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. 2023 Aug;13(8):a041179. doi: 10.1101/cshperspect.a041179

Gut Microbiota and the Microvasculature

Klytaimnistra Kiouptsi 1,2, Giulia Pontarollo 1, Christoph Reinhardt 1,2,✉
PMCID: PMC10411863  PMID: 37460157

Abstract

The gut microbiota is increasingly recognized as an actuating variable shaping vascular development and endothelial cell function in the intestinal mucosa but also affecting the microvasculature of remote organs. In the small intestine, colonization with gut microbiota and subsequent activation of innate immune pathways promotes the development of intricate capillary networks and lacteals, influencing the integrity of the gut–vascular barrier as well as nutrient uptake. Since the liver yields most of its blood supply via the portal circulation, the hepatic microcirculation steadily encounters microbiota-derived patterns and active signaling metabolites that induce changes in the organization of the liver sinusoidal endothelium, influencing immune zonation of sinusoids and impacting on metabolic processes. In addition, microbiota-derived signals may affect the vasculature of distant organ systems such as the brain and the eye microvasculature. In recent years, this gut-resident microbial ecosystem was revealed to contribute to the development of several vascular disease phenotypes.

Prenatally (in utero), the fetus develops under sterile conditions. Sterility is lost at birth due to a wave of microbial inoculation via the vaginal flora (Mueller et al. 2015; Gabriel et al. 2018). Yet, in recent years, reports on the presence of bacterial communities in the placenta, the amniotic fluid, and the meconium in healthy pregnancies suggested that the environment is not completely sterile (Aagaard et al. 2014; Collado et al. 2016). However, this “in utero colonization hypothesis” has been questioned due to the lack of explanatory insights (Walter and Hornef 2021), especially since the studies that support it used molecular methods with insufficient detection limits, lacked appropriate controls for contamination, and did not provide evidence for bacterial viability. The most convincing argument against the “in utero colonization hypothesis” is the ability to reliably derive germ-free animals via C-section when kept free of microbes in sterile isolator systems over many generations (Perez-Muñoz et al. 2017). Hence, direct microbiota–host interactions are first initiated when babies leave their mother's wombs.

The de novo assembly of microbial communities commences at birth (Costello et al. 2012). Microbial communities colonizing all body surfaces of mammals (microbiota) are complex mixtures of microorganisms that coevolved with their host (Dethlefsen et al. 2007). In infants, microbial colonization occurs after exposure to various bacteria from environmental sources such as skin, mouth, and mother's milk (Reinhardt et al. 2009). The microbial colonization pattern is defined by the mode of delivery, diet, and antibiotic treatment but also by the genotype of the host (Zoetendal et al. 2009; Bäckhed et al. 2015; Roswall et al. 2021). In term infants, there are indications for the inheritance of early colonizers (i.e., in vaginally delivered newborns, mother-to-infant transmission occurs, which is compromised in C-section-delivered neonates) (Bäckhed et al. 2015). Culture-based studies demonstrated that colonization occurs rapidly. Upon delivery, the neonatal skin is exposed to environmental microbes (Dominguez-Bello et al. 2010). From 6 hours after birth, cultivable bacteria are present in the mouth (Rotimi and Duerden 1981). The initial microbiota is relatively unstable and undergoes dramatic changes during the initial period of life, facilitating the transition from a high-fat, milk-based diet to a diet rich in carbohydrates (Bjursell et al. 2006; Palmer et al. 2007). The adult gut microbiota is dominated by the Firmicutes and Bacteroides genera, whereas the great majority of bacterial taxa in the skin microbiota belong to Proteobacteria and Firmicutes (Naik et al. 2012). Bacterial diversity increases with age (Yatsunenko et al. 2012). However, over the age range of 40–85 yr, aging scarcely influenced the bacterial community and compositional changes of the intestinal microbiota (Schütte et al. 2021). In fact, compositional changes during aging are more likely to be associated with health status of the elderly and confounding factors than aging itself (An et al. 2018).

The microbiota exists in a mutualistic relationship with its host (Bäckhed et al. 2005), influencing many facets of host physiology and development throughout the host's life span. Therefore, animals should be regarded as metaorganisms (Esser et al. 2019). Although bacterial translocation is restricted by the gut barrier (Spadoni et al. 2015), colonization studies on germ-free rodent models and antibiotic microbiota depletion have shown that colonizing commensals strongly affect host physiology, organ development, and morphogenesis (Sommer and Bäckhed 2013; Bayer et al. 2019, 2021). Distinctive and versatile organ function requires the formation and adaptation of the organotypic vasculatures (Augustin and Koh 2017).

Interestingly, the microbiota was revealed as an environmental factor that impacts angiogenesis, the formation of new vessels from preexisting vessels (Stappenbeck et al. 2002). The development of new vessels in the gastrointestinal tract, a highly capillarized organ, occurs during the period of postnatal development, which overlaps with the microbial colonization, thus increasing the absorptive capacity of the intestine (Stappenbeck et al. 2002). On the other hand, mucosal angiogenesis is also triggered by inflammation and is influenced by innate immune pathways (Schirbel et al. 2013). There is mounting evidence showing that the colonization status of the host influences the organotypic microvasculature of additional organs.

MICROBIOTA–HOST INTERACTIONS AFFECT THE GUT MICROVASCULATURE

In laboratory mice, during the 19-day gestational period, the intestine forms between embryonic days 8 and 9.5 through tubulogenesis of the splanchopleure (Hatch and Mukouyama 2015; Bayer et al. 2021). In the developing mouse intestine, the vasculogenic cells originate from the serosal mesothelium. At embryonic day 9.5, platelet endothelial cell-adhesion molecule-1 (PECAM-1)-positive endothelial tubes appear in the proximal half of the intestine and sprouting endothelial cells in the distal (Hatch and Mukouyama 2015). In the small intestine, at embryonic day 10.5, the primary capillary plexus has been formed. At embryonic day 13.5, the tube-forming endothelial cells extend from the vascular plexus to the surface of the gut. This capillary network undergoes extensive angiogenic remodeling forming the hierarchically branched enteric vascular network by embryonic day 15.5 when arteries and veins can be distinguished (Hatch and Mukouyama 2015). At embryonic day 15.5, the submucosal vasculature is connected to the superior mesenteric artery and the superior mesenteric vein by mesenteric vessels and vasa recta. The lymphatics develop later than the blood vessels. Between embryonic day 13.5 and embryonic day 15.5, the lymphatic vasculature develops from the mesentery (Hatch and Mukouyama 2015). Beginning at embryonic day 16, endothelial-to-mesenchymal transition is observed, differentiating into the smooth muscle cells of the mesentery and the intestine (Wilm et al. 2005). The villus vasculature of the mature intestine consists of a lymphatic vessel located at the center of the villus, the lacteal, surrounded by intricate blood capillary networks that are in close proximity to the villus epithelium.

The mammalian intestine is subject to a significant extent of postnatal plasticity. In mice, during the suckling period at postnatal day 1 until day 14, the crypt stem cell hierarchy is established, and Paneth cells undergo maturation (Schmidt et al. 1988; Bry et al. 1994). From postnatal day 1 to day 14, the villus blood capillaries lack cross-linking branches (Stappenbeck et al. 2002). After completion of the suckling–weaning transition at postnatal day 28, the small intestinal villus capillaries develop into branched interconnected vessels (Stappenbeck et al. 2002). Postnatally, the functional separation of the blood vasculature and the lymphatic vasculature is actively preserved by angiopoietin-like protein 4 (ANGPTL4), which was previously referred to as fasting-induced adipose factor (Bäckhed et al. 2007).

Postnatal stages of gut development are paralleled by the establishment of the commensal gut microbiota. The pre-weaning microbiota is dominated by facultative anaerobes that, between postnatal day 14 and 28, undergo a transition toward a microbiota that is dominated by obligate anaerobes (Savage 1977). Strikingly, the small intestine of adult germ-free mice, kept in sterile plastic isolators and lacking microbial colonization, show underdeveloped villus capillaries in the distal small intestine (Stappenbeck et al. 2002; Reinhardt et al. 2012). Experimentation with germ-free mouse models demonstrated that this arrested angiogenic program is rapidly restarted by colonization with a gut microbiota or the abundant polysaccharide-degrading, Gram-negative bacterium Bacteroides thetaiotaomicron (Stappenbeck et al. 2002). Furthermore, the minimal microbial consortium oligo-mouse microbiota (OMM12), a community of 12 mouse intestinal bacteria, was demonstrated to enhance the maturation of small intestinal villus capillaries (Garzetti et al. 2017; Romero et al. 2022).

Based on germ-free mouse models, several mechanisms were identified to promote the microbiota-induced formation of capillary networks in the small intestinal mucosa. Figure 1 shows the capillary network differences observed between a germ-free mouse and a conventionally raised mouse. Lineage ablation of Paneth cells by cell-type-specific expression of an attenuated diphtheria toxin A fragment impaired the formation of villus capillary networks both in germ-free and conventionally raised housing conditions, indicating that these cells of the secretory lineage are involved in mucosal angiogenesis in the distal small intestine (Stappenbeck et al. 2002). Another key molecule involved in microbiota-induced intestinal angiogenesis is the coagulation initiator tissue factor (Reinhardt et al. 2012). The gut microbiota enhances tissue factor glycosylation, resulting in the cell surface localization of tissue factor on enterocytes, where the receptor activates coagulation proteases. The expansion of villus capillaries is promoted via protease-activated receptor-1-dependent coagulation factor signaling and epithelial-to-endothelial cross-talk (Reinhardt et al. 2012). Moreover, microbial patterns are recognized by the Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) of human intestinal microvascular endothelial cells. In cell culture studies, innate immune receptor signaling was shown to induce proliferation, migration, transmigration, and sprout formation (Pollet et al. 2003; Schirbel et al. 2013, 2019). Interestingly, TLR/interleukin-1 receptor signaling impacts the development and angiogenesis of the murine small intestine but not the colon (Rakoff-Nahoum et al. 2015). For instance, activation of TLR2 expressed by small intestinal epithelial cells reduced epithelial neuropilin-1 (NRP1) protein levels and gut mucosal vascularization was diminished in mice deficient in epithelial NRP1 (Pontarollo et al. 2023). Of note, in the inflammatory intestinal microenvironment, tumor necrosis factor α–induced endothelial cell apoptosis is efficiently prevented through the protective action of TGF-β-activated kinase-1, ensuring microvascular integrity (Naito et al. 2019). Consequently, several innate immune-related signaling pathways influence developmental angiogenesis of the postnatal small intestine.

Figure 1.

Figure 1.

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Immunofluorescence images of distal small intestinal sections of a conventionally raised (CONV-R, left) and a germ-free (GF, right) mouse, stained for PECAM-1 (green), smooth muscle cell actin (SMA, red), and Hoechst nuclear dye (blue). Compared to GF controls, the CONV-R mouse shows higher capillary density (green) and increased villus width.

In addition to the development of blood capillary networks, the gut microbiota is also crucial for the maturation of the specialized lymphatic vessels in the small intestinal villus structures, the lacteals (Bernier-Latmani et al. 2015; Suh et al. 2019). Interestingly, the density of both blood vessels and lymphatic vessels, as quantified in the small intestinal crypt region by comparing the ratio of CD31-positive and LYVE1-positive vessels per 100 crypts, was found reduced in germ-free mice relative to mice colonized with the minimal microbial consortium altered Schaedler flora (ASF) (Moghadamrad et al. 2015). Postpartum, microbial colonization activates vascular endothelial growth factor C (VEGF-C) expression in villus macrophages via myeloid differentiation factor 88 (MYD88)-dependent signaling, thus augmenting lacteal maturation during the postnatal weaning period (Suh et al. 2019). Similar to germ-free mice that have 20% shorter lacteals relative to their conventionally raised counterparts, antibiotic treatment of conventionally raised mice resulted in a 15% reduction in lacteal length and a reduction in complexity of the villus capillary network in the jejunum and the ileum (Suh et al. 2019). Key mechanisms involved in microbiota-driven capillary network expansion and lacteal maturation are shown in Figure 2. In conclusion, the development and architecture of the intestinal microvasculature are strongly influenced by the gut microbiota.

Figure 2.

Figure 2.

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Mechanisms promoting microbiota-induced blood capillary network expansion (left) and maturation of lymphatic vessels (right). To maximize the surface for nutrient absorption, the small intestinal mucosa is organized in finger-like villus structures and crypts. At the base of the crypts, multipotent intestinal stem cells self-renew and differentiate into absorptive (enterocytes) or secretory (goblet, enteroendocrine, tuft, Paneth cells) cell lineages. This monolayer of terminally differentiated intestinal epithelial cells faces the gut lumen, forming a physical barrier against the gut microbiota. Underneath the epithelium, in the lamina propria, each villus structure contains a single lymphatic vessel (the lacteal), surrounded by a network of arterial and venous blood capillaries, mediating metabolite uptake. Innate immune signaling influences developmental angiogenesis, whereas Paneth cell signaling impacts microbiota-induced intestinal angiogenesis in the adult gut. Coagulation factor signaling in intestinal epithelial cells augments the expansion of villus capillaries. Vascular endothelial growth factor C (VEGF-C) from gut resident macrophages enhances the maturation of lacteals during the postnatal weaning period.

On the functional level, the gut microbiota not only regulates the paracellular permeability of the gut epithelial lining but is also an important determinant of the gut–vascular barrier (Spadoni et al. 2015; Thevaranjan et al. 2017). Lacteals are the vessels that govern fat transport through the uptake of chylomicrons as well as the transport of microbial antigens and antigen-presenting cells to the mesenteric lymph node (Bernier-Latmani et al. 2015). In lacteals, the discontinuously sealed button-like junctions favor the uptake of chylomicrons, whereas the continuously sealed zipper-like junctions prevent their uptake (Suh et al. 2019). The lacteals of germ-free mice display vastly reduced proportions of the discontinuously sealed button-like junctions, associated with reduced triglyceride levels in the thoracic duct, a phenotype that is restored upon colonization (Suh et al. 2019). Interestingly, antibiotic depletion of gut commensals reduces the proportion of button-like junctions and at the same time increases the proportion of zipper-like junctions (Suh et al. 2019). Lacteal zippering and the absorption of chylomicrons are regulated via the bioavailability of VEGF-A, which is reduced by endothelial NRP1 and VEGFR-1 (FLT1) (Zhang et al. 2018). Most interestingly, and in contrast to chylomicron uptake, high-density lipoprotein (HDL) particles derived from the enterocytes of the ileum do not travel into draining lymphatic vessels but rather enter the portal vein via fenestrated villus capillaries (Han et al. 2021). Enterocyte-derived HDL particles (HDL3) neutralize lipopolysaccharides from Gram-negative gut bacteria by masking it with lipopolysaccharide (LPS)-binding protein, preventing the activation of liver macrophages. Interestingly, the postnatal deficiency of forkhead-box-protein c2 (Foxc2) in the lymphatic endothelium, a mechanosensitive transcription factor crucially involved in the hierarchical organization of the lymphatic network in different organs, results in enlarged lacteals, disruption of the intestinal epithelial barrier, gut microbiota translocation, an altered composition of the gut microbiota, and changed plasma metabolites (González-Loyola et al. 2021). Thus, in line with its mutualistic role, the gut microbiota is an actuating variable that regulates nutrient uptake by influencing the constitution of the small intestinal microvasculature.

MICROBIOTA–HOST INTERACTIONS AFFECTING THE MICROVASCULATURE OF THE LIVER

The impact of the commensal microbiota on organotypic microvasculatures is not restricted to the intestine. Dependent on nutrition and gut barrier regulation (Wang et al. 2011; Thevaranjan et al. 2017; Sorribas et al. 2019), signaling-active, microbiota-derived metabolites and microbial products can reach the portal circulation and induce remote effects in distal organs (Nicholls et al. 2003; Cani et al. 2008, Balmer et al. 2014). Moreover, the gut microbiota aids immune maturation with effects on remote organ systems (Benakis et al. 2016; Schaupp et al. 2020). Since the liver receives ∼70% of its blood supply from the intestinal portal circulation, the microbiota affects hepatic endothelial phenotypes and the development of liver diseases (Mouries et al. 2019; Safari Gérard 2019; Formes et al. 2021).

The fenestrations of the specialized sinusoidal endothelium of the liver are dynamic structures, which are phenotypically and functionally influenced by dietary manipulation. Scanning electron microscopy on the luminal surface of liver sinusoidal endothelial cells revealed reduced porosity associated with dietary fat intake (Cogger et al. 2016). Interestingly, the analysis of scanning electron micrographs of the luminal surface of liver sinusoids demonstrated a positive correlation of porosity and diameter of hepatic liver endothelial cell fenestrae with the abundance of gut bacteria of the Firmicutes phylum and a negative correlation with Bacteroidetes abundance (Cogger et al. 2016). Moreover, the porosity of the liver sinusoidal endothelial cells was found reduced by elevated circulating LPS levels and pseudomonal pyocyanin (Dobbs et al. 1994; Cheluvappa et al. 2007). Defenestration of the liver sinusoidal endothelium was linked to an impaired transfer of small chylomicrons from sinusoidal blood into the perisinusoidal space (space of Disse), thus favoring hyperlipidemia (Hilmer et al. 2005).

The exposure of liver sinusoidal endothelial cells to physiological LPS concentrations was suggested to constitute a physiological event that is crucial for LPS clearance from the portal circulation, preventing the entry of LPS into the systemic circulation (Jacob et al. 1977; Freudenberg et al. 1982). Liver sinusoidal endothelial cells constitute a type of mature and efficient antigen-presenting cells, engaged in T-cell activation. Hence, it is interesting to note that in case of LPS challenge with concentrations found in portal venous blood, liver sinusoidal endothelial cells, in contrast to other antigen-presenting cell types, down-regulate their antigen-presenting function, relevant for the induction of T-cell tolerance (Lohse et al. 1996; Knolle et al. 1999; Limmer et al. 2000). Intriguingly, the immune zonation in liver sinusoids (i.e., the spatial localization of Kupffer cells) is strongly determined by the gut microbiota (Gola et al. 2021). The localization of Kupffer cells in liver sinusoids is regulated by MYD88-mediated innate immune signaling of liver sinusoidal endothelial cells. This points to a hitherto underestimated functional impact of the commensal microbiota on organotypic endothelia in the regulation of immune surveillance.

As a driving factor of liver pathology, LPS derived from gut bacteria promotes hepatic endothelial TLR4/MYD88 signaling, promoting angiogenesis and aggravating fibrosis in a bile duct ligation mouse model (Pollet et al. 2003; Jagavelu et al. 2010; Caesar et al. 2012; Zhu et al. 2012). Interestingly, the absence of commensals at germ-free housing conditions attenuated portal hypertension, diminished the increase in intestinal lymphatic vessel density relative to the number of crypts in the small intestinal crypt region, and prevented the development of portosystemic collaterals, an abnormal connection between the portal and the systemic circulation, in a model of partial portal vein ligation (Moghadamrad et al. 2015). Portal hypertension and the resulting increase of blood vessels in the intestine and mesentery are driven by Paneth cells, the cell type responsible for the secretion of antimicrobial peptides (Hassan et al. 2020, 2022). Moreover, colonization with gut commensals affects acute mesenteric ischemia-reperfusion injury by restricting the formation of neutrophil extracellular traps (NETs) (Ascher et al. 2020).

Of note, the gut microbiota also affects the hemostatic properties of the hepatic microvascular endothelium (Reinhardt 2019). Via the gut–liver axis, the colonization with microbiota stimulates tonic TLR2 signaling in hepatic endothelial cells, leading to von Willebrand factor synthesis and elevated von Willebrand factor plasma levels that promote arterial thrombus growth (Jäckel et al. 2017). Furthermore, the microbiota can impact on vascular thrombosis by influencing prothrombotic platelet function through various mechanisms (Roberts et al. 2018; Skye et al. 2018; Kiouptsi et al. 2019, 2020). In endothelial cell culture models, the release of von Willebrand factor and coagulation factor VIII was induced by stimulation with microbial-associated molecular patterns, such as LPS (Into et al. 2007; Carnevale et al. 2017). In line, coagulation factor VIII, which in plasma is stabilized by its interaction with von Willebrand factor, was directly correlated with LPS serum levels in cirrhosis patients (Carnevale et al. 2017). Taken together, the liver sinusoidal endothelium senses microbiota-derived signals (Formes et al. 2021), resulting in adaptive and maladaptive transcriptional, metabolic, and functional changes with broad implications for host physiology.

MICROBIOTA–HOST INTERACTIONS AFFECTING THE MICROVASCULATURE OF THE BRAIN AND THE EYE

The gut microbiota modulates the blood–brain barrier, brain development, and even influences behavioral traits like motor activity and anxiety-like behavior (Diaz Heijtz et al. 2011; Braniste et al. 2014). Interestingly, germ-free mouse models indicated that the presence of a maternal gut microbiota supports blood–brain barrier development in embryos, and the lack of gut microbiota is associated with increased blood–brain barrier permeability in adult mice (Braniste et al. 2014). This involves the translocation of microbial patterns, such as peptidoglycan, through the blood–brain barrier and their recognition in the developing brain (Arentsen et al. 2017). After birth, during the first weeks of life, peptidoglycan levels increase in the cerebellum, the prefrontal cortex, and the striatum (Arentsen et al. 2017). There is increasing evidence that remote signaling effects induced by the commensal microbiota affect the brain microvasculature. For instance, microbiota-derived patterns stimulate the development of cerebral cavernous malformations via TLR4 signaling, thus generating abnormally formed blood vessels that are a cause of stroke (Tang et al. 2017).

Besides innate immune signaling, microbiota-derived metabolites interacting with host metabolism and microbiota-regulated host metabolic pathways may influence developmental angiogenesis in the brain. For example, monocolonization experiments on germ-free mice with the short-chain fatty acid–producing bacteria B. thetaiotaomicron and Clostridium tyrobutyricum resulted in reduced vascular permeability in the cortex, hippocampus, and striatum (Braniste et al. 2014). B. thetaiotaomicron predominantly produces the short-chain fatty acid acetate, whereas C. tyrobutyricum is a butyrate-producing bacterium (Samuel and Gordon 2006; Braniste et al. 2014). In accordance with the protective effects of short-chain fatty acid–producing bacteria, oral gavage with sodium butyrate strengthened the blood–brain barrier of adult germ-free mice (Braniste et al. 2014). The free fatty acid receptor was demonstrated to be expressed on the human brain endothelium (Hoyles et al. 2018). Endothelial cell culture studies demonstrated a protective role of physiological concentrations of gut bacterial short-chain fatty acids, such as propionate, against LPS-induced barrier disruption (Hoyles et al. 2018). To give another example, odd chain sphingolipids, produced by gut bacteria of the phylum Bacteroidetes, efficiently inhibit host de novo synthesis of even chain sphingolipids (Heaver et al. 2018; Johnson et al. 2020). Moreover, colonization with gut microbiota suppresses the sphingolipid synthesis pathway as well as the expression of components of sphingosine-1-phosphate signaling in the liver sinusoidal endothelium (Formes et al. 2021). Interestingly, sphingosine-1-phosphate signaling is involved in region-specific angiogenesis in the developing brain. The germinal matrix, a primordial brain tissue giving rise to the striatum that is highly susceptible to hemorrhage, sphingosine-1-phosphate receptors, and the Gα-protein-regulating guanine nucleotide exchange factor Ric8a, is engaged in the regulation of germinal matrix angiogenesis via p38 mitogen-activated protein kinase activation (Ma et al. 2017). However, so far, the functional role of microbiota-derived metabolites acting on the brain microvasculature remains poorly explored.

Apart from remote effects of gut commensals on the brain microvasculature, modulation of the gut microbiota influences pathological angiogenesis at the choroid of high-fat diet–fed mice in a laser-induced photocoagulation model of age-related macular degeneration (Andriessen et al. 2016). Demonstrating the contribution of the gut microbiota, choroidal neovascularization was reduced in high-fat diet–fed mice that were treated with antibiotics or by fecal microbiota transfer. The intestinal microbiota of the high-fat diet–fed mice augments the recruitment of microglia and other mononuclear phagocytes that play a central role in the disease progression.

CONCLUDING REMARKS

While during the past decade the influence of the gut microbiota on epithelial cell physiology and immunity was comprehensively studied, we are just beginning to appreciate the broad implications of the commensal microbiota on endothelial cell functions and its role in the adaptation of organotypic vasculatures. So far, the impact of microbial colonization on epithelial–endothelial communication remains a neglected but certainly relevant area connecting functional microbiome research with vascular biology. Indeed, there is first evidence for the communication of microbiota-derived remote signals with organotypic endothelia, required to fine-tune immunosurveillance and to adapt organ physiology and metabolic processes. First prominent examples of microbiota-dependent changes in endothelial phenotypes are the formation of discontinuously sealed button-like junctions in the lacteals of small intestinal villus structures influencing lipid uptake or altered immune zonation of liver sinusoids (Suh et al. 2019; Gola et al. 2021). Most likely, future studies will reveal additional signaling active metabolites originating from colonizing microbial communities (Roberts et al. 2018; Johnson et al. 2020), but also further define the microbiota's capacity to influence epithelial and immune-related signals, which may act on the microvascular endothelia of remote organs.

ACKNOWLEDGMENTS

The authors state that no conflicts of interest exist. C.R. acknowledges funding by a project grant from the Boehringer Ingelheim Foundation (cardio consortium “novel and neglected cardiovascular risk factors”), the Forschungsinitiative Rheinland-Pfalz and ReALity, the BMBF Cluster4Future CurATime (MicrobAIome; 03ZU1202CA), and a Fellowship of the Gutenberg Research College at the Johannes Gutenberg-University Mainz. K.K. acknowledges funding by the DZHK “Promotion of women scientists” Excellence Programme. K.K. is a member of Young DZHK. C.R. is a DZHK Scientist. C.R. is a member of the Centre for Translational Vascular Biology (CTVB) and a member of the Research Center for Immunotherapy (FZI) at the University Medical Center Mainz.

Footnotes

Editors: Diane R. Bielenberg and Patricia A. D'Amore

Additional Perspectives on Angiogenesis available at www.perspectivesinmedicine.org

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