Gut Microbiome and Cardiovascular Health: Mechanisms, Therapeutic Potential and Future Directions.

The Microbiome Hype Integrative analyses of metagenomics, metatranscriptomics, metaproteomics, and metabolomics have provided unprecedented insight into the physiologic role of the human microbiome in health and disease. Studies using genome-scale metabolic networks and metagenome-assembled genomes reveal that several metabolic pathways in humans are the result of the combined activities of the human genome and microbiome. A recent study showed that gut microbiota associate with 38 self-reported common diseases and 51 medications (1). Changes in the gut microbiota could promote CKD progression through alterations in immune response, BP regulation, and metabolic changes. In this Perspective, we focus on the recent advances in the field of microbiome that are relevant to kidney disease. Dysbiosis in CKD The concepts of "niche partitioning" and "functional redundancy" are highly relevant to the shaping of microbiome in CKD. The former refers to the process by which competing species use the environment differently, permitting them to coexist. Functional redundancy is a mechanism by which many phylogenetically unrelated taxa carry similar genes and perform similar functions. It is possible that CKD milieu results in loss of "key taxa," shifting the community structure. The resulting dysbiosis drives CKD progression through generation of a multitude of uremic toxins. Impaired protein digestion in CKD results in delivery of undigested protein to the colon, which fosters the preferential proliferation of bacteria with urease and uricase enzymes and taxa involved in indole and phenol metabolism. Concomitant reduction in saccharolytic bacteria leads to reduced generation of short-chain fatty acids (2), which are involved in energy homeostasis, maintaining gut barrier, BP control, and immune regulation. Gut and BP Hypertension is an important risk factor for CKD progression. Disturbed gut microbiota and hypertension could be causally related. Experimental studies suggest T cell subsets, such as T helper and T regulatory cells are involved in the regulation of BP. A high-salt diet caused depletion of Lactobacillus murinus in mice (3). Treatment of mice with L. murinus reduced T helper 17 cell numbers and prevented salt-sensitive hypertension (3). Reduced potassium consumption and low urinary potassium excretion are associated with higher risk for developing hypertension. A recent study showed that microbiome and host cometabolism are altered by potassium (4). Renin release from the afferent arteriole, mediated by olfactory G protein-coupled receptor (Olfr78) activated by short-chain fatty acids, is counteracted by the vasodilatory action of G-protein-coupled receptor 43 (GPR43) expressed in major blood vessels. Interestingly, gut microbiota encode several enzymes that influence the metabolism of xenobiotics that might affect the excretion, transport, and bioavailability of antihypertensive medications. Dysmetabolism in CKD Protein catabolism by gut microbiota is generally viewed as detrimental because it results in production of toxins, such as ammonia, amines, phenols, indoles, and sulfurous compounds, which accumulate in CKD. Gut microbiota convert tryptophan to indole and indole derivatives, such as indoxyl sulfate. Bacterial fermentation of the aromatic amino acids tyrosine and phenylalanine generates phenolic compounds, such as p-cresol sulfate. Dietary choline can be metabolized to trimethylamine by the microbiota, which is oxidized in the liver to trimethylamine N-oxide. Several studies have shown that trimethylamine N-oxide alters cholesterol transport, promotes formation of foam cells, and exacerbates atherosclerosis. Members of Lactobacilli, Bifidobacteria, and Clostridia genera can deconjugate bile acids and convert them to secondary bile acids, including deoxycholic acid and lithocholic acid. Deoxycholic acid is elevated in CKD and is directly toxic to vascular smooth muscle cells. Mechanistic studies have shown that microbiome-derived indoles, phenols, and amines could mediate CKD progression through glomerular and interstitial fibrosis. It is becoming evident that elevated plasma levels of microbiome-derived uremic retention solutes in CKD cannot be fully explained by differences in bacterial generation rates alone (5). Retention of these solutes due to decreased tubular secretion and, to a smaller extent, reduced glomerular filtration contribute to accumulation of these molecules in CKD (5). Microbiome Therapeutics With the expanding knowledge of the microbiome, recent efforts have sought to harness the power of microbiome for health benefit (Figure 1). These therapeutics could be broadly classified as (1) supplementing the host microbiota with fecal transplantation, specific strains of microbiota, or a consortium of natural or engineered micro-organisms; (2) elimination of specific deleterious members of the microbiota using nonspecific or targeted antimicrobials, such as bacteriocins and bacteriophages; (3) modulation of host microbiota by administration of agents, such as prebiotics; and (4) postbiotics that target downstream signaling pathways of the microbiome. Advances in orthogonal niche engineering in which uncommon/unused nutrients are employed has enabled engraftment of therapeutic bacteria.Figure 1.: Microbiome-based therapeutics and their site of action. Fecal transplants could be least specific with large-scale changes in microbial community, whereas engineered bacteria are specific. Recent advances in our understanding of the molecular basis for disease have enabled us to alter the function rather than change the microbiome profile. CVD, cardiovascular disease; DMB, 3,3-dimethyl-1-butanol; FMO3, flavin-containing mono-oxygenase 3; FMO3 KO, FMO3 knockout; SCFA, short-chain fatty acid; Th17, T helper 17 cell; TMA, trimethylamine; TMAO, trimethylamine N-oxide; Treg, T regulatory cell.For a probiotic to be effective, the bacteria should be able to colonize, proliferate, and be metabolically active in that environment. Furthermore, microbes are interdependent on each other for nutrients and signaling molecules, so the effective probiotic needs a supportive microbiome as well. These phenomena explain the mixed results seen with prebiotic- and probiotic-based interventions in patients with CKD. Cardiovascular disease contributes to CKD progression and remains the leading cause of death in patients with CKD. Researchers have explored several avenues to reduce trimethylamine N-oxide and stall the atherosclerotic process. Methanogenic archaea can use methylated amines, such as trimethylamine, as growth substrates. Colonization of ApoE−/− mice with Methanobrevibacter smithii resulted in a sustained reduction in plasma trimethylamine N-oxide concentrations and a tendency for reduction in atherosclerosis (6). 3,3-Dimethyl-1-butanol is a structural analogue of choline that inhibits trimethylamine lyases (7). 3,3-Dimethyl-1-butanol inhibits choline-induced endogenous macrophage foam cell formation and atherosclerotic lesion development in ApoE−/− mice (7). Flavin-containing mono-oxygenase 3 is the rate-limiting enzyme in the conversion of trimethylamine to trimethylamine N-oxide. Knockdown of flavin-containing mono-oxygenase 3 mice has been shown to attenuate atherosclerosis. Iodomethylcholine is a suicide substrate inhibitor, which selectively accumulates within gut microbes, reducing production of trimethylamine by inhibiting trimethylamine-lyase. In animal models, iodomethylcholine reduces kidney fibrosis and preserves kidney function (8). Knowledge about the biochemical pathways in disease and the microbiome has led to novel therapies. In the intestine, bacterial urease converts host-derived urea to ammonia and carbon dioxide, contributing to hyperammonemia. A consortium of eight bacteria, with minimal urease gene content, resulted in sustained reduction in ammonia production in antibiotic-treated mice (9). Tryptophanase, involved in the conversion of tryptophan to indole, is expressed by gut commensal Bacteroides. Delvin et al. (10) showed that indole production could be inhibited by deleting the tryptophanases or eliminating the bacteria carrying the enzyme. Bacterial catabolism of the sulfur-containing amino acids produces hydrogen sulfide, which could function as an endogenous signaling molecule and a substrate for mitochondrial energization. A high sulfur amino acid–containing diet resulted in post-translationally modified microbial tryptophanase activity and preservation of kidney function in a mouse model of CKD (11). Advances in DNA technologies for the manipulation of microbial genome have permitted scientists to engineer smart bacteria that could deliver therapeutic molecules and reprogram host cells by delivering transcription factors. However, safety and biocontainment remain major concerns that have not yet been fully addressed. In our quest for microbiome therapeutics, we need to be mindful of the undesired propagation of genetically modified bacteria or genetic material into the ecosystem. Concluding Remarks The lack of large-scale metagenomic data has greatly impeded progress in understanding the role of the microbiome in CKD. Existing evidence indicate that dysbiosis drives the production of many uremic retention solutes. The field of microbiome therapeutics is transitioning from prebiotic and probiotic to postbiotics. The use of bacteria as engineered therapeutics is a rapidly evolving field that is poised to transform the management of many chronic diseases, including CKD. As we strive to decipher the language of microbiome, healthy skepticism is good, but we should be open to embrace true scientific discoveries and be prepared for future microbiome-based therapies. Disclosures D.S. Raj reports having other interests in or relationships with the American Association of Kidney Patients; serving in an advisory or leadership role for National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and Novo Nordisk; receiving research funding from the National Institutes of Health (NIH); and having consultancy agreements with, and receiving honoraria from, Novo Nordisk. The remaining author has nothing to disclose. Funding D.S. Raj is supported by NIH grants 1U01DK099914-01, 1U01DK099924-01, and RO1DK125256-01.

Background: The symbiotic relationship between the gut microbiota and cardiovascular health has become a main point in contemporary research, offering valuable insights into the pathogenesis of cardiovascular diseases (CVDs). This review aims to comprehensively examine the bidirectional communication between gut microbial communities and the cardiovascular system, explaining the intricate mechanisms that connect gut dysbiosis to the initiation and progression of CVDs. Material and Methods: A systematic literature review was conducted to compile and analyze relevant studies investigating the impact of the gut microbiota on cardiovascular health. Emphasis was placed on explaining the molecular and physiological mechanisms underlying the interaction between gut microbes and cardiovascular function. Results: Our review confirmed evidence linking gut microbiota-derived metabolites, such as short-chain fatty acids, trimethylamine N-oxide and lipopolysaccharides to vascular function and inflammation. Additionally, we explored the modulation of host metabolism and immune responses by gut microbes, providing insights into their roles in atherosclerosis and hypertension. The review highlight the influence of diet and lifestyle on shaping the gut microbiome and, consequently, cardiovascular outcomes. Conclusions: Gut microbiota plays a crucial role in cardiovascular health and is involved in the start and development of various heart diseases. The identified molecular and physiological mechanisms highlight the need for complete understanding of the gut-cardiovascular axis. Moreover, the review emphasizes the potential of microbiota-targeted interventions, including probiotics and fecal microbiota transplantation, as innovative strategies for preventing and managing CVDs.

The gut microbiota is a complex and dynamic ecosystem that plays a crucial role in human health and disease, including obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, and cancer. Chronic inflammation is a common feature of these diseases and is closely related to angiogenesis (the process of forming new blood vessels), which is often dysregulated in pathological conditions. Inflammation potentially acts as a central mediator. This abstract aims to elucidate the connection between the gut microbiota and angiogenesis in various diseases. The gut microbiota influences angiogenesis through various mechanisms, including the production of metabolites that directly or indirectly affect vascularization. For example, short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate are known to regulate immune responses and inflammation, thereby affecting angiogenesis. In the context of cardiovascular diseases, the gut microbiota promotes atherosclerosis and vascular dysfunction by producing trimethylamine N-oxide (TMAO) and other metabolites that promote inflammation and endothelial dysfunction. Similarly, in neurodegenerative diseases, the gut microbiota may influence neuroinflammation and the integrity of the blood–brain barrier, thereby affecting angiogenesis. In cases of fractures and wound healing, the gut microbiota promotes angiogenesis by activating inflammatory responses and immune effects, facilitating the healing of tissue damage. In cancer, the gut microbiota can either inhibit or promote tumor growth and angiogenesis, depending on the specific bacterial composition and their metabolites. For instance, some bacteria can activate inflammasomes, leading to the production of inflammatory factors that alter the tumor immune microenvironment and activate angiogenesis-related signaling pathways, affecting tumor angiogenesis and metastasis. Some bacteria can directly interact with tumor cells, activating angiogenesis-related signaling pathways. Diet, as a modifiable factor, significantly influences angiogenesis through diet-derived microbial metabolites. Diet can rapidly alter the composition of the microbiota and its metabolic activity, thereby changing the concentration of microbial-derived metabolites and profoundly affecting the host's immune response and angiogenesis. For example, a high animal protein diet promotes the production of pro-atherogenic metabolites like TMAO, activating inflammatory pathways and interfering with platelet function, which is associated with the severity of coronary artery plaques, peripheral artery disease, and cardiovascular diseases. A diet rich in dietary fiber promotes the production of SCFAs, which act as ligands for cell surface or intracellular receptors, regulating various biological processes, including inflammation, tissue homeostasis, and immune responses, thereby influencing angiogenesis. In summary, the role of the gut microbiota in angiogenesis is multifaceted, playing an important role in disease progression by affecting various biological processes such as inflammation, immune responses, and multiple signaling pathways. Diet-derived microbial metabolites play a crucial role in linking the gut microbiota and angiogenesis. Understanding the complex interactions between diet, the gut microbiota, and angiogenesis has the potential to uncover novel therapeutic targets for managing these conditions. Therefore, interventions targeting the gut microbiota and its metabolites, such as through fecal microbiota transplantation (FMT) and the application of probiotics to alter the composition of the gut microbiota and enhance the production of beneficial metabolites, present a promising therapeutic strategy.

The last decade has provided extensive information on the human gut microbiota. The microorganisms populating the gastrointestinal tract play important roles in maintaining the body's homeostasis. It turns out that the intestinal microbiota can affect many diseases from various branches of medicine. The importance of the function of the microflora can also affect cardiovascular diseases (CVD), including heart failure (HF). The microflora influences among other things, nutrient digestion, vitamin production or the production of bioactive metabolites including trimethylamine/trimethylamine N-oxide, short-chain fatty acids and bile acids. Therefore, changes in the composition of the intestinal microflora, defined as dysbiosis, have become one of the key pathogenic factors in many diseases. There is emerging evidence of a strong correlation between gut microflora and the occurrence of cardiovascular disease. In patients with cardiovascular disease and corresponding risk factors, the composition and proportions of the intestinal microflora differed significantly from healthy subjects. Differences in microbial composition and marked fluctuations in the levels of biomarkers such as TMAO, zonulin, LPS, SCFAs may become helpful in the diagnosis of cardiovascular diseases. For this reason, the intestinal microflora and its metabolic pathways have recently become the subject of numerous studies. A very important issue is the fact that it is possible to regulate the intestinal microflora through diet, the use of prebiotics, probiotics or influence through a much larger intervention - for example, fecal mass transplantation. These possibilities have become new strategies in the treatment of HF. The main purpose of this review is to summarize recent studies that illustrate the complex interactions between the microbiome and the occurrence of HF. Conclusions. The gut microbiota is a complex ecosystem of microorganisms that live in the human gut. The gut microbiota plays an important role in maintaining the body's health, including the cardiovascular system. Dysbiosis, or an imbalance in the gut microbiota, has been linked to the development of heart failure. Gut microbiota metabolites, such as trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and bile acids, can have harmful effects on the heart. Diet, probiotics, and fecal microbiota transplantation (FMT) are all potential interventions for improving gut microbiota and reducing the risk of heart failure. More research is needed to fully understand the role of gut microbiota in heart failure and to develop effective treatment strategies.

Thousands of microorganisms reside in the human gut, and extensive research has demonstrated the crucial role of the gut microbiota in overall health and maintaining homeostasis. The disruption of microbial populations, known as dysbiosis, can impair the host’s metabolism and contribute to the development of various diseases, including cardiovascular disease (CVD). Furthermore, a growing body of evidence indicates that metabolites produced by the gut microbiota play a significant role in the pathogenesis of cardiovascular disease. These bioactive metabolites, such as short-chain fatty acids (SCFAs), trimethylamine (TMA), trimethylamine N-oxide (TMAO), bile acids (BAs), and lipopolysaccharides (LPS), are implicated in conditions such as hypertension and atherosclerosis. These metabolites impact cardiovascular function through various pathways, such as altering the composition of the gut microbiota and activating specific signaling pathways. Targeting the gut microbiota and their metabolic pathways represents a promising approach for the prevention and treatment of cardiovascular diseases. Intervention strategies, such as probiotic drug delivery and fecal transplantation, can selectively modify the composition of the gut microbiota and enhance its beneficial metabolic functions, ultimately leading to improved cardiovascular outcomes. These interventions hold the potential to reshape the gut microbial community and restore its balance, thereby promoting cardiovascular health. Harnessing the potential of these microbial metabolites through targeted interventions offers a novel avenue for tackling cardiovascular health issues. This manuscript provides an in-depth review of the recent advances in gut microbiota research and its impact on cardiovascular health and offers a promising avenue for tackling cardiovascular health issues through gut microbiome-targeted therapies.

The discovery that gut-microbiota plays a profound role in human health has opened a new avenue of basic and clinical research. Application of ecological approaches where the bacterial 16S rRNA gene is queried has provided a number of candidate bacteria associated with coronary artery disease and hypertension. We examine the associations between gut microbiota and a variety of cardiovascular disease (CVD) including atherosclerosis, coronary artery disease, and blood pressure. These approaches are associative in nature and there is now increasing interest in identifying the mechanisms underlying these associations. We discuss three potential mechanisms including: gut permeability and endotoxemia, increased immune system activation, and microbial derived metabolites. In addition to discussing these potential mechanisms we highlight current studies manipulating the gut microbiota or microbial metabolites to move beyond sequence-based association studies. The goal of these mechanistic studies is to determine the mode of action by which the gut microbiota may affect disease susceptibility and severity. Importantly, the gut microbiota appears to have a significant effect on host metabolism and CVD by producing metabolites entering the host circulatory system such as short-chain fatty acids and trimethylamine N-Oxide. Therefore, the intersection of metabolomics and microbiota research may yield novel targets to reduce disease susceptibility. Finally, we discuss approaches to demonstrate causality such as specific diet changes, inhibition of microbial pathways, and fecal microbiota transplant.

The human microbiota is a hot topic at present because increasing evidences demonstrate that it should be considered an organ based on its importance to human health . Dysbiosis of the gut microbiota is significantly related to many human disorders. In turn, correcting such imbalances and taking advantage of gut microbes are possible methods for alleviating or even curing host diseases. A recent study published in Cell indicated that inhibition of gut microbial production of trimethylamine(TMA) specifically prevents atherosclerosis in vivo. Another study found that a diet supplemented with TMA Noxide (TMAO) increased the level of atherosclerosis in mice , which suggested TMAO might be a causative factor in cardiovascular disease (CVD). However, direct inhibition of flavin-containing monooxygenase (FMO3), a hepatic enzyme that catalyzes the conversion of TMA to TMAO, results in TMA accumulation and several unpleasant side effects. The small-molecule 3,3-dimethyl-1-butanol (DMB), identified by Wang et al., reduces TMAO through non-lethal inhibition of microbial TMA formation in mice, even when fed a western diet, including high choline. DMB is a non-toxic compound found naturally in foods such as olive oil and red wine. Therefore, the risk of CVD could be reduced by some dietary habits (such as a Mediterranean diet), which might stem from changes in gut microbiota. Although the impact of DMB on microbial TMA has only been observed in mouse models, it provides a guideline for the treatment of CVD in humans by regulating gut microbes. There are many similar studies that target gut microbes to treat host disorders. For example, Sarkis’ group verified that a human commensal bacterium could improve autism spectrum disorder (ASD)-related gastrointestinal deficits and behavioral abnormalities in mice , which indicated that microbiome-mediated therapies might be a safe and effective treatment for ASD. In addition, fecal microbiota transplantation, which has aroused strong interest in recent years, is reported to be a highly successful therapy for recurrent Clostridium difficile infection . These studies support novel research ideas that are no longer focused solely on the host, but rather on the intimacy of the host-microbiota relationship. Considering the relative ease of regulating the gut microbiota, targeting these organisms through diet, prebiotics, probiotics, or other methods may become a useful strategy for curing diseases. To date, a large number of studies have been devoted to uncovering the relationship between microbial metabolites and human diseases, and it is highly likely that more bacterial or related pathways involved in human disease will be identified. In the future, targeting the microbiome may represent an effective and complementary strategy to current approaches for preventing and treating diseases.

Nutritional and Botanical Approaches for Inflammatory Bowel Disease

The bidirectional communication between the gut and brain or gut-brain axis is regulated by several gut microbes and microbial derived metabolites, such as short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides. The Gut microbiota (GM) produce neuroactives, specifically neurotransmitters that modulates local and central neuronal brain functions. An imbalance between intestinal commensals and pathobionts leads to a disruption in the gut microbiota or dysbiosis, which affects intestinal barrier integrity and gut-immune and neuroimmune systems. Currently, fecal microbiota transplantation (FMT) is recommended for the treatment of recurrent Clostridioides difficile infection. FMT elicits its action by ameliorating inflammatory responses through the restoration of microbial composition and functionality. Thus, FMT may be a potential therapeutic option in suppressing neuroinflammation in post-stroke conditions and other neurological disorders involving the neuroimmune axis. Specifically, FMT protects against ischemic injury by decreasing IL-17, IFN-γ, Bax, and increasing Bcl-2 expression. Interestingly, FMT improves cognitive function by lowering amyloid-β accumulation and upregulating synaptic marker (PSD-95, synapsin-1) expression in Alzheimer's disease. In Parkinson's disease, FMT was shown to inhibit the expression of TLR4 and NF-κB. In this review article, we have summarized the potential sources and methods of administration of FMT and its impact on neuroimmune and cognitive functions. We also provide a comprehensive update on the beneficial effects of FMT in various neurological disorders by undertaking a detailed interrogation of the preclinical and clinical published literature.

Fecal Microbiota Transplantation for Ulcerative Colitis: Not Just Yet

Background and purpose:Gut microbiota has a symbiotic relationship with their host. It is known that the gut microbiome has the potential to affect the host and vice versa. Cardiovascular disease and its comorbidities are the leading cause of death worldwide. Patients with various heart conditions have been observed to have a different composition of the gut microbiome. It has been postulated that the gut microbiome and its derivatives exert various effects on the cardiovascular system, termed the gut-heart axis. In this study, we aim to explore how the gut microbiome and the active metabolites produced by these microorganisms affect patient cardiovascular health. Additionally, we will discuss how gut microbiota can become a target for the new era of precision cardiology.Methods:Data were collected through the online databases PubMed, Google Scholar, Ovid MEDLINE, and ScienceDirect. Articles regarding cardiovascular health and pathology as well as its overlap with gut microbiome and health were used.Results:Emerging evidence suggests that gut microbiome has a significant influence on cardiovascular disease through its metabolites, such as trimethylamine N-oxide and short-chain fatty acids, which impact cholesterol metabolism, systemic inflammation, and plaque stability. Targeting said derivatives has proven to provide beneficial results for patients suffering from cardiovascular disease.Conclusions:Finding reported here highlights the importance of microbiome in cardiovascular disease and health and suggest that microbiome-based interventions hold promise for prevention and treatment of cardiovascular disease. More research needs to be conducted to study more concrete effects of specific microorganisms on cardiovascular health. Multicenter, longitudinal studies with a large sample size will provide the best evidence for clinically significant findings. Using precision cardiology, to target the gut microbiome and its derivatives, with medications like antibiotics, and nonpharmacologic interventions like lifestyle modification and fecal transplantation can positively influence cardiovascular health and help with the effective management of ongoing diseases.

Cardiovascular disease (CVD) has been classified as one of the leading causes of morbidity and mortality worldwide. CVD risk factors include smoking, hypertension, dyslipidaemia, obesity, inflammation and diabetes. The gut microbiota can influence human health through multiple interactions and community changes are associated with the development and progression of numerous disease states, including CVD. The gut microbiota are involved in the production of several metabolites, such as short-chain fatty acids (SCFAs), bile acids and trimethylamine-N-oxide (TMAO). These products of microbial metabolism are important modulatory factors and have been associated with an increased risk of CVD. Due to its association with CVD development, the gut microbiota has emerged as a target for therapeutic approaches. In this review, we summarise the current knowledge on the role of the gut microbiome in CVD development, and associated microbial communities, functions, and metabolic profiles. We also discuss CVD therapeutic interventions that target the gut microbiota such as probiotics and faecal microbiota transplantation.

The effect of the gut microbiota extends beyond their habitant place from the gastrointestinal tract to distant organs, including the cardiovascular system. Research interest in the relationship between the heart and the gut microbiota has recently been emerging. The gut microbiota secretes metabolites, including Trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile acids (BAs), indole propionic acid (IPA), hydrogen sulfide (H2S), and phenylacetylglutamine (PAGln). In this review, we explore the accumulating evidence on the role of these secreted microbiota metabolites in the pathophysiology of ischemic and non-ischemic heart failure (HF) by summarizing current knowledge from clinical studies and experimental models. Elevated TMAO contributes to non-ischemic HF through TGF-ß/Smad signaling-mediated myocardial hypertrophy and fibrosis, impairments of mitochondrial energy production, DNA methylation pattern change, and intracellular calcium transport. Also, high-level TMAO can promote ischemic HF via inflammation, histone methylation-mediated vascular fibrosis, platelet hyperactivity, and thrombosis, as well as cholesterol accumulation and the activation of MAPK signaling. Reduced SCFAs upregulate Egr-1 protein, T-cell myocardial infiltration, and HDAC 5 and 6 activities, leading to non-ischemic HF, while reactive oxygen species production and the hyperactivation of caveolin-ACE axis result in ischemic HF. An altered BAs level worsens contractility, opens mitochondrial permeability transition pores inducing apoptosis, and enhances cholesterol accumulation, eventually exacerbating ischemic and non-ischemic HF. IPA, through the inhibition of nicotinamide N-methyl transferase expression and increased nicotinamide, NAD+/NADH, and SIRT3 levels, can ameliorate non-ischemic HF; meanwhile, H2S by suppressing Nox4 expression and mitochondrial ROS production by stimulating the PI3K/AKT pathway can also protect against non-ischemic HF. Furthermore, PAGln can affect sarcomere shortening ability and myocyte contraction. This emerging field of research opens new avenues for HF therapies by restoring gut microbiota through dietary interventions, prebiotics, probiotics, or fecal microbiota transplantation and as such normalizing circulating levels of TMAO, SCFA, BAs, IPA, H2S, and PAGln.

BACKGROUNDChemotherapy-induced cardiotoxicity is a significant complication in cancer therapy, limiting treatment efficacy and worsening patient outcomes. Recent studies have implicated the gut microbiome and its key metabolites, such as short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO), in mediating inflammation, oxidative stress, and cardiac damage. The gut-heart axis is increasingly recognized as a pivotal pathway linking microbiota dysregulation to chemotherapy-related cardiac dysfunction.AIMTo systematically review existing evidence on the role of gut microbiome alterations in chemotherapy-induced cardiotoxicity and evaluate emerging microbiome-based therapeutic strategies aimed at mitigating cardiovascular risk in cancer patients.METHODSA systematic literature search was conducted in PubMed, Scopus, and Web of Science for studies published between January 2013 and December 2024. Studies were included if they examined chemotherapy-induced cardiotoxicity in relation to gut microbiota composition, microbial metabolites (e.g., SCFAs, TMAO), or microbiome-targeted interventions. Selection followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data extraction focused on microbiota alterations, mechanistic pathways, cardiac outcomes, and quality assessments using standardized risk-of-bias tools.RESULTSEighteen studies met the inclusion criteria. Chemotherapy was consistently associated with gut dysbiosis characterized by reduced SCFA-producing bacteria and increased TMAO-producing strains. This imbalance contributed to gut barrier disruption, systemic inflammation, and oxidative stress, all of which promote myocardial damage. SCFA depletion weakened anti-inflammatory responses, while elevated TMAO levels exacerbated cardiac fibrosis and dysfunction. Preclinical studies showed promising cardioprotective effects from probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation, though human data remain limited.CONCLUSIONGut microbiome dysregulation plays a crucial role in the development of chemotherapy-induced cardiotoxicity. Altered microbial composition and metabolite production trigger systemic inflammation and cardiac injury. Microbiome-targeted therapies represent a promising preventive and therapeutic approach in cardio-oncology, warranting further clinical validation through well-designed trials.

Objective:The purpose of this review is to stress the complicated interactions between the microbiota and the development of heart failure. Moreover, the feasibility of modulating intestinal microbes and metabolites as novel therapeutic strategies is discussed.Data sources:This study was based on data obtained from PubMed up to March 31, 2019. Articles were selected using the following search terms: “gut microbiota,” “heart failure,” “trimethylamine N-oxide (TMAO),” “short-chain fatty acid (SCFA),” “bile acid,” “uremic toxin,” “treatment,” “diet,” “probiotic,” “prebiotic,” “antibiotic,” and “fecal microbiota transplantation.”Results:Accumulated evidence has revealed that the composition of the gut microbiota varies obviously in people with heart failure compared to those with healthy status. Altered gut microbial communities contribute to heart failure through bacterial translocation or affecting multiple metabolic pathways, including the trimethylamine/TMAO, SCFA, bile acid, and uremic toxin pathways. Meanwhile, modulation of the gut microbiota through diet, pre/probiotics, fecal transplantation, and microbial enzyme inhibitors has become a potential therapeutic approach for many metabolic disorders. Specifically, a few studies have focused on the cardioprotective effects of probiotics on heart failure.Conclusions:The composition of the gut microbiota in people with heart failure is different from those with healthy status. A reduction in SCFA-producing bacteria in patients with heart failure might be a notable characteristic for patients with heart failure. Moreover, an increase in the microbial potential to produce TMAO and lipopolysaccharides is prominent. More researches focused on the mechanisms of microbial metabolites and the clinical application of multiple therapeutic interventions is necessarily required.