Gut Microbiota Modulation in Cardiometabolic Diseases Treatment: Comparison
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The diverse relationship between cardiometabolic diseases (CMD) vulnerability and changes in gut microbiota make-up and metabolites has emphasized that gut microbiota is an unfamiliar modulator of CMD. These connections are possible targets for new CMD therapy. The host–microbiota interaction is made up of various levels at which potential therapeutic interventions can be instituted. These levels include dietary substrates, microbial ecology, and microbiota–host pathways that liberate metabolites that modulate host processes. Agents that inhibit recognized gut microbial enzymes can also be produced. The interesting part of this is that interventions directed at gut microbiota and/or their metabolism in lieu of the host may not necessarily be taken up into the host circulation, hence minimizing the likely adverse effects in comparison to those directed at host metabolism. Among the challenges of therapeutically targeting the gut microbiota are the individual variations, in addition to differences, in gut microbiota make-up, which can affect the action of the medication. This may call for individualized treatment. The gut-microbiota-directed therapeutic concept is based on targeting microbiota compositions, metabolic pathways, and mucosal barrier protection.

  • dysbiosis
  • cardiovascular disease
  • metabolic disease
  • probiotics
  • prebiotics
  • drug development
  • treatment
  • bacteria metabolite

1. Targeting Whole Gut Microbiota

Gut microbiota, apart from acting as a medication target, may be used as a live treatment in the microbial intervention of management of disorders [19][1]. Live microbial therapy and/or whole gut microbiota target include fecal microbiota transplantation (FMT), single-strain microorganism or microbial consortia, and the use of antibiotics [9,19,21][1][2][3].
FMT is the process of direct transfer of healthy microbiota from an individual donor into the gut of a dysbiotic recipient with the aim of restoring the normal intestinal microbiota composition and function [216,217,218,219,220][4][5][6][7][8]. The recipient individual goes through a gut lavage of laxative therapy before undergoing FMT to improve the success rate of FMT [221][9]. FMT has been successfully employed for the treatment of Clostridium difficile infection and is lately gaining attention in the management of cardiometabolic diseases (CMD) [216,222,223,224][4][10][11][12]. A remarkable enhancement of peripheral and liver insulin sensitivity by 176% and 119%, respectively, was observed 6 weeks after fecal transfer from lean healthy individuals to metabolic syndrome patients and the observed enhancement was irrespective of weight differences [222][10]. This form of transplantation brought about a generalized intestinal microbial abundance, especially a higher proportion of butyrate-generating organisms [106,141][13][14]. Furthermore, FMT restored intestinal microbial equilibrium and prevented cardiac cell injury in a mouse myocarditis model [225][15].
Since the therapeutic application of fecal preparations was a practice of early Chinese [226][16], intestinal microbiota can be explored as a favorable derivation of live organisms for the treatment of CMD. Currently, the major drawback of FMT is a concomitant transfer of infectious organisms or endotoxins [9,12,227,228,229][2][17][18][19][20]. This could be bypassed by transplant of a specific category of bacteria rather than the whole fecal transfer [230,231][21][22]. The refinement of the CMD therapeutic role of FMT in terms of composition, route of administration, and dosage calls for additional research.
The application of live organisms to generally adjust microbial ecology in the management of CMD has received some great consideration. Probiotics are live microorganisms that provide their host with health benefits when used in the right quantity [232][23]. Only very few of them were endorsed as drugs, and the majority are being used as food supplements. They can be utilized therapeutically for varying cardiometabolic conditions. Remarkable reductions in blood lipid and/or glucose levels were observed following patient consumption of Bifidobacteria- and Lactobacilli-containing probiotics [233,234,235][24][25][26]. L. acidophilus ATCC 4358 treatment lessened atherosclerosis in ApoE−/− mice [236][27]. Supplementation with probiotics also enhanced the metabolic profiles of diabetic patients [237][28].
Intake of L. plantarum by carotid atherosclerotic individuals increased bacterial diversity and affected intestinal SCFA generation [238][29]. Additionally, intake of L. acidophilus, L. casei, and L. rhamnosus each induced differential gene regulatory pathways in the human mucosa, as determined by transcriptome analysis. These response profiles were similar to those obtained for specific bioactive molecules and drugs, indicating the potential of gut microbiota used as naturally evolved drug candidates [239][30]. Obesity and type 2 diabetes (T2DM) were associated with reduced availability of intestinal A. muciniphila [110,240][31][32]. Improved metabolic profiles were therefore observed in obese and diabetic mice given A. muciniphila [241][33]. Christensenella minuta treatment was demonstrated to change the gut microbiota community and prevent obesity in mice [242][34]. Lactobacillus rhamnosus treatment decreased infarct dimensions and enhanced heart functions [243][35]. Saccharonyces boulardii was documented to enhance left ventricular ejection fraction in HF patients [244][36]. Other examples of probiotics are Enterococcus, Bifidobacterium, and Streptococcus [245][37]. Therapeutically administered probiotics to immunodeficient, debilitated patients may turn to opportunistic pathogens that can cause endocarditis [246][38]. This means that the probiotics approach in susceptible individuals should be used with caution.
Other research revealed contradictory effects in the use of probiotics on CVD and risk factors [12,116][17][39] probably due to preintervention microbial variability. For therapeutic purposes, an isolated microorganism or a specific category of microorganisms, known as consortia, can be established while trials in humans are conducted to establish their safety and efficacy.
Dietary habits also determine intestinal microbial heterogeneity. Acute dietary modification has resulted in commensurate alterations in the composition and quantity of gut microbiota [247][40]. Even though individual gut microbiota tend to be resilient, the abrupt nutritional alteration can adjust the microbial ecology [248,249,250,251][41][42][43][44]. Alterations in dietary sugar content were associated with alterations in E. rectale and Roseburia [252,253][45][46].
Some of the currently available antihypertensive drugs have been demonstrated to exert their action via gut microbiota modulation. For example, captopril, in addition to its inhibiting effect on the angiotensin-converting enzyme, also proliferates the gut bacteria Allobaculum. As a result of this bacteria, the stoppage of captopril treatment preserves the antihypertensive state [254][47]. Similarly, angiotensin II receptor blockers were demonstrated to maintain Lactobacillus levels, prevent gut dysbiosis, and restore the normal F/B ratio [255,256,257][48][49][50]. Moreover, statin drugs have been demonstrated to modulate gut microbiota. For instance, atorvastatin elevated proteobacteria levels and decreased Firmicutes levels in addition to normalization of dominant taxa in high-fat-diet-fed rats [258,259][51][52].
Pathogens are implicated in the pathophysiology of some CVDs, such as atherosclerosis [260,261,262,263][53][54][55][56]. Therefore, researchers have given attention to the use of antibiotics for the eradication of pathogen-associated CVD. For instance, decreased lipoprotein levels result from ampicillin therapy [264][57], while a reduction in systolic blood pressure was observed in spontaneously hypertensive rats following minocycline and vancomycin treatment [265][58]. Depletion of microorganisms and subsequently decreased plasma leptin and myocardial infarction ensued from oral vancomycin administration to rats [213,266][59][60]. Oral minocycline therapy modified hypertension after restoring gut microbiota balance and decreasing the F/B ratio [132,144][61][62]. This therapeutic approach is, however, limited by the restriction of effect to the period of antibiotic administration, therefore requiring chronic use, with its consequent likelihood of antibiotic resistance and depletion of beneficial bacteria [9,21,30][2][3][63]. There is presently no proof of the overall beneficial effect of vague antibiotic therapy in human CVD management. Antibiotics, therefore, appear to be more appropriate for the elimination of disease-causing microorganisms, instead of a prolonged prophylactic application.
Higher Bacteroidetes and lower Firmicutes were observed after 10 weeks of moderate to severe aerobic exercise by obese adults [267][64]. Similarly, regular exercise attenuates obesity development and causes changes in the gut microbiota composition in a mice obesity model [268,269][65][66]. Furthermore, exercise increased the percentage of Bacteroidetes and decreased the percentage of Firmicutes regardless of diet [270][67], and high-intensity interval training increased the gut Bacteroidetes to Firmicutes ratio during diet-induced obesity [271][68]. Rugby players were found to have a higher number and more diverse gut microbiota compared to their non-athletic counterparts of similar age and body mass index [272][69]. This restudyearch also revealed that exercise may increase the α-diversity of gut microbiota and the abundance of the bacterial genus Akkermansia. Voluntary exercise impacted the Bacteroidetes/Firmicutes balance and prevented diet-induced obesity, in addition to causing improved glucose tolerance [273][70].
A recent study has demonstrated a depletion of opportunistic pathogens and accumulation of intestinal-wall-protecting bacteria in association with improved lipid profile and insulin sensitivity after nutritional intervention with prebiotics and whole grains [274][71]. Anthocyanin-containing fruits such as blueberries could also heighten the diversity of gut microbiota [275][72]. Dietary fortification with magnesium acetate also modified hypertension after the restoration of intestinal microbiota balance and decreased the F/B ratio [132,144][61][62].

2. Treatment Targeting LPS/Strengthen Intestinal Barrier

Interventions leading to the reduction of circulating LPS have been explored for the management of CMD. Some of the interventions are listed below:
The high quantities of circulating LPS associated with certain CMD could be reduced through physical exercise [276,277][73][74]. This will subsequently ameliorate CMD. For instance, physical exercise led to changes in the structure of intestinal bacteria that favor reduced LPS and avert heart impairment in mice with myocardial infarction [278][75]. In rats fed a high-fat diet, both acute and chronic exercise may induce a significant decrease in the TLR4-mediated signaling pathway in the liver, muscle, and adipose tissue, accompanied by the concomittant reduction in serum LPS levels and improved insulin signaling and sensitivity in metabolic target tissues [279,280][76][77].
Decrease atherosclerosis of the aorta related to reduced plasma and fecal LPS as well as lower gut penetrability was observed following oral administration of Akkermansia muciniphila to Apolipoprotein E (ApoE)−/− mice fed with a Western diet [281][78]. Similarly, reduced circulating LPS from A muciniphila treatment of metabolic syndrome patients improved their lipid profile and insulin resistance without alteration of body weight [282][79].
Antibiotics can reduce the fecal and circulating LPS. Rifaximin, tobramycin, and polymyxin B, for instance, could decrease gut bacterial translocation and decrease gut LPS, aside from their regular bacteriostatic and bactericidal action [283,284][80][81]. The limitations of antibiotic intervention were nonetheless mentioned earlier on.

3. Treatment Targeting Inflammation

Studies have associated inflammation with CMD [121][82]. The recognition of intestinal microbiota associated with immunological reactions involved in the pathogenesis of CMD can serve as a therapeutic target in inflammation-associated CMD [21][3]. Prebiotics are indigestible food materials that enhance the growth of beneficial gut microorganisms [17][83]. Inflammatory cell invasion in rats was significantly decreased with prebiotic oligofructose [285][84]. An appreciable alleviation of inflammation and hypertension was demonstrated in patients with hypertension following consumption of the dietary approach to stop hypertension (DASH) and the Mediterranean diet [286,287,288,289][85][86][87][88]. The application of immunotherapy may however be limited by a higher likelihood of opportunistic infections, especially in individuals with multimorbidity [17][83].

4. Treatment Targeting SCFAs

Several researchers including Gordon [121][82] have evaluated the role of SCFAs in CMD. The enhanced insulin sensitivity observed in metabolic syndrome patients after FMT from lean individuals was linked to higher butyrate-generating microorganisms and subsequent higher fecal SCFAs [222][10].
Supplementation with 1% butyrate halved aortic lesions in mice [290,291][89][90]. SCFAs also reduce hypertension in animals [135][91]. Another research revealed that treatment with Roseburia intestinalis (butyrate-liberating bacteria) attenuated atherosclerosis development via butyrate [146][92]. Lifestyle modification (including diet and exercise), which is presently a vital clinical intervention in the management of CMD, alters gut microbiota composition and function, including SCFA production [23][93].
Studies have demonstrated the attenuation of CMD by SCFAs liberated from gut microbiota degradation of prebiotic fibers [126,154,174][94][95][96]. Prebiotics are indigestible molecules that provide a beneficial effect to the host via alteration in the make-up and/or actions of the gut microbiota. They are usually in form of complex saccharides or oligosaccharides [292][97]. An energetic tool in the prevention and treatment of CMD is the regulation of gut microbiota through diet. For example, intestinal microbiota modulation via a high-fiber diet and acetate intake attenuated cardiac diseases and hypertension [144][62]. Similarly, modulation of intestinal microbiota with a high-fiber diet resulted in the growth of beneficial bacteria, heightened generation of SCFAs, and caused attenuation of elevated blood pressure [293][98]. A high abundance of acetate-liberating intestinal bacteria and subsequent remarkable reduction in fibrosis and hypertrophy of heart cells, as well as blood pressure and HF prevention, were demonstrated in mice fed a high-fiber diet [144][62]. Furthermore, hypertension reversal ensued through intake of butyrate- and acetate-generating corn and Clostridium butyricum by hypertensive rodents [294][99]. Additionally, oral intake of butyrate, propionate and acetate decreased insulin resistance and body weight in high-fat-diet-induced obese mice [46][100].
A high generation of SCFA can also result from the consumption of vegetables, legumes, and fruits [295][101]. The favorable role of a plant-based diet compared to animal-based ones has been attributed to their ability to modulate local and systemic SCFA generation [23][93]. A remarkable decrease in fecal butyrate and acetate level was demonstrated with the shifting of individuals from plant- to animal-based foods [251][44]. Propionate averts hypertension, vascular dysfunction, heart fibrosis, and hypertrophy [296][102]. A decrease in adverse cardiac remodeling and hypertension ensued when gut microbial metabolite (acetate) or a prebiotic (high-fiber diet) was administered in a rodent hypertension model [144][62]. Furthermore, carotid artery endothelial dysfunction was attenuated following administration of prebiotic inulin-like fructans to ApoE−/− mice [297][103]. Prebiotic inulin treatment also remarkably reduced atherosclerotic lesions in ApoE−/− mice [298][104]. A plant polysaccharide-rich diet increased butyrate generation by gut microbiota and attenuated atherosclerosis compared to low-plant polysaccharide diets [146][92]. Similarly, atherosclerosis was attenuated by microbiota of ApoE−/− mice when fed a high-plant-polysaccharide-containing diet, as contrasted to a Western diet-fed one [299][105]. Augmentation of the diet with ginger also modifies gut microbial ecology and incites enhanced metabolism of fatty acids [170][106].
Studies have revealed the ability of probiotics to positively modulate fat metabolism [300,301][107][108]. The probable mechanisms of probiotics involve opposition of disease-causing organisms, the liberation of antimicrobial agents, and pH modification [302,303][109][110]. Lactobacillus sp. administration was linked with remarkable alteration in colonic SCFAs in carotid atherosclerotic patients [238][29]. Symbiotic formulations are dietary adjuncts with a blend of probiotics and prebiotics that can modify intestinal metabolism [294][99]. The commonly adjoined probiotics in symbiotic formulations are Bifidobacteria, Lactobacilli, S. boulardii, and B. coagulans, while the prebiotics are oligosaccharides, dietary fibers, and inulin [304][111].
FMT to metabolic syndrome patients from lean individuals was linked to a higher abundance of butyrate-generating bacteria (such as Roseburia) and resulted in improved insulin sensitivity [222][10].
Current studies demonstrate that exercise modifies the intestinal microbiota for its cardiovascular effects. Research revealed that it increases the ratio of Firmicutes to Bacteroidetes [305,306][112][113] as well as elevates the amount of the microbial product butyrate [307][114]. The positive effect of exercise on intestinal microbiota was interim and abated following the stoppage of the exercise [307][114]. This makes a longer period of exercise a necessity for remarkable long-lasting effects [9][2]. The gut metabolism of athletes is found to generate a high level of SCFA [308][115]. Voluntary running in animals is also associated with microbiota diversity and attendant elevated butyrate levels [309][116]. The butyrate may inhibit the activity of histone deacetylases and therefore influence immune modulation and decrease oxidative stress [310][117]. It can also regulate gut motility and barrier integrity as well as inflammation and visceral sensitivity [310,311][117][118]. All these partake in CMD modulation. Huang et al. [312][119] studied rats and demonstrated a pronounced antioxidant function and tricarboxylic acid cycle with endurance training. With regards to the use of exercise to modulate gut microbiota for CMD treatment, further research is needed to answer the questions about the types, timing, and conditions of exercise to achieve a remarkable impact on CMD.
Favorable effects of SCFAs have been demonstrated in hypertension models in rats. Local inoculation of acetate into the colon overturned hypertension in rats [313][120]. Oral administration of propionate led to enhanced vascular action, decreased blood pressure, and adverse cardiac events in hypertensive mice [296][102]. Butyrate or propionate administration prevents myocardial harm in hypertension models [135,296][91][102]. Sodium butyrate therapy in rodents resulted in improved insulin sensitivity and attenuation of obesity [314][121]. Tributyrin was synthesized to solve butyrate’s problem of offensive taste and odor. It is a prodrug that carries three molecules of butyrate esterified to glycerol and with comparable cardiometabolic action to and better pharmacokinetic parameters than butyrate [315][122]. Tributyrin treatment of obese mice diminished insulin resistance and inflammation [19][1]. Another research revealed that fat accumulation and atherosclerosis were remarkably attenuated with tributyrin treatment in ApoE−/− mice. This is an optimistic approach for CVD prophylaxis [146][92].

5. Treatment Targeting TMA

Therapeutic approaches that are directed toward halting TMAO generation and elimination of TMAO and its progenitor (TMA) have gained recognition owing to the association of TMAO with cardiometabolic diseases by several studies, as mentioned earlier. Hence, targeting the gut microbiota for reduction of TMA generation will be a likely treatment strategy for CMD [19][1]. Apart from pharmacological agents, probiotics can be employed for the inhibition of metabolic pathways in gut microbes to reduce TMAO liberation [168][123].
Mediterranean diet consumption led to remarkably reduced TMAO and could attenuate CMD [316,317][124][125]. CMD can be prevented by limiting the intake of a choline/carnitine-rich diet since nutritional intake is the main source of TMAO [128][126]. Western diets are carnitine/choline-rich while vegetarian diets are carnitine-choline depleted [170,318][106][127]. A high-fiber diet decreased plasma TMAO [319][128]. Although there is no consensus on the effect of saturated fat and red meat intake on TMAO levels [170[106][129][130],320,321], individuals following a vegetarian diet regimen had reduced plasma and urinary TMAO [292,322][97][131]. It is therefore thought that this dietary approach could reduce TMAO generation and subsequently attenuate CMD [323][132].
It is postulated that the transfer of low TMAO-liberating microbiota to patients with heart failure or its risk factors could decrease TMAO, yet none of such has been demonstrated clinically [17][83].
Broad-spectrum antibiotic administration to individuals led to decreased intestinal microbiota and a remarkable reduction in TMAO levels [173,175][133][134]. The use of broad-spectrum antibiotics in elderly mice reduced plasma TMAO and subsequently attenuated endothelial dysfunction and aortic stiffening to a similar level as the young mice [324][135]. CVD prevention in humans using long-term antibiotics is not practicable due to the previously mentioned challenges of this approach [21][3].
Reduction in TMAO and altered platelet aggregation were observed in individuals with high TMAO that were treated with low-dose aspirin [96,318][127][136]. The low-dose aspirin can also change the gut microbial composition [325][137].
Targeting bacterial enzymes involved in TMA generation for inhibition are being investigated as a preventive or therapeutic approach for CMD [95,128,158,160][126][138][139][140]. For example, a structural analog of choline 3,3-dimethyl-1-butanol (DMB) is a model microbial TMA lyase inhibitor used for this purpose [326][141]. Reduction in TMA/TMAO ensued inhibition of TMA lyase and inhibition of TMA lyase modified CVD [327][142]. Foam cell production and subsequent atherosclerosis were impaired after oral administration of DMB, which resulted in decreased plasma TMAO in ApoE−/−mice on a choline-augmented diet [95][138]. Another study also demonstrated the anti-atherogenesis effect of DMB [328][143]. Furthermore, decreased ventricular remodeling and enhanced hemodynamic status followed DMB administration [329][144]. More potent TMA lyase inhibitors such as fluoromethylcholine, iodomethylcholine, chloromethylcholine, and bromomethylcholine have been invented. These compounds specifically act locally on the gut microbiota with minimal systemic exposure of the host, thereby limiting adverse effects [21,330][3][145]. TMA lyase inhibitors, including DMB, are harmless to the microbes. Therefore, they do not cause selective pressure like antibiotics do, and the risk of resistance is minimal [21][3].
Aside from TMA lyase (CutC/D), other enzymes involved in the generation of TMA from other precursors include CntA/B [160][140], betaine reductase [161][146], TMAO reductase [162][147], and YeaW/X [163][148]. Clinical trials have demonstrated that dietary indoles of Brussels sprouts inhibited FMO3 and thereby prevented the conversion of TMA to TMAO [331][149]. Drug development that targets a reduction of TMAO production via inhibition of TMA lyase is preferred to specific FMO3 inhibition because elevated plasma levels of TMA result in a condition termed trimethylaminuria, which brings about an offensive “fishy” odor [332][150]. Another enzyme inhibitor (meldonium), which is an analog of carnitine, produces an anti-atherosclerotic effect by competitively inhibiting microbial carnitine palmitoyltransferase-1 (CPT1), resulting in the attenuation of microbial TMA generation [333][151]. Furthermore, phospholipase D (PLD) is one more intestinal microbial enzyme that can be targeted for drug development. PLD is involved in TMA generation by liberating free choline from phosphatidylcholine, the predominant dietary form of choline. The good news is that gut microbial PLD can be preferentially inhibited without affecting the host enzyme, owing to the phylogenetic differences between host and microbial PLD enzymes [334][152]. Therefore, future therapeutic action with innocuous enzyme inhibitors directed at gut microbiota presents an innovative strategy for the prevention and treatment of CMD. This nonetheless requires clinical studies for validation [12,21][3][17].

6. Treatment Targeting Bile Acids

A secondary bile acid, ursodeoxycholic acid (UDCA), was studied as an innovative treatment for rodent obesity [335][153]. An FXR agonist and semisynthetic analog of bile acid, obeticholic was thought to have the ability to decrease bacterial translocation and inflammation [336][154]. It was the first FXR agonist to reach the clinical stage [337][155]. Investigations have demonstrated that obeticholic modified fat metabolism and improve insulin sensitivity as a result of the role FXR signaling plays in the control of lipid and glucose balance [19][1]. Similarly, TGR5 agonists enhance a myocardial reaction to stress in mice [209][156], hence they, as well as FXR agonists, can be innovative targets for the management of heart failure [17][83]. Furthermore, targeting BSH microbiota–host interplay could be a strategy for metabolic disorders and obesity since studies have shown that microbial BSH action may remarkably decrease weight gain as well as plasma cholesterol [338,339][157][158]. Statin drugs were demonstrated to affect the BA pool as well as decrease gut butyrate generation [340][159].

7. Targeting Other Metabolites/Enzymes

Significant advancement has been recorded in the comprehension of intestinal microbial metabolism. The exposition of more microbial products allows additional likely therapeutic targets for CMD [19][1]. The intestinal microbiota tryptophan decarboxylase was identified to be accountable for the generation of tryptamine [341][160]. Microbial dissimilatory sulfite reductases (DsrAB) are responsible for hydrogen sulfide production [342][161] while tryptophanases lead to indole generation [343][162]. The gut microbiota glycyl radical enzyme was also recognized to break the C-S bond of taurine to produce hydrogen sulfide [344][163]. The applicability of the mentioned microbial enzymes and the production of their inhibitors as innovative therapeutic targets require further studies. This is with the aim of improving the liberation of useful metabolites and attenuating the generation of harmful ones [19][1].

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