Endothelium–gut communication: IGF‐1Rs crosstalk with microbiota

The gut, with its extensive microbiota, plays a fundamental role in metabolism. While alterations of the gut microbiota can induce dysfunction of the endothelium, it remains unclear whether the endothelium can directly impact the gut microbiota. To answer this question, in this issue of EMBO Reports Haywood and colleagues deployed a murine model with endothelial‐specific overexpression of human insulin‐like growth factor‐1 receptor (IGF‐1R), termed hIGFREO mice (Haywood et al, 2021). When fed a high‐fat diet, hIGFREO mice gained less weight and adiposity, with improved glucose tolerance, as compared to their wild‐type littermates. Such protection was attributed to the difference in gut microbiota, exemplified by an increase in the beneficial genus Akkermansia. Furthermore, depletion of microbiota through broad‐spectrum antibiotics nullified the advantageous metabolic phenotype observed. Collectively, these findings demonstrate a novel communication axis between the endothelium and the gut wall, specifically through endothelial IGF‐1R modulation of gut microbiota, that promotes whole body metabolic homeostasis.

Gut microbiota alterations can induce dysfunction of the endothelium, but it is unclear whether the endothelium can directly impact microbiota. A new study now describes that endothelial IGF‐1R mediates crosstalk with the gut wall to promote metabolic homeostasis via microbiota modulation.

Diet‐induced obesity and its associated complications are currently devastating the western world and are rising in developing countries. Numerous efforts are being made to better understand the pathogenesis of obesity and type 2 diabetes. While it has long been recognized that endothelium, the vital interface between the circulating blood and vascular wall, becomes impaired early upon onset of a high‐fat diet (HFD) (Miller et al, 2009), whether this impaired endothelial function constitutes a driving force of metabolic disorder is unclear. Recent evidence reveals that the endothelium itself may orchestrate metabolic disorders. Leveraging transgenic mouse models, several groups have convincingly demonstrated that genetic perturbation specifically in the endothelium can significantly impact whole‐body metabolism through modulation of metabolic organs, e.g., skeletal muscle, adipose tissues, and liver (Das et al, 2018; Tang et al, 2020).

The gut is a pivotal site that controls nutrient uptake and whole‐body metabolic homeostasis. Dysbiosis and perturbation of the gut microbiome have been implicated as causal factors for obesity and type 2 diabetes, in addition to the known nutritional and genetic factors (Turnbaugh et al, 2006). Furthermore, the composition of gut microbiota has been linked to various diseases, including cardiovascular, through the vascular endothelium (Leslie & Annex, 2018). However, it is currently unknown whether intestinal microbiota simply influences endothelial cells (ECs), or whether the relationship is bidirectional, with ECs also able to affect the gut microbiota.

In this issue of EMBO Reports, Haywood and colleagues address this question using hIGFREO mice (Haywood et al, 2021). The current study emanated from previous work from the same group, who reported a decline in IGF‐1R expression in the vasculature of mice under HFD and generated of mice with endothelial overexpression of human IGF‐1R driven by Tie‐2 promoter (Imrie et al, 2012; Mughal et al, 2019). When fed a HFD (containing 60% of energy from fat), hIGFREO animals gained significantly less weight and adiposity than wild‐type animals, without substantial difference in activity, food intake, or energy expenditure. These obesity‐protective phenotypes were accompanied by lower fasting glucose levels, higher glucose tolerance, and higher expression and phosphorylation (at serine 437) of AKT in skeletal muscle, markers of improved insulin sensitivity. Importantly, all these changes occurred only in the HFD setting, but not under baseline condition (i.e., chow diet). Of note, despite the known role of IGF‐1R in fetal and neonatal development, there was no evidence of growth restriction in hIGFREO animals (Haywood et al, 2021).

To probe the underlying mechanisms, the authors found a significant difference in the fecal microbial composition between the hIGFREO and wild‐type mice under HFD (Haywood et al, 2021). In particular, the microbiota from hIGFREO mice featured an increase in gram‐negative bacteria Akkermansia, which has been suggested to exert anti‐obesity and anti‐diabetic effects (Everard et al, 2013), and a decrease in Bilophila, which has been shown to contribute to HFD‐induced metabolic dysfunction (Natividad et al, 2018). In order to deduce whether the altered gut microbiota is a cause for the observed metabolic phenotype, the authors demonstrated that administration of broad‐spectrum antibiotics led to a reduction in Akkermansia in hIGFREO mice and abolished the difference between hIGFREO and wild‐type mice, both under HFD (see Fig 1). To provide direct link between endothelial hIGFREO and gut microbiota, the authors showed the following: (i) differential expression of several genes that influence gut microbiota, such as increased Mucin 2 and decreased CD36 and apolipoprotein B in the small intestines as a result of endothelial overexpression of IGFREO; and (ii) conditioned media from primary ECs isolated from hIGFREO mice increased regenerating islet‐derived III‐γ (REG3G), a C‐type lectin with anti‐gram‐positive bactericidal activity, in Caco‐2 intestinal epithelial cells, which explains the decrease in several gram‐positive bacteria in hIGFREO mice (Haywood et al, 2021). Collectively, these results provide novel evidence that endothelial IGF‐1R acts as a nutrient sensor to influence intestinal epithelial function and its associated gut microbiome.

Figure 1. Endothelial IGF‐1 receptor mediates crosstalk with the gut wall to regulate microbiota in obesity.

Endothelial cell‐specific overexpression of IGF‐1 receptor (hIGFREO) mice fed with high‐fat diet has reduced weight, adiposity, and improved glucose tolerance compared with wild type (WT—top). hIGFREO mice (middle) have an altered gut microbiota including an increase in the beneficial genus Akkermansia and a decrease in Bilophila. Depletion of microbiota (bottom) results in hIGFREO mice that have lost the favorable metabolic effects seen in the untreated cohort.

As the first report illuminating an endothelial modulation of the gut microbiome in the context of metabolic disruption, the work by Haywood and colleagues may open a new area for investigation. Several outstanding questions warrant future studies. First, what are the vehicles that mediate endothelial communication with the gut microbiome? While the current work suggests paracrine signals are involved, the detailed characterization of endothelium‐derived paracrine factors, e.g., cytokines and small molecule metabolites that mediate the functional changes in intestinal cells, and the gut microbiome architecture would offer valuable insight to delineate endothelium–gut crosstalk. Second, given the prominent role of IGF‐1R in insulin pathways and cellular metabolism, it is conceivable that IGF‐1R overexpression impacts endothelial metabolism, which is yet to be explored. Finally, as the current work is largely built upon diet‐induced obesity mouse models, in which male mice are predominantly used, it would be of great interest to determine the effect of IGF‐1R gain of function in females as well. This would corroborate the promise of harnessing endothelial IGF‐1R–gut microbiome crosstalk in preventing or ameliorating metabolic disorders. Further investigation in a clinical setting to extend the translational relevance of this innovative work would be of significant impact and likely lead to new treatments for people with obesity and type 2 diabetes.

Conflict of interest

The authors declare that they have no conflict of interest.

EMBO reports (2021) 22: e52896.