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The gut microbiota is a key element in the regulation of various human processes, including metabolisms, immunity, and the overall health. Hypertension, like other metabolic and chronic diseases, has several contributing factors, some of which have not been clarified. Known factors include diet, genetic inheritance, hormonal imbalance, and inflammation.
- food peptides
- microbiota
- hypertension
1. Introduction
The gut microbiota is a key element in the regulation of various human processes, including metabolisms, immunity, and the overall health. Factors that influence the growth, microbial diversity and composition of the gut include diet, genetic inheritance, and the use of medications especially antibiotics [1][2][1,2]. Food is, however, considered the main contributor to the composition and functional capacity of the microbiota; as such, there is a growing body of research emphasizing the food-microbiota interaction as a modulator of health and disease [2][3][4][2,3,4]. There are several microbial communities in the gut meanwhile, Firmicutes (F) and Bacteroidetes (B) are the most abundant. Ratios of F/B are used to assess gut microbiota imbalances commonly known as dysbiosis and their relationships to health [5]. The dysbiosis of gut microbiota has then been linked to the development of conditions such as hypertension, diabetes, cardiovascular diseases, and obesity. Amongst the diseases, hypertension growth is projected to be present in 1.56 billion worldwide by 2025 [6][7][6,7]. Currently, hypertension accounts for about 13% of all deaths, or an estimated seven million premature deaths yearly [8]. One way to decrease the incidence of hypertension can be through the modulation of gut microbiota which in turn can inhibit or attenuate immune responses associated with chronic inflammation [9] and other biomarkers of hypertension [10].
2. Gut Microbiota
The human gastrointestinal tract comprises communities of microbes made of bacteria, fungi, and viruses with an estimated count of more than hundred trillion and plays important roles during regular biochemical processes while also modulating the overall health of the host [11][12][20,21]. Generally, five major divisions at the phyla level of bacteria are present in the human gut: Firmicutes, Actinobacteria, Fusobacteria, Proteobacteria, and Bacteroidetes. However, Firmicutes and the Bacteroidetes are more numerous than the remaining three others, accounting for up to 90% of the total microorganisms [11][20]. Under a gut microbiome balance, the ratio of Firmicutes to Bacteroidetes (F/B) is expected to be equivalent to one. Under different conditions, including metabolic disorders, chronic diseases, the use of antibiotics, and dietary habits, there can be an imbalance of the gut microbiota, to which the term dysbiosis has been assigned [11][20]. In addition to the F/B ratio, alpha diversity (i.e., the diversity of microorganisms within a sample) is used to characterize the state of the gut microbiota. Indices of alpha diversity include community richness (estimation of the total number of species), observed species (number of different operational taxonomic units per sample), and abundance-based coverage [13][14][22,23]. The gut can also be characterised by Alpha diversity (microbial diversity of an ecological community) [14][23], and community richness, a metric to estimate the total number of species, including the Chao 1 abundance-based coverage estimator index and observed species (the number of different operational taxonomic units, OTUs, per sample). Microbial communities of the gut differ in composition and their location in the gastrointestinal tract and have co-evolved with the host for millennia to form a mutually beneficial complex role [15][16][27,28]. The gut microbiota composition is shaped by environmental factors, diet, and possibly also by host genetics [17][29], geographic location, surgery, smoking, depression, and living conditions (urban or rural), and by the chemical, nutritional, and immunological gradients along the gut [18][30]. The microbiota can also be shaped by the host’s immune system since intestinal epithelial cells produce antimicrobial proteins such as angiogenin-4, α-defensins, cathelicidins, histatins, lipopolysaccharide-binding protein, lysozymes, secretory phospholipase A2 and lectins [19][31] which often are located in the mucus layer due to poor diffusion through the mucus or luminal degradation [20][21][32,33].
The effect of diet on the formation of the colonic microbiota depends on the availability of microbiota-accessible carbohydrates present in dietary carbohydrates or fibres [22][34]. The beneficial effect of human milk on the infant microbiota is due to the presence of fucosylated oligosaccharides (2′-fucosyllactose, lactodifucotetraose, 3-fucosyllactose) that is used for example by Bifidobacteria (Actinobacteria phylum) and several species of the Bacteroides phylum [23][24][35,36], N-acetylgalactosamine, galactose and N-acetylglucosamine [25][26][37,38] found in mucus play a crucial role in mediating the host-microbiota relationship [27][39], and O-glycans that provide an energy source and preferential binding sites for commensal bacteria [28][29][30][40,41,42]. Differences in microbial composition have been associated with chronic disease states, including inflammatory bowel disease, diabetes, and cardiovascular disease [31][43]. In terms of function, microbial metabolites provide key signals that help maintain healthy human physiology. Some benefits that the microbiota offers to the host in the form of physiological functions are, among others, the strengthening of the intestinal integrity or the formation of the intestinal epithelium [32][44], the recovery of energy [33][45], the protection against pathogens [34][46], and the regulation of host immunity [35][47].
3. Gut Microbiota in Hypertension
Hypertension, like other metabolic and chronic diseases, has several contributing factors, some of which have not been clarified. Known factors include diet, genetic inheritance, hormonal imbalance, and inflammation [36][37][38][39][48,49,50,51]. The microbiota impacts on health occur through various processes that include the immune system, the brain, the kidney, and the cardiovascular system. These effects are associated with the production of metabolites (e.g., short-chain fatty acids, polysaccharides, trimethylamine-N-Oxide, biogenic amines, bile acids) [37][38][39][49,50,51], degradation of metabolites (e.g., oxalate) [36][48], electrolyte balance and synthesis of vitamins. Strategies (including the use of bioactive food molecules) that maintain a proper balance of the gut microbiota are then important to maintain optimum physiological processes, optimize the production of microbial metabolites or postbiotics, and control blood pressure to reduce the risks of hypertension.
Physiological Systems Involved in Hypertension: There are several systems that link the gut microbiota to hypertension. A bidirectional communication between the microbiome and the host via the nervous system has been described. Neural pathways from the gut to regions of the brain, such as the paraventricular nucleus, involved in blood pressure (BP) control are impaired in animal models of hypertension [40][41][52,53]. Hypertension activates the sympathetic system which elevates intestinal permeability, increases inflammatory state, and causes microbial dysbiosis [42][54]. It was found for example that elevated sympathetic nerve activity and mild gut pathology in prehypertensive rodents precede hypertension-related gut dysbiosis [43][55], which suggests that strategies to prevent gut dysbiosis can contribute to the prevention of hypertension. The increased intestinal permeability was associated with reduced expression of tight junction proteins, including zonula occludens-1, claudin-1, and occludin, and an imbalance between death and regeneration of intestinal epithelial cells [44][45][56,57]. When the intestinal epithelial barrier is impaired, the invasion of pathogen-associated molecular patterns drives an immune response and leads to systemic and tissue-specific inflammation which also negatively affects blood pressure [44][56]. Accordingly, alterations in the integrity of the intestinal barrier-induced dysbiosis have been suggested as a risk factor for chronic inflammation and hypertension. The mechanisms by which an altered intestinal permeability increases the risks of hypertension include an increase in microbial-derived products such as lipopolysaccharides, trimethylamine N-oxide, short-chain fatty acids (SCFA), and bile acids [44][56]. Additionally, damages to the gut epithelial cells create a less hypoxic environment of the lumen which is needed by the microbiota for aerobic growth [46][47][58,59] and the production of sufficient quantities of useful postbiotic molecules. In fact, the intestines of Angiotensin II hypertensive mice were less hypoxic and correlated with greater aerobic bacteria in feces [48][60]. In hypertensive patients, their fecal samples displayed an alteration of butyrate production with a concomitant increase in plasma of intestinal fatty acid binding protein, lipopolysaccharide, and gut proinflammatory T helper 17 which indicated either an inflammation of the intestine or a gut barrier dysfunction [48][60]. In spontaneously hypertensive rats (SHR), decreased abundance of anaerobic bacteria in feces was also found due in part to the dysfunction of the gut [49][61].
Evidences of the role of the immune system and microbiota on blood pressure exist in the literature [50][62]. Preclinical models for example indicate that subsets of T lymphocytes such as T helper (Th)1, Th2, Th17, and regulatory T (Treg) cells are involved in hypertension by either contributing to the development and maintenance of blood pressure (Th1 and Th17) or protecting against an increase in pressure (Treg cells) [51][63]. A proper balance of the microbiota composition is important to maintain the integrity of the gut and integral homeostasis and regulate physiological processes through different mechanisms including the biosynthesis of specific molecules.
4. Bacterial Products, Hypertension and Food Ppeptides
The gut microbiota produces a variety of metabolites that can enter the bloodstream and serve as signalling molecules in the human host. Bacteria-generated metabolic compounds such as biogenic amines, neurotransmitters, short-chain fatty acids (SCFA), bile acids, and trimethylamine N-oxide [52][53][64,65], as well as bacterial cell wall components (i.e., liposaccharides or LPS) [54][66], have significant effects on host cell physiology. They are then among the mediators that can affect, for example, the renal, neuronal, and cardiovascular systems, and consequently hypertension.
Short Chain Fatty Acids: they are organic acids derived from the fermentation of undigested carbohydrates, which are especially abundant in areas of the gastrointestinal tract dominated by anaerobic microorganisms [67]. Meanwhile, their concentration is determined by the overall microbiome’s composition, the number of individual microorganisms in the colon, and the type of substrate used by the microorganisms. The most abundant SCFAs have 2 to 4 carbon atoms (acetate, propionate, butyrate), while valeric acid (five carbon atoms) and caproic acid (six carbon atoms) are relatively less abundant [70]. Food peptides alone or in combination with carbohydrates can affect the concentration of SCFA in the gut which in turn can affect hypertension and other diseases. A mixture of oligosaccharides and hydrolyzed fish was reported to increase the concentration of propionate but not butyrate in the cecum region of the colon relative to individual doses of either ingredient. The effect varies according to the region of the colon and the type of SCFA as in the proximal colon, the concentration of isobutyrate was significantly higher in rats fed a diet supplemented with protein hydrolysates alone relative to other groups [55][81]. The effect varies based on the mode of administration as whey peptide-based enteral diet increased acetate and propionate concentrations not butyrate in the cecum [56][82].
Polysaccharides: Bacterial polysaccharides in the form of lipopolysaccharides (LPS) and capsular polysaccharides (CPS) are components of cell walls which also serve as storage units and the virulence of factors of species such as Klebsiella pneumoniae and Prevotella spp. [57][58][83,84]. The bacterial polysaccharides are generally associated with inflammation and increased blood pressure because their translocation into the systemic circulation leads to metabolic endotoxemia. In inflammatory mice, the inclusion of oyster hydrolyzed proteins in the diet or hydrolyzed gelatin reduced the concentration of LPS and several markers of inflammation in the blood [59][60][88,89]. In vitro, hydrolyzed whey proteins suppressed LPS-stimulated inflammation by inhibiting LPS binding to the Toll-like receptor 4 of the cells [61][90].
Trimethylamine-N-Oxide: The microbial activities of species of the Clostridia and Enterobacteriaceae families in the gut produce trimethylamine from carnitine, choline, and lecithin, which are found for example in meat and eggs [62][91]. Trimethylamine, upon absorption and transport to the liver, is oxidized by a flavin mono-oxygenase to trimethylamine-N-oxide, a potential hypertensive metabolite that inhibits the activation of bile acid Takeda G protein-coupled receptor 5 (TGR5) thereby causing hyperlipidemia [63][92]. Trimethylamine-N-oxide promotes endothelial inflammation while suppressing endothelial nitric oxide, hence preventing vasodilation in the vasculature [64][65][93,94]. In hypertensive rats, there was an increased plasma concentration of trimethylamine due to increased permeability of the colon, suggesting its role as a marker of colon permeability and possible hypertension [66][95]. Studies that investigated the effects of proteins find either no change in trimethylamine N-oxide or an increase when the intake of proteins was twice the recommended daily value [67][99]. This is likely because animal protein-rich foods typically contain precursors of trimethylamine N-oxide but purified proteins, specifically from plants, their hydrolysates and peptides may have different effects as they will be devoid of the amine precursor compounds.
Bile Acids: Primary bile acids (e.g., cholic acid and chenodeoxycholic acid) are synthesized in the livers, while in the gut they are converted into secondary bile acids through conjugation, dehydroxylation, oxidation and epimerization reactions. Bile acids are essential for metabolism, cell signalling, and the composition of the microbiome [51]. Secondary bile acids such as lithocholic acid and deoxycholic acid reduce the risk of hypertension by being farnesoid X receptors and TGR5 agonists, the regulation of inducible nitric oxide synthase, IL18, and angiogenin pathways [100,101]. The overall effect is reduced inflammation and fibrosis. There are works in vitro demonstrating the capacity of food protein hydrolysates to chelate bile acids, while in vivo, casein hydrolysates stimulated the function of the gut barrier, and the concentration of deoxycholic acid and lithocholic acid, which was attributed to a greater abundance of Eubacterium spp. capable of releasing the 7α-dehydroxylating enzyme necessary for their synthesis [104]. The bile acids chelating effect of peptides is generally associated with cardiovascular diseases and consequently may also affect hypertension by maintaining a proper vascular system.
Biogenic Amines: These are low molecular weight nitrogen-containing organic compounds often formed due to microbial protease. The monoamine histamine and the polyamines spermidine, spermine, cadaverine, and putrescine are implicated in immune homeostasis and hypertension. Gut microorganisms expressing glucuronidase enzymes (e.g., Clostridium species) are able to convert glucuronidated biogenic (norepinephrine, dopamine) to the free form and then help maintain their function as reported in mice [68][105]. Biogenic amines produced in the gut but from foods at the right concentration have a wide range of functions, some of which are related to hypertension. Polyamines (spermidine, spermine, putrescine) play a role in the division of epithelial cells, can regulate ion channels and scavenge free radicals. Putrescine and spermine roles in hypertension include protection against inflammation via the inhibition of caspase-1 and secretion of IL-18 [69][70][107,108]. In pigs, infusion of soy protein hydrolysates through a duodenal fistula twice daily for two weeks increased the concentration of cadaverine and putrescine [71][112]. In acute inflammatory mice, diets containing hydrolysates of casein and whey proteins showed after 18 h consumption an increase in putrescine but a decrease in spermidine and spermine relative to undigested proteins [72][113]. By modulating the production of polyamines in the gut, food peptides may be beneficial but the implication on hypertension is still lacking.
5. Modulation of Gut Microbiota and Hypertension by Food Peptides
Dietary fibres are the main components of the diet that affect the gut microbiota meanwhile, secondary metabolites like polyphenols but also food-derived peptides can act alone or in combination with fibres to maintain the microbial balance [73][74][114,115]. Non-digested peptides can reach the intestinal lumen, where they will be in contact with microorganisms. It was reported that about 1% of gut microorganisms are amino acid-fermenting bacteria, while the colon can get about 3–12 g of proteins and peptides daily [75][76][13,116]. Gut bacteria appear to preferentially ferment peptides over free amino acids, with those belonging to Bacteroidetes having the greatest effects and yielding mainly propionate while the action of Firmicutes produces butyrate [77][117].
Protein hydrolysates and peptides can act by inhibiting the growth of pathogenic bacteria such as Escherichia coli and Clostridium perfringens or those that produce lipopolysaccharides, which trigger the production of inflammatory cytokines [78][132] while also enhancing the growth beneficial species such as Streptococcus thermophilus [79][133]. In hypertensive rat models, purified peptides and hydrolyzed proteins have been shown to lower both systolic and diastolic blood pressure via mechanisms that include lowering the concentration of the vasoconstrictor molecule angiotensin II, reducing the expression of the AT1R receptor (responsible for vasoconstriction) while also correcting (e.g., normalize Firmicutes to Bacteroidetes ratio) the gut microbial imbalance found in hypertensive rats [80][118].
In hypertensive rat models, food-derived peptides also regulate hypertension by increasing the richness of Allobaculum, Bifidobacterium, and Lactobacillus which are related to the inhibition of angiotensin-converting enzyme, lower concentration of the vasoconstrictor angiotensin II which in turn can lower the inflammation of mesenteric blood vessels [81][125]. Inflammatory markers affected include nuclear factor kappa-B, monocyte chemoattractant protein-1, and vascular cell adhesion molecule-1 [82][126]. The beneficial effect of food peptides in hypertensive gut is also associated with a reduce oxidative stress (i.e., less reactive oxygen species and increase activity of antioxidant enzymes), and the prevention of endothelial dysfunction).