were fed a simple sugar diet. In addition, a higher relative abundance of a microbial group does not automatically imply a higher microbial activity. Comparative analyses of microbiota composition and metaproteome in obese and non-obese human subjects revealed that obese subjects had lower levels of Bacteroidetes in their faeces, but these were more active compared with Bacteroidetes in non-obese subjects.7 Altogether, it is evident that extrapolation of 16S rRNA gene profiles to a functional description, and thus a mechanistic explanation, should be done with caution.

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. We argue that care should be taken when extrapolating microbial functionality from compositional data only, even if it perfectly fits with the host observations and current hypotheses.



  • Contributors EGZ and HS wrote the manuscript.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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