Gut microbiota and renin-angiotensin system: a complex interplay at local and systemic levels

Abstract

Gut microbiota is a potent biological modulator of many physiological and pathological states. The renin-angiotensin system (RAS), including the local gastrointestinal RAS (GI RAS), emerges as a potential mediator of microbiota-related effects. The RAS is involved in cardiovascular system homeostasis, water-electrolyte balance, intestinal absorption, glycemic control, inflammation, carcinogenesis, and aging-related processes. Ample evidence suggests a bidirectional interaction between the microbiome and RAS. On the one hand, gut bacteria and their metabolites may modulate GI and systemic RAS. On the other hand, changes in the intestinal habitat caused by alterations in RAS may shape microbiota metabolic activity and composition. Notably, the pharmacodynamic effects of the RAS-targeted therapies may be in part mediated by the intestinal RAS and changes in the microbiome. This review summarizes studies on gut microbiota and RAS physiology. Expanding the research on this topic may lay the foundation for new therapeutic paradigms in gastrointestinal diseases and multiple systemic disorders.

INTRODUCTION

A growing number of studies indicate the critical role of gut microbiota in health and disease. It seems that the interplay between the host and its microbiome is complex and bidirectional. On the one hand, various pathological states, like gastrointestinal diseases, diabetes, hypertension, or depression, may shape the composition and activity of microbiota (1). On the other, gut bacteria and their metabolites may influence the host homeostasis, triggering or contributing to the initiation of pathological processes. (2–4). The critical link in this interaction may be the renin-angiotensin system (RAS). The local gastrointestinal RAS (GI RAS) deserves special attention due to its proximity to the intestinal lumen—the habitat of gut microflora. The GI RAS is involved in glycemic and electrolyte homeostasis, inflammatory process, carcinogenesis, aging-related changes, and many other functions. By modulating the GI RAS, gut bacteria may impact these processes. At the same time, the effects of the RAS-targeted therapies might be mediated, in part, by their actions on the GI RAS and the gut microbiome. This review summarizes the biological role of RAS and current evidence on its reciprocal relationship with microbiota (see Fig. 1).

Figure 1.

Key interactions between gut microbiome and renin-angiotensin system (details are given in the text). ACE1, angiotensin-converting enzyme 1; ACE2, angiotensin-converting enzyme 2; ANG I, angiotensin I; ANG II, angiotensin II; ANG (1–7), angiotensin (1–7); AT1, type 1 angiotensin II receptor; AT2, type 2 angiotensin II receptor; BP, blood pressure; B⁰AT1; broad neutral amino acid transporter 1; LPS, lipopolysaccharide; MAS, Mas receptor; RAS, renin-angiotensin system; SCFA, short-chain fatty acids; TMA, trimethylamine; Trp, tryptophan.

SYSTEMIC RAS

In the mid-1970s, the classical RAS consisted of circulating renin, angiotensinogen, angiotensin I, angiotensin II, and angiotensin-converting enzyme (ACE) (5). Since then, the view of the RAS has been gradually expanded by the addition of new elements to the system. These include the (pro)renin receptor, which retains and activates renin in tissues, whereas the ACE2–MAS axis mainly counteracts angiotensin II effects (6). The systemic RAS is a major regulator of cardiovascular and renal functions and plays a crucial role in controlling blood volume and pressure (7). However, under pathophysiological conditions, the effects of the RAS can intensify, triggering inflammation and structural remodeling, promoting cardiac, and vascular damage (8).

Circulating renin, mainly produced by the kidneys, is responsible for the first and rate-limiting step in the RAS cascade. It hydrolyzes angiotensinogen, a liver-secreted peptide, to create angiotensin I. Following that, ACE1, a membrane-bound exopeptidase predominantly expressed in the pulmonary endothelium, cleaves angiotensin I to form the octapeptide angiotensin II (9). The latter is the most potent, biologically active component of the RAS, inducing all of the system's classical actions, such as blood pressure increase, vasoconstriction, tissue remodeling, and proinflammatory and profibrotic effects (10). Angiotensin II stimulates the AT1 and AT2 receptors, which usually mediate opposite functions (11). Most effects of angiotensin II are conveyed by the AT1 receptors (12), which form the pathway known as the ACE1-AT1R axis. The alternative RAS axes involve the activation of the AT2 receptor instead of AT1 and the ACE2-MAS axis; angiotensin-converting enzyme II (ACE2) can form angiotensin (1–7), which is a Mas-receptor agonist (MAS).

Blocking various RAS components proved to be an effective therapy in multiple disorders, such as hypertension, diabetes, and renal or heart failure. In fact, due to multitargeted actions, ACE-inhibitors and angiotensin receptor blockers became a cornerstone of the strategies to reduce cardiovascular risk. Their effects go beyond lowering blood pressure alone, most likely owing to the local (tissue) RAS interactions.

LOCAL GASTROINTESTINAL RAS

Components of the RAS are found locally within tissue systems, such as the brain, heart, kidney, adipose tissue, skeletal muscles, adrenal glands, and last but not least, digestive organs (13). The most significant contribution of these local systems is their activity at the cellular level via paracrine and autocrine mechanisms. They mediate cell-specific effects on growth, proliferation, and metabolism (13). It should be noted that they may interact with endocrine RAS and other peptide systems (e.g., the endothelin system) on various levels (14). Notably, the concept of tissue RAS explains the beneficial effects of ACE inhibitors and angiotensin receptor blockers that are independent of blood pressure change, e.g., the cardioprotective outcome of these drugs (15).

This review focuses on the gastrointestinal RAS (GI RAS) as the system is the most likely to relate to gut microbiota. GI RAS regulates intestinal physiological functions, such as electrolyte homeostasis, digestion, peptide transport, glucose, sodium, and water absorption, gastrointestinal motility, and secretion through the intestinal epithelium (13, 16, 17). Moreover, this system partly controls the mechanisms responsible for intestinal inflammation, apoptosis, fibrosis, and mucosal protection (16, 18). Similar to the systemic RAS, the GI RAS effects depend mainly on balance between the ACE1-AT1R and the ACE2-MAS axes (19). Generally, the activation of the ACE1-AT1R axis causes vasoconstriction and is involved in the induction of apoptosis, vascular remodeling, atherosclerosis, and inflammation (20, 21) In contrast, the ACE2-MAS axis protects the gastrointestinal mucosa and promotes its regeneration after damage (18).

Figure 2 summarizes major pathways and their effects, and Table 1 lists the GI RAS key components expressed in the intestines.

Figure 2.

Main pathways and effects of the gastrointestinal renin-angiotensin system. ACE 1, angiotensin-converting enzyme 1; ACE 2, angiotensin-converting enzyme 2; AT1R, type 1 angiotensin II receptor; AT2R, type 2 angiotensin II receptor; MAS, Mas receptor.

Table 1.

Expression of key components of the gastrointestinal renin-angiotensin system in the intestine

Tissue	ACE1	ACE2	AT1R	AT2R	ANG II	MAS	References
Small intestine
Brush border of epithelial cells	+	+	+				(22–24)
Mesenteric microvascular endothelium	+	+					(23, 24)
Muscularis mucosa		+	+	+			(24)
Muscularis propria		+					(24)
Circular and longitudinal muscle layers			+	+		+	(25–27)
Myenteric plexus			+			+	(25–27)
Small vessels in the muscularis propria			+				(25, 26)
Crypt and crypt-villus junction epithelial cells					+		(22)
Mucosal mast cells						+	(27)
Large intestine							(28)
Surface epithelial cells	+		+	+			(23, 29)
Crypts			+	+			(29)
Lamina propria macrophages			+				(29)
Myofibroblasts			+				(29)
Mucosal vessel walls			+				(29)
Mesenteric microvascular walls	+	+					(29)
Colonic dorsal root ganglion neurons						+	(30)

ACE1, angiotensin-converting enzyme 1; ACE2, angiotensin-converting enzyme 2; AT1R, type 1 angiotensin II receptor; AT2R, type 2 angiotensin II receptor; ANG II, angiotensin II; MAS, Mas-receptor.

RAS AND GUT MICROBIOTA IN HEALTH AND DISEASE

Cardiovascular System

Recent studies show that there is a crosstalk between the gut microbiome and the cardiovascular system. Gut microbiota-derived molecules may affect cardiovascular homeostasis acting directly on the blood vessels and the heart (31, 32). Reciprocally, changes in the cardiovascular system may affect gut microbiota by altering the structure and function of bacterial habitat, i.e., intestines (33). It has been found that gut bacteria may affect the circulatory system indirectly by modulating gut sympathetic activity (34) and RAS. In this regard, both the sympathetic nervous system and RAS are key factors contributing to numerous cardiovascular pathologies, including hypertension and heart failure (35).

The interplay between the microbiome and RAS is most evident in the regulation of blood pressure. Experimental studies suggest an important role for gut microbiota in developing angiotensin II-induced hypertension and organ damage related to hypertension. For example, Karbach et al. (36) showed that germ-free mice infused with angiotensin II had lower blood pressure and less cardiac fibrosis than mice that received a fecal transplant before the experiment or sham germ-free group. In addition, it has been found that the administration of probiotics, i.e., bacteria intended to have health benefits, reduces blood pressure (37–39).

It has been found that bacterial proteases interact in vitro with human RAS peptides (40). Furthermore, research indicates that ACE inhibitory peptides are released during the bacterial fermentation processes (41, 42) producing a blood pressure-lowering effect (43). For example, Nakamura et al. showed that two tripeptides (Val-Pro-Pro and Ile-Pro-Pro) with an inhibitory effect on ACE were produced in milk fermented by the Lactobacillus helveticus (44), which resulted in a decrease in blood pressure (45). The ability of individual Lactobacillus helveticus to produce antihypertensive peptides is most likely related to their proteolytic system's completeness and efficiency (46). A study conducted by Ramchandran and Shah (47) suggests that among the probiotic organisms, Bifidobacterium longum 5022 has the maximal ACE-inhibitory potential.

Moreover, prebiotics and probiotics may shift GI RAS balance towards the ACE2-MAS axis. It has been shown that inulin or Lactobacillus casei supplementation received by mothers prevented high-fat diet-induced hypertension in offspring, which was associated with the lower ACE1 and AT1 receptor expression and activation of ACE2 (48). Those data suggest that dietary approaches with probiotic and prebiotic supplementation may be an attractive therapeutic option in the treatment or primary prevention of hypertension. However, further investigation is warranted.

Importantly, gut microbiota produces many biologically active compounds, i.e., bacterial metabolites that may interact with the GI RAS and systemic RAS. Short-chain fatty acids (SCFA), such as butyrate, acetate or propionate, affect blood pressure by modulating local RAS in the kidneys. For example, sodium butyrate inhibits angiotensin II-induced hypertension by suppressing the (pro)renin receptor and the intrarenal RAS (49). Acetate supplementation also resulted in the downregulation of the local RAS in the kidney and heart (50). On the contrary, succinate, an intermediate in microbial propionate synthesis, has recently emerged as an activator of the renal RAS through the SUCNR1 signaling (51). In addition, gut bacteria-derived uremic toxins such as indoxyl sulfate probably cause chronic kidney injury by activating intrarenal RAS (52).

Another important group of bacterial metabolites is methylamines, i.e., trimethylamine (TMA) and its oxide (TMAO). Their pathological role, especially in the cardiovascular system, is widely discussed; however, the potential mechanisms of action remain obscure (3). Several lines of evidence suggest that RAS, at least in part, may mediate their biological effects. It has been shown that TMAO infusion alone did not increase blood pressure but combined with a low dose of angiotensin II, TMAO prolonged the hypertensive effect (53). We have recently shown that TMAO causes a favorable shift in the RAS axes in heart failure-induced remodeling. Namely, chronic treatment with TMAO in rats reduced expression of AT1 receptor with a concomitant increase in the expression of AT2 receptor in the heart. Similar changes were observed in the kidneys (32).

It must be emphasized that changes in RAS activity, presumably locally in the intestines, may reciprocally modulate gut microbes. Angiotensin II treatment significantly altered gut bacteria and their metabolites in plasma and feces (54). In line with these findings, chronic angiotensin II infusion in the rat model of hypertension is associated with gut microbiota changes. Specifically, there was a decrease in microbial richness and an increase in Firmicutes/Bacteroidetes ratio. Moreover, treatment with minocycline significantly lowered blood pressure in angiotensin II–infused rats (4). However, the possible role of microbiota in the latter findings should be interpreted with caution as minocycline is known to have bacteria-independent effects on neuro-immune signaling (55). Finally, changes in RAS activity may modify the gut-blood barrier permeability to bacterial metabolites, limiting their systemic effects. It has been shown that treatment with enalapril, an ACE inhibitor, attenuated hypertension-induced disturbances in the intestines, including leaky gut, and decreased TMA passage into the circulation (56).

Absorption and Digestion

Most GI RAS-mediated effects have been shown with respect to water and sodium transport through the intestinal epithelium. In the jejunum, angiotensin II at low doses increased sodium and fluid absorption by stimulating sympathetic activity (57). Conversely, a higher dose with simultaneous pressure response reduced absorption or induced net fluid secretion, probably by forming prostaglandins (58). A possible mechanism for this inconsistent outcome may be the activation of different axes; Jin and others showed that stimulation of AT2 receptors improves intestinal sodium and water absorption, whereas AT1 receptors inhibited absorption or stimulated fluid secretion (59). In the proximal colon, angiotensin II promotes water and sodium absorption by stimulating conjugated transport of NaCl (60). It is worth noting that disturbances in endogenous ion transport alter the intestinal microenvironment and thereby modulate the gut microbiome composition. This concept has been elegantly demonstrated using various ion transport knockout models (61). For example, sodium/proton exchanger NHE3 deficiency results in a higher luminal pH, promoting dysbiotic and proinflammatory shifts in the intestinal microbiome (62). On the other hand, gut microbes may reciprocally affect water and ion homeostasis. Traditionally, clinical medicine's focus was on the water-electrolyte disturbances caused by the local action of pathological bacteria producing diarrhea. However, accumulating evidence points to the critical role of gut bacteria composition and their metabolites in the systemic RAS-dependent control of water-electrolyte balance. A perfect example is the above-mentioned control of renin release by SCFA. It has been found that SCFA receptors (i.e., Olfr78 and Gpr41) in the renal juxtaglomerular apparatus mediate renin secretion in response to the signals from gut microbiota, which is weakened by antibiotic treatment and in Olfr78 and Gpr41 knockout mice (63).

Apart from water-electrolyte balance, the GI RAS plays a role in peptides digestion. ACE1 and ACE2 of the intestinal brush border are considered peptidases, enabling digestion and absorption of peptides (64). ACE2 increases the amino acid transporter activity (B⁰AT1), which has been recently linked to the microbial ecology in the gut. Hashimoto et al. (65) demonstrated that the reduction of tryptophan uptake in ACE2-knock out mice resulted in impaired expression of antimicrobial peptides and consequently altered gut microbial composition. Since angiotensin (1–7) has been shown to increase jejunal tryptophan absorption (66), it may similarly modulate the gut microbiome. In this regard, a very recent study by Oliveira et al. (67) showed that deletion of MAS, angiotensin (1–7) receptor, in mouse model produced lower neutral amino acids absorption and changes in the gut microbiome. Specifically, the malnourishment profile leads to a compensatory increase in intestinal villi length and an unfavorable shift in bacterial composition.

Glucose Homeostasis

Patients with diabetes are characterized by an unfavorable shift in bacterial composition, especially with regards to butyrate and endotoxin-producing bacteria (68). Moreover, an altered microbiome has been observed in prediabetic patients (69) and recent findings highlight the role of the gut microbiome in glucose homeostasis. Notably, bacterial metabolites like short-chain fatty acids can affect blood glucose levels and insulin release (70). A study conducted by Lu et al. (61) showed that acetate produced by intestinal microbiota might be involved in the diabetic-induced early kidney injury acting via RAS modulation. Antibiotic treatment in diabetic rats markedly lowered plasma acetate, inhibited intrarenal RAS activity, and reduced kidney damage. Also, several probiotic strains have been found to exert antidiabetic modulatory effects, i.e., by inhibiting enzymes that increase glucose absorption in the intestines (71) and by regulating postprandial blood glucose (72). In this regard, it is worth noting that alterations in GI RAS activity induced by diabetes disturb intestinal glucose transport and thereby contribute to postprandial hyperglycemia (73). Diabetes promotes glucose transport via sodium/glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2) (74). Angiotensin II inhibits intestinal glucose uptake in a rapid and dose‐dependent manner through the SGLT-1 (75). Interestingly, in diabetic rats, ACE1 and AT1 receptors on the brush border were reduced. There was a disproportionate increase in GLUT2 expression compared with SGLT1, which significantly reduced RAS-dependent inhibition of glucose uptake via SGLT1 (76).

On the other hand, diabetes increases the expression of ACE2 and MAS receptors in the jejunum. Angiotensin (1–7), a critical component of the ACE2-MAS axis, was also able to inhibit glucose uptake and significantly improved oral glucose tolerance in type 1 diabetes (17). Therefore, the activity of ACE1 and ACE2 determines the overall rate of glucose transport through the intestinal epithelium. In this respect, recent studies showed that probiotics could activate the ACE2-MAS axis. Bifidobacterium longum supplementation increased the expression of ACE2 and MAS and had beneficial effects on the glycemic and lipid profiles (77). Interestingly, Verma et al. (78, 79) showed that the engineered probiotic species Lactobacillus paracasei may serve as a live vector for oral delivery of ACE2 and angiotensin (1–7) to attenuate diabetic retinopathy in animal models. Therefore, probiotics-based regulation of RAS emerges as an important therapeutic approach in managing metabolic diseases and diabetic complications.

Inflammation

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a group of serious gastrointestinal disorders, where inflammation plays a central role. Although the IBD etiology is not fully understood, it is generally believed that improper activation of the intestinal mucosal immune system is the main contributor to this disorder (80). Recent years have provided more evidence that the diverse microbiota-host interactions influence the immune response and inflammation within the intestine (81). It is postulated that altered composition of gut microbiota contributes to inflammatory diseases like IBD. In fact, clinical trials show promising results of the use of fecal microbiota transplantation in ulcerative colitis, but the evidence for its efficacy is still limited (82). In addition, there is currently little knowledge of the exact immune mechanisms stimulated by microbiota modulation. However, the interplay with RAS is highly expected since extensive literature suggests a pivotal role of RAS in the inflammatory process.

In general, the renin-angiotensin II cascade promotes colitis. Overexpression of renin significantly increases the large intestine’s susceptibility to inflammation (83). Also, many experimental studies have shown that ACE inhibitors or AT1 receptors blockers alleviate chemically induced colitis (84–86). There are several potential mechanisms by which RAS promotes inflammation. Among them, stimulating TH17 activation seems to be of particular interest in terms of a possible microbiota-RAS-inflammation linkage. Angiotensin II both directly (via JAK2/STAT1/3) and indirectly (via cytokine production) promotes lymphocyte polarization in TH17 but not in TH1 (87). Also, data show that activated CD4+ T cells have high expression of AT1 receptors on their surface, and the RAS promotes autoimmunity through TH1/TH17 (88). Recent studies suggest that TH1/TH17 balance is modulated by gut microbiota. Namely, fecal transplants from IBD donors induce a greater proportion of Th17 cells in the gut than healthy donors (89). In line with this, the proportion of Th17 cells was reduced following microbiota transplant from healthy individuals (90). Also, colonization with a certain Escherichia coli induced systemic TH17 immunity and aggravated colitis development (91).

RAS may also contribute to the translocation of leukocytes into extravascular compartments during inflammation by increasing leukocyte adhesion to the endothelium. Activating AT1 receptor signaling, angiotensin II promotes the colonization of leukocytes, followed by an increase in cell adhesion molecules (86). Other studies also confirmed that pharmacological inhibition of ACE and angiotensin receptors decreases the severity of colitis by reducing the infiltration of inflammatory cells (84). Recently, mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), which belongs to endothelial cell adhesion molecules, has become a potential target for IBD treatment (92). MAdCAM-1 increases dramatically during inflammation (93) and may contribute to the development of colitis. It seems that both GI RAS and gut microbiota play a role in MAdCAM-1 regulation. Western diet-induced dysbiosis has increased its expression (94), whereas probiotics exerted the opposite effect (95). AT1 receptor also affects the expression of MAd-CAM-1 by controlling the translocation of NF-κB into the nucleus (86, 96). Therefore, appropriate modulation of bacterial composition and GI RAS activity may be a new target in IBD therapy through the modification of MAdCAM-1.

It is worth noting that the ACE2-MAS axis protects the mucous membrane and aids in the repair process after damage. In particular, angiotensin (1–7) protects the gastric mucosa by reducing inflammatory cytokines (97). It can be speculated that inflammatory response to bacterial endotoxemia is related to ACE2 actions. Ye et al. (98) showed that cells challenged with lipopolysaccharide (LPS) had upregulated expression of renin, angiotensin II, ACE1, and AT1 receptors. At the same time, the mice model of LPS-induced lung injury exhibited lower expression of ACE2. Injection of ACE2 attenuated inflammation and significantly improved the pathological injury.

Taking together, the GI RAS seems to play an essential role in the inflammatory process in the intestine and, therefore, may be a mediator of microbiota-induced effects. Proper selection of microbiome-based therapeutics, i.e., probiotics or prebiotics, in terms of activity against RAS, may introduce new strategies in inflammatory or autoimmune diseases management. However, it is necessary to gain a complete understanding of the microbiome-RAS-related effects before the widespread implementation of such therapeutic interventions.

On the other hand, it needs to be stressed that such interactions are bidirectional. Changes in the intestinal environment caused by inflammation promote dysbiotic shifts in bacterial composition. For example, inflammation produces an expansion of Enterobacteriaceae populations (99), which exacerbates inflammation and epithelial damage (100). At least, in theory, it may be the altered activation of GI RAS during inflammation that makes the intestinal habitat more propathogenic. The already mentioned study by Oliveira et al. (67) demonstrated that MAS receptor deletion produced dysbiosis, which was associated with increased proliferation and cell inflammation, most likely due to overproduction of LPS.

Carcinogenesis

Much attention has been paid to the pro- and anticarcinogenic role of the gut microbiome. A broad description of the topic is beyond the scope of this review and has been elegantly summarized elsewhere (101). We would like to highlight the existing evidence for an association between cancer and microbiota composition changes (102–104). Some studies revealed distinct commensal bacteria that promote tumor development in genetically predisposed animals (105). Others demonstrate that targeted changes in gut bacteria composition reduces carcinogenesis in mouse models of colorectal cancer (106). A number of possible mechanisms behind bacterial actions have been proposed, including inflammation, metabolic activity, and genotoxicity (107).

Likewise, by stimulating the ACE1-AT1R axis, the RAS plays a role in angiogenesis, cell proliferation, and fibrosis, which constitute crucial carcinogenesis processes (108, 109).

In fact, the GI RAS and microbiome may share the same signaling pathways. A prominent example is the Toll-like receptors (TLRs) which recognize pathogen-derived molecules like LPS and have an established role in tumor development. For example, prebiotic treatment counteract neoplastic lesions via downregulation of TLR4 (110). Furthermore, carcinogenic actions of pathogens like Fusobacterium nucleatum or Escherichia coli have been linked to TLR4 signaling (111, 112). Likewise, angiotensin II upregulates TLR4 expression, thereby contributing to the development of liver fibrosis (113). Importantly, several lines of evidence suggest a synergy between RAS and microbiome effects on TLR. Simultaneous treatment with angiotensin II and LPS exerted a much higher level of TGF-β in hepatic fibrogenesis than either agent alone (113). Analogously, cotreatment with probiotic and AT1 receptor blocker exerted a more potent and synergistic inhibitory effect on liver fibrosis than either agent administered independently (114).

Another important mechanism by which RAS exerts a carcinogenic effect is the stimulation of tumor angiogenesis - angiotensin II activates the expression of several angiogenesis and growth factors, including vascular endothelial growth factor (VEGF) (109) and angiopoietin 2 (115). Moreover, cancer-related angiogenesis was decreased after administrating captopril (ACE inhibitor) and irbesartan (AT1 antagonist) in a mouse model of colorectal cancer (116). In light of this, bacterial ligands also promoted angiogenic response by the upregulation of VEGF receptor 2 (117), whereas probiotics exerted the opposite effect downregulating VEGF and angiopoietin 2 (118).

As described in Local Gastrointestinal RAS, the ACE2-MAS axis with angiotensin (1–7) has an inhibitory effect on many angiotensin II-induced processes. However, its role with respect to cancer development is complex and not fully elucidated. Generally, angiotensin (1–7) has antimetastatic, antiproliferative and antiangiogenic effects (119). Surprisingly though, it also promoted migration and invasion of renal cell carcinoma (120). Nevertheless, the ACE2-MAS axis constitutes a promising therapeutic target and represents a potential factor that underlies microbiome-related effects. It has been shown that modulation of bacterial composition may impact the amount of ACE2 in the intestine (121–123). In line with this, it has been shown that ACE2 gene expression in tissues from colorectal cancers was positively correlated with the abundance of specific bacterial taxa, most prominently Chlamydia (124). Therefore, pro- or anticarcinogenic features of a microbial community may be, at least in part, due to changes in the RAS activity.

Aging

Aging is associated with various physiological and pathophysiological changes in local RAS activity and other gastrointestinal functions, including dysfunction of the intestinal epithelium, gastrointestinal motility, and absorption (125, 126), as well as increased susceptibility to enteritis (125, 127). RAS components may cause or aggravate the degenerative changes associated with aging in the intestine (19). On the other hand, the physiological aging process affects the local expression of RAS. Garrido-Gil et al. (128) reported that older rats showed higher colonic expression of the AT1 receptor but lower expression of the AT2 receptor than younger rats. Also, the ACE1/ACE2 ratio was elevated in adult rats compared with juvenile animals in the jejunum and colon. This finding suggests that the ACE2 activity decreases with age and the GI RAS balance moves towards the ACE1-AT1R axis (19).

Such pathological changes induced by aging are likely to alter intestinal habitat and presumably affect the microbial community (129). On that account, some studies have reported that composition, diversity, and metabolic function of gut microbiota change with age (130, 131). Alternatively, studies using animal models suggest that pathogenic gut bacteria and their metabolites contribute to frailty, aging-associated diseases, and reduced longevity (130, 132, 133). Therefore, therapeutic interventions aimed at healthier aging and lifespan extension should target microbiota and their habitat, i.e., GI RAS activity and other intestinal functions. Importantly, microbiome-based therapy may act by shifting the GI RAS balance towards the ACE2-MAS axis. It has been demonstrated that recombinant probiotics can increase circulating levels of angiotensin (1–7) and decrease levels of angiotensin II in a well-characterized rodent model of aging (134). All in all, the knowledge of the microbiome-RAS relationship in aging-related pathologies is still limited but may prove useful in the effective healthcare of the elderly.

COVID-19

ACE2 has recently gained special attention due to a novel coronavirus outbreak. Published data confirmed that ACE2 is the receptor for SARS-CoV-2 (135). Since the expression of ACE2 is very high in enterocytes, the intestines and gut microbiota emerge as important players in SARS-CoV-2 infection (136). Zang et al. (137) demonstrated explicitly that SARS-CoV-2 could infect ACE2+ mature enterocytes in the human small intestine, a mechanism mediated by TMPRSS2 and TMPRSS4 proteases. Importantly, the infection reduces ACE2 expression in the lung and other tissues due to spike protein-mediated downregulation of ACE2 (138), which may explain multiorgan failure in COVID-19 (139, 140). Therefore, the administration of ACE2 soluble forms may provide a double beneficial effect during SARS-CoV-2 infection by slowing virus entry into host cells while ensuring the putative preservation of ACE2 contraregulatory functions on RAS, thus assisting in lung injury defense (141).

Ample evidence indicates that SARS-CoV-2 infection causes a defect of the gut-blood barrier, increasing the penetration of microbes, bacterial lipopolysaccharide, or peptidoglycan into the circulation, possibly disrupting the immunological reaction to COVID-19 infection, and resulting in multisystem dysfunction or septic shock (139, 142, 143). It was suggested that in the pathogenesis of SARS-CoV-2, any disturbances in host-microbiota crosstalk could act as an initiating or reinforcing factor (144).

Hospitalized patients with COVID-19 had a disparity in intestinal microflora diversity, characterized by lower levels of probiotic bacteria (e.g., Lactobacillus and Bifidobacterium) (145) and a significantly higher abundance of opportunistic pathogens (e.g., Streptococcus, Veillonella, and Actinomyces) (146). It has been proposed that gut microbes modulate colonic ACE2 and thereby influence COVID-19 infectivity. Feng et al. (121) investigated the effect of enteritis caused by Salmonella enterica and treatment with segmented filamentous bacteria, a probiotic, on ACE2 expression. They found that the coronavirus receptor expression was elevated in both cases. On the contrary, Yang et al. (122) demonstrated that reconstitution of the gut microbiota in germ-free rats markedly decreased the colonic ACE2 expression. The latest study on mice supports these results as ACE2 levels in intestines were significantly higher in germ-free animals than in conventional mice. The germ-free phenotype was partially recapitulated by antibiotic treatment (123).

PERSPECTIVES

Despite numerous reports about the influence of gut bacteria on the host and vice versa, there is still much to be elucidated regarding mechanisms determining this interaction. Current evidence suggests that gut microbiota and their metabolites may modulate the RAS. The pleiotropic actions of RAS in homeostatic processes support its role in mediating microbiota-related effects. On the other hand, changes in the intestinal habitat caused by the GI RAS disturbances related to hypertension and other diseases may shape microbiota metabolic activity and composition. Also, it can be speculated that the effects of RAS-targeted therapies can be mediated, in part, by their actions on the GI RAS and microbiome. Both the RAS and gut microbiome play a role in glycemic and electrolyte homeostasis, inflammation, carcinogenesis, and aging-related changes. Still, many of these connections remain largely underinvestigated. Nevertheless, appropriate manipulation of the RAS, either directly or by altering gut bacteria, could be beneficial in treating many pathologies. Further studies on the reciprocal relation between RAS and gut bacteria are needed to lay a foundation for new therapeutic paradigms.

GRANTS

K. Jaworska was supported by the Foundation for Polish Science (FNP).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

K.J. and M.U. conceived and designed research; M.K. prepared figures; K.J. and M.K. drafted manuscript; K.J., M.K., and M.U. edited and revised manuscript; K.J., M.K., and M.U. approved final version of manuscript.