Gut microbial metabolites and cardiometabolic disorders: new targets for prevention and treatment

Graphical Abstract

The human gastrointestinal tract (gut) is inhabited by diverse microorganisms including bacteria, viruses, fungi, archaea, and protozoa, which are collectively known as the gut microbiota. These microorganisms, along with their genetic materials (metagenome) and surrounding environment, are termed the gut microbiome. Gut microbiota function like a metabolically active ‘organ’ that may affect host metabolism and health. In healthy states, gut microbiota contribute to the maintenance of essential host functions. However, unfavourable alterations in microbial diversity, abundance, and linked activity, i.e. microbial dysbiosis, may adversely affect host health. In the past three decades, numerous population-based studies have consistently linked the gut microbiome to a broad range of disorders including cardiometabolic diseases.¹

Incessant efforts have also been made to illustrate the mechanistical pathways that connect gut microbiota with host health and to decipher the microbiota–host interactions. Gut microbiota-derived metabolites, which are produced in ingestion, digestion, and absorption of foods and xenobiotics by gut microbiota in the gastrointestinal tract, have attracted considerable attention due to their roles in microbiota–host cross-talk and links with human diseases. In 2011, Dr Stanley Hazen’s team at the Cleveland Clinic published a ground-breaking study in which circulating trimethylamine N-oxide (TMAO), a metabolite synthesized from gut microbiota metabolism of dietary precursors including choline, l-carnitine, and betaine that come mainly from red meat, egg, and full-fat dairy products, was associated with risk of cardiovascular disease (CVD). Analyses in animal models demonstrated that TMAO accelerated atherosclerosis, through promoting vascular inflammation and reducing reverse cholesterol transport.² Since then, the relationships between TMAO and CVD events have been unswervingly demonstrated in various populations. In addition to TMAO, a group of studies have identified other cardiometabolic disease-associated gut microbial metabolites such as secondary bile acids, short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), phytoestrogens, and lipopolysaccharide.³

In this issue of the European Heart Journal, Wenzl et al. report a study performed in three independent prospective cohorts of European populations from Switzerland and Germany, including a total of >7100 participants with acute or chronic coronary syndrome (coronary artery disease; CAD).⁴ Circulating imidazole propionate (ImP) levels were measured in baseline samples, and the primary outcomes were major adverse cardiovascular events (MACE), defined as the first occurrence of a composite of death, non-fatal myocardial infarction, or non-fatal stroke during 1–3 years of follow-up. The study found that each log2 increase of circulating ImP was associated with a 22%–134% higher risk of MACE, and a 34%–138% higher risk of mortality in the study cohorts. The analyses were adjusted for traditional risk factors and blood TMAO, indicating an independent predictive value of ImP. In addition, high ImP levels were associated with cardiometabolic characteristics including high body mass index (BMI), systemic inflammation, impaired glucose metabolism, and hypertension, as well as coronary microvascular obstruction. These findings, taken together, suggest that high levels of circulating ImP may detrimentally affect the prognosis of CAD and increase risks of cardiometabolic diseases and mortality in patients with CAD. Therefore, ImP holds promise to be a new therapeutic target.

Imidazole propionate is a derived metabolite produced by gut microbiota from histidine, an essential amino acid obtained solely from dietary sources; and its metabolic pathways are mediated by multiple bacterial groups and microbial enzymes. ImP was first discovered in patients with intestinal inflammation in 1970,⁵ with effects including inducing intestinal inflammation, impairing the intestinal barrier, and influencing goblet cell proliferation. In 2018, Koh et al. reported that circulating ImP was associated with type 2 diabetes, through impairing insulin signalling at the level of insulin receptor substrate.⁶ In another study, it was found that ImP levels were increased in subjects with pre-diabetes and diabetes, and with low bacterial gene richness and Bacteroides 2 enterotype, which was related to increased abundance of the genes involved in ImP biosynthesis from dietary histidine. In addition, ImP showed an association with systemic inflammation.⁷

Imidazole propionate may influence not only the prognosis of cardiovascular diseases, but also the development of these disorders from the incipient stage. In a recent study, Mastrangelo et al. screened plasma un-targeted metabolomics in atherosclerosis-prone Apoe^−/− mice fed high-cholesterol (HC) diets.⁸ Plasma levels of ImP were significantly associated with atherosclerosis and changes in gut microbial ecology, particularly with a relative enrichment of Escherichia and Shigella, or Eubacterium. Further analyses in 400 asymptomatic people, including 295 participants with subclinical atherosclerosis assessed by multiterritorial and multimodal imaging and 105 controls without atherosclerosis, indicated that plasma concentrations of ImP were selectively increased in individuals with subclinical atherosclerosis compared with controls. Such observations were replicated in an independent cohort with impaired glucose tolerance (IGT). In addition, 16S rDNA sequencing of faecal samples indicated correlations of ImP with the relative abundance of Veillonella and Acidaminococcus, and inverse correlations with Erysipelotrichaceae and Coriobacteriaceae families, which were altered in individuals with CVD.⁸ The findings by Wenzl et al. also align with the results from a prior study including two cohorts of European (n = 1985) and North American (n = 2155) populations, in which serum ImP was cross-sectionally associated with reduced ejection fraction and risks of CVD and heart failure, and prospectively associated with 5 year mortality.⁹

The studies by Wenzl et al. and others provide important evidence linking circulating ImP to cardiometabolic disorders. However, a significant research gap remains. First, current evidence is mainly from observational studies in less ethnically diverse populations with a relatively short-term follow-up or small sizes, subject to various biases such as reverse causation and type I error. Further investigations in diverse cohorts with long follow-up and large sizes are warranted to validate the findings and demonstrate their generalizability. Second, while observational studies provide promising evidence, the causal relationship between ImP and cardiometabolic disorders has yet to be established. Because a ‘gold-standard’ clinical trial testing the effects of ImP on health outcomes in humans is ethically challenging, Mendelian randomization analysis could be applied to validate the causality. Notably, the results from Mendelian randomization studies are conflicting for other microbial metabolites such as TMAO.¹⁰ Third, the specific bacterial communities involved in the production of ImP have yet to be comprehensively elucidated. Such knowledge will advance precision interventions for modulating ImP. Moreover, in previous studies, blood ImP showed associations with dietary factors such as fibre and unsaturated fat,⁷ as well as dietary pattern such as the Mediterranean diet.⁹ Testing the effectiveness of dietary and lifestyle modifications on changes of ImP in clinical trials will inform the development of new prevention and treatment strategies.

The accumulating data from epidemiological and experimental studies have progressively deepened our understanding of microbiota–host interactions. However, thus far, our knowledge on the role of gut microbial metabolites in the development and prognosis of cardiometabolic disorders is still inadequate. Previous studies have identified hundreds of circulating metabolites correlated with functional components of the gut microbiome.¹¹ The advances of technologies for metagenome sequencing and metabolomics profiling will lead to the discovery of more gut microbial metabolites. Further studies are called for to investigate the expanding panel of microbial metabolites in relation to cardiometabolic disorders, and validate the causality.

In addition, most previous studies on gut microbial metabolites have focused on those in the blood, while metabolites inside the gastrointestinal track, particularly faecal metabolites, are severely understudied. Faeces contain a wide array of microbial metabolites, and the faecal metabolome has strong relationships with the compositions (abundance and diversity) of the gut microbiome.¹² In a recent study, it was found that the faecal metabolome explained on average 67.7% of the variance of gut microbial compositions, and acted as functional readouts of the microbial activity in connection with host health phenotypes.¹³ In another study, it was found that gut microbial metabolic pathways were associated with 95% of faecal metabolites, indicating that faecal metabolites might play a pivotal role in metabolic pathways driving microbiota–host interactions.¹⁴ Notably, a sizable group of metabolites are shared between faeces and blood. Zierer et al. reported that, among 1116 metabolites detected in faeces, 469 were also found in blood.¹³ However, the faecal metabolome encompasses separate and unique microbial metabolites that are not present in blood and may independently affect host health, which merits extensive investigations.

Cardiometabolic diseases represent the leading causes of death worldwide. Currently, prediction of cardiometabolic risk primarily relies on traditional risk factors such as age, sex, smoking status, blood pressure, glucose, lipids, etc. The gut microbiome and its derived metabolites have emerged as new risk factors, and hold great promise in predicting the risk and prognosis of cardiometabolic diseases. These new risk factors are modifiable, and therefore have the potential to become novel targets in interventions for disease prevention and treatment. Dietary and lifestyle modifications have shown effects in improving gut microbial metabolites such as TMAO.¹⁵ Faecal microbiota transplantation (FMT) introducing a diverse and balanced microbiota into the recipient’s gut has also shown effectiveness in lowering microbial metabolites, and is potentially an effective approach for modulating ImP. In addition, drugs such as statins may change circulating gut microbial metabolites.¹⁶ Unbalanced microorganisms in the gastrointestinal track generate various harmful metabolites which may jointly impact host health. Pharmacological interventions that improve the global microbial community would be more efficient and engender greater benefits.