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We'd like to understand how you use our websites in order to improve them. Register your interest. With the expanding use of next-gen sequencing NGS to diagnose the thousands of rare Mendelian genetic diseases, it is critical to be able to interpret individual DNA variation. To calculate the significance of finding a rare protein-altering variant in a given gene, one must know the frequency of seeing a variant in the general population that is at least as damaging as the variant in question. We developed a general method to better interpret the likelihood that a rare variant is disease causing if observed in a given gene or genic region mapping to a described protein domain, using genome-wide information from a large control sample. Based on data from individuals in the Genomes Project dataset, we calculated the number of individuals who have a rare variant in a given gene for numerous filtering threshold scenarios, which may be used for calculating the significance of an observed rare variant being causal for disease.

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We'd like to understand how you use our websites in order to improve them. Register your interest. Evidence from the literature keeps highlighting the impact of mutualistic bacterial communities of the gut microbiota on human health. The gut microbita is a complex ecosystem of symbiotic bacteria which contributes to mammalian host biology by processing, otherwise, indigestible nutrients, supplying essential metabolites, and contributing to modulate its immune system.

Advances in sequencing technologies have enabled structural analysis of the human gut microbiota and allowed detection of changes in gut bacterial composition in several common diseases, including cardiometabolic disorders. Biological signals sent by the gut microbiota to the host, including microbial metabolites and pro-inflammatory molecules, mediate microbiome—host genome cross-talk.

This rapidly expanding line of research can identify disease-causing and disease-predictive microbial metabolite biomarkers, which can be translated into novel biodiagnostic tests, dietary supplements, and nutritional interventions for personalized therapeutic developments in common diseases.

Here, we review results from the most significant studies dealing with the association of products from the gut microbial metabolism with cardiometabolic disorders. We underline the importance of these postbiotic biomarkers in the diagnosis and treatment of human disorders. It functions as a bioreactor with enormous metabolic capacity and cooperates with the host in many biological functions to form a symbiotic mammalian superorganism [ 3 ].

Gut bacteria release bioactive molecules in the gut that can be used by gut mucosal cells or absorbed in the circulation and transported to the liver where they are transformed. The gut microbiota has raised considerable interest due to the possibility of carrying out deep microbiome sequence analysis [ 4 , 5 ] and to use this information in association studies with various disease conditions.

Changes in the architecture of the gut microbiome have been consistently associated with type 2 diabetes and obesity [ 6 , 7 , 8 ], which may be accounted for by low microbial gene richness suggesting reduced gut bacterial diversity in patients [ 9 ].

Relative resistance to diet-induced obesity and improved glucose tolerance in germ-free rodents also suggest that gut microbiota depletion affects host metabolism and susceptibility to diabetes and obesity [ 10 ]. However, the effects of antibiotic-mediated reduction in gut microbiota diversity on host metabolism and insulin sensitivity in humans remain controversial [ 11 , 12 ]. The gut microbiota is the central regulator of mammalian fuel intake by processing nutrients into absorbable compounds.

It also produces vitamins and essential metabolites that are not synthesised by the host. Changes in the architecture of the gut microbiota are likely to have important repercussion on the regulation of host biochemical pathways and metabolic networks. Many bacterial metabolite end-products of the gut microbiota play crucial roles in the host metabolic homeostasis, immunological processes, and neurobiology, and underline the fundamental importance of this extended genome in human health and disease [ 13 , 14 , 15 ].

This article reviews results from association studies of phenotypes relevant to cardiometabolic disorders with products from gut microbial metabolism illustrated in Fig.

We do not address intestinal nutrient sensing that triggers humoral and neural responses underlying important gut—brain cross-talk signaling mechanisms in diabetes and obesity, which has been recently reviewed [ 16 ] and addressed in landmark papers [ 17 , 18 ]. This review paper underlines the enormous metabolic capacity of gut bacteria essential for the host and further underscores the importance of high-density metabolic data acquisition from biological samples to address whole-body regulation of biological processes mediated by microbial metabolites.

Examples of essential metabolites synthesised by gut bacteria. Metabolites produced by the gut microbiota from dietary substrates are transported to the liver where they can undergo enzymatic modification e. SCFAs predominantly butyrate can be used locally as an energy source by gut mucosal cells. Short-chain fatty acids SCFAs are produced by anaerobic gut bacteria in the caecum and the proximal colon principally through the fermentation of dietary fibers e.

The most abundant SCFAs are butyrate, acetate, and propionate [ 20 ]. SCFAs are used as an energy source by gut mucosal cells or transferred to the circulation to generate an important source of calory and energy for the organism and to act as signaling molecules. Upon synthesis by the gut microbiota, both propionate and butyrate have local effects as the primary energy source in by gut mucosal cells butyrate and by activating intestinal gluconeogenesis propionate through distinct mechanisms [ 18 , 21 ].

Distal effects of SCFAs are illustrated by propionate-mediated stimulation of liver gluconeogenesis, de novo lipid synthesis, and protein synthesis, whereas acetate is a precursor for cholesterol synthesis. SCFAs have multiple regulatory roles in energy homeostasis, insulin sensitivity, and glucose and lipid metabolism [ 22 ]. Association between elevated fecal SCFAs and obesity has emerged from studies in humans [ 23 ] and in mice treated with low doses of antibiotics [ 24 ].

However, there is a general agreement for their association with reduced risk of cardiovascular and metabolic diseases. Increased plasma insulin in response to propionate was initially demonstrated in healthy volunteers following long-term intracolonic administration of propionate, and was subsequently confirmed in vitro in human islets incubated with propionate [ 25 ]. Treatment of overweight individuals with colonic delivery of propionate results in reduced energy intake, adiposity, and lipid liver content, and increased plasma levels of peptide YY PYY and glucagon-like peptide 1 GLP-1 produced locally by enteroendocrine L cells [ 26 ].

The effect of propionate on the production of PYY and GLP-1 was confirmed in mouse and rat models following intracolonic propionate administration, and in isolated colonocytes incubated with propionate [ 27 ]. Results from an extensive study in obese patients showed that rectal administration of individual SCFAs was associated with increased fasting fat oxidation and energy expenditure, decreased carbohydrate oxidation, and reduced whole-body lipolysis [ 28 ].

Further evidence of the beneficial role of microbial SCFAs on human health was obtained in a series of experiments in mice transplanted with gut microbiota from twin pairs discordant for obesity [ 29 ]. Mice inoculated with microbiota from lean co-twins showed higher caecal levels of butyrate and propionate than mice inoculated with gut bacteria from obese co-twins, suggesting that capacity to breakdown and ferment polysaccharides into SCFAs is greater in the microbiota from lean individuals than in that of obese patients.

Experiments in animal models have confirmed the associations of SCFAs with host metabolism and diseases. Glucose tolerance and insulin sensitivity are significantly improved in rats treated with diet enriched in butyrate or propionate [ 18 ].

HFD-induced insulin resistance and obesity in rats is associated with increased plasma concentration of acetate produced by the gut microbiota [ 17 ]. Relationship between acetate and phenotypes related to diabetes and obesity is consistent with results from oral administration of acetate in the Otsuka Long Evans Tokushima Fatty OLETF rat model of genetically determined obesity and diabetes, which improved glucose tolerance and decreased body weight, hepatic lipid content, and abdominal fat [ 33 ].

Data in humans and in experimental models also demonstrated that elevated SCFA can contribute to lowering blood pressure and improving vascular phenotypes. Results from two independent meta-analyses of randomized-controlled trials suggested that increased SCFA induced by probiotics or dietary fiber intake was associated with a reduction in blood pressure in patients with hypertension [ 34 , 35 ].

More recently, results from the metabolic analyses in the INTERMAP study population showed that h urinary excretion of formate was positively correlated with urinary sodium excretion and inversely associated with both systolic and diastolic blood pressure [ 36 ].

Experiments in vivo in mice and in in vitro systems confirmed these observations. Intravenous administration of propionate in vivo in mice lowered blood pressure [ 37 ]. Mice fed diet rich in fiber or supplemented with acetate showed a significant reduction in high blood pressure, cardiac fibrosis, and left-ventricular hypertrophy induced by deoxycorticosterone acetate DOCA treatment in mice [ 38 ]. Repeated intraperitoneal injections of butyrate in mice chronically infused with angiotensin II were able to significantly reduce blood pressure [ 39 ].

In vitro experiments showed that butyrate, propionate, and acetate induced dilatation of human colonic resistance vessels [ 40 ], and exhibited vasorelaxant properties when tested in isolated rat caudal artery [ 41 ]. The cellular mediators of the effects of SCFAs are partly elucidated. In a series of elegant experiments in mice and in 3T3-L1 adipocytes, Kimura and colleagues showed that activation of GPR43 by SCFAs results in the inhibition of insulin signaling and reduction of lipid accumulation in fat [ 44 ].

On the other hand, another study suggests that relative resistance to obesity in mice-fed HFD supplemented with butyrate and propionate is independent from GPR41 activation [ 32 ].

GPR41 is also expressed in the vascular endothelium where it mediates the role of SCFAs in blood pressure regulation [ 37 , 45 ]. Butyrate also plays an important role in gene expression through its inhibitory effect of histone deacetylases [ 30 ], which affects chromatin structure by deacetylation of proteins, and may affect nucleosome positioning [ 31 ].

Results from extensive studies of the metabolism of choline and methylamines in humans and rodent models are, perhaps, the most compelling illustrations played by the role of gut bacterial metabolites in cardiometabolic diseases. Trimethylamine TMA is an amine synthesised from dietary components, l -carnitine, lecithin, choline, and betaine by microbial enzymes Fig. Representation of the methylamine pathway illustrating the microbiota—host co-metabolism.

The TMA substrate betaine can be synthesised from choline and l -carnitine. Relationships between TMAO and cardiovascular risk are based on correlative inferences. The multiple detrimental roles of TMAO on human health are still debated [ 48 , 49 , 50 ] and thus keep raising interest. For example, elevated plasma levels of TMAO secondary to l -carnitine treatment in ApoE knock-out mice expressing the cholesteryl-ester transfer protein CEPT resulted in a reduction of aortic lesions regardless of plasma lipid and lipoprotein levels, and did not alter the formation of macrophage foam cell [ 51 ].

The initial observations in humans showing that choline deficiency results in hepatic steatosis reversible by choline supplementation have demonstrated the importance of choline metabolism for the host [ 52 ]. Fat-fed S6 mice exhibited the disruptions of choline metabolism characterised by reduction in plasma levels of phosphatidylcholine and elevated urinary excretion of dimethylamine, TMA, and TMAO. Conversion of choline into methylamines by microbiota in S6 mice on HFD resulted in the reduction of the bioavailability of choline.

Subsequent investigations in humans mostly focused on the endpoint of the methylamine pathway TMAO , which is synthesised by the mammalian metabolism, rather than on its substrate TMA synthesised by the gut microbiome.

Elevated plasma levels of TMAO have been associated with increased risk of type 2 diabetes mellitus [ 54 ], cardiovascular and cerebrovascular diseases [ 55 , 56 , 57 ], incident thrombosis risk [ 58 ], and carotid intima-media thickness [ 59 ] in population-based and intervention studies. Further experiments in mice indicated that elevated levels of circulating TMAO resulted in enhanced aortic atherosclerotic plaque lesions, increased thrombus formation in the carotid artery, perturbed bile acid metabolism, downregulated expression of genes involved in reverse cholesterol transport, and stimulated expression of two macrophage scavenger receptors CD36, SRA , without significant changes in plasma lipids, glycemia, and hepatic triglycerides [ 56 , 57 , 58 ].

Most recently, a study in HFD-fed mice showed that urinary TMAO prior to the dietary challenge is the most significant predictive marker of future heterogeneity in physiological and behavioral anomalies [ 60 ]. These changes already exist prior to the dietary challenge and predicted future divergence in disease patterns characterised by various degrees of glucose intolerance and obesity, which correlated with significant divergences in insulin secretion, circulating triglycerides and lipoproteins, and measures of anxiety and activity between extreme responder groups [ 60 ].

For example, mice that developed glucose intolerance in response to HFD exhibited a significant increase in urine concentration of products of choline metabolism e. This study also showed that chronic subcutaneous infusion of TMAO in HFD-fed mice resulted in paradoxical improvement of both glucose tolerance and glucose-induced insulin secretion, which was confirmed in vitro in isolated pancreatic islets incubated with TMAO.

These findings suggest the existence of differences in the composition or the activity of gut bacteria between isogenic individuals prior to any dietary stimulus contribute to the biosynthesis of TMA and predispose to future development of disease phenotypes. The possible implication of the epigenome in this phenomenon is supported by a recent study, showing that depletion of circulating choline in mice caused by intestinal colonisation of choline-utilising bacterial communities results in reduced DNA methylation in several organs and deteriorated metabolic and behavioral phenotypes [ 63 ].

Adapted from Dumas et al. Methylamine-mediated discrimination of adaptation to dietary challenge in isogenic mice. Despite growing interest in TMAO biology, its cellular ligands remain unknown.

Identification of cellular ligands of TMAO is the next milestone to demonstrate causality with diseases. In contrast, a specific ligand for its precursor TMA has been identified [ 64 ]. Following a screening of 42 amines and amine-related compounds, TMA, and to a lesser extent dimethylethylamine DMEA , activate the trace amine-associated receptor TAAR5, an olfactory G protein-coupled receptor, in a concentration-dependent manner.

However, little is known about the biological roles of TMA. The branched-chain amino acids BCAAs , leucine, isoleucine, and valine, are among the nine essential amino acids synthesised by gut bacteria [ 67 ].

A significant association of the biosynthesis of BCAAs and tryptophan with the bacterial species Prevotella copri provided the evidence of functional relationships between changes in the composition of the gut microbiome and these metabolites, as well as potentially indolelactic acid, in insulin-resistant patients [ 68 ]. The direct role of BCAAs in the stimulation of insulin secretion [ 69 ] and correlations between elevated concentration of plasma BCAAs with obesity and serum insulin [ 70 ] have been known for decades.

The possible exploitation of BCAAs as biomarkers of cardiometabolic diseases has been addressed in multiple independent patient and population studies, and underlined the complex relationships between circulating BCAAs and disease risk, and the possible implication of confounding factors.

Association of plasma BCAAs with insulin resistance was reported in obese [ 71 ], non-obese [ 72 ], and non-diabetic [ 68 , 73 , 74 ] individuals, and confirmed in twins [ 75 ]. Similarly, association between levels of circulating BCAAs and adipokine was evidenced in both diabetic [ 76 ] and non-diabetic [ 74 ] individuals. Using various study designs and analytical systems, plasma concentrations of all three BCAAs were also found significantly increased in diabetic patients of the German KORA study [ 77 ], in female patients for the TwinsUK collection [ 78 ], and in a Swedish prospective case control study [ 79 ].

The impact of BCAAs on cardiometabolic phenotypes has been further explored in rodent models and in humans. Conversely, dietary restriction in BCAAs improved glucose homeostasis in mice fed control chow diet [ 80 ] and reduced adiposity and glucose intolerance induced by HFD in mice [ 81 ].

Inoculation of gut microbiota prepared from twin pairs discordant for obesity in mice showed that BCAAs were more elevated when the donor was the obese co-twin, leading to an obese phenotype in transplanted mice, than when the donor was the lean co-twin [ 29 ].

Evidence for a causal role of BCAAs in human diabetes was suggested in longitudinal and genetic studies. Most recently, extensive statistical analysis based on Mendelian randomisation in several large populations showed association between variables related to insulin resistance homeostasis model assessment of insulin resistance—HOMA-IR, fasting insulin and fasting plasma levels of these BCAAs, but failed to identify significant causal effect of BCAAs on either fasting insulin or HOMA-IR [ 83 ].

In contrast, the genetic risk score for insulin resistance traits was significantly associated with increased concentration of plasma BCAAs, indicating a causal impact of insulin resistance on circulating BCAAs. In a large-scale genome-wide association study GWAS , causal relationships between increased type 2 diabetes risk and high levels of BCAAs determined genetically by genetic polymorphisms at five independent genomic regions were further evidenced through Mendelian randomisation in a meta-analysis [ 84 ].

The strongest evidence of association was found with BCAA-raising polymorphisms upstream the gene encoding the protein phosphatase PPM1K on chromosome 4q Bile acids are steroid molecules produced in the liver from cholesterol and, subsequently, processed into secondary bile acids by the gut microbiota. Knowledge of the relationship between gut microbiota and bile acid homeostasis stems from experiments in germ-free mice [ 85 ], in animals treated with broad-spectrum antibiotics [ 86 ] and in gastrectomised mice [ 87 ].

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We'd like to understand how you use our websites in order to improve them. Register your interest. Evidence from the literature keeps highlighting the impact of mutualistic bacterial communities of the gut microbiota on human health. The gut microbita is a complex ecosystem of symbiotic bacteria which contributes to mammalian host biology by processing, otherwise, indigestible nutrients, supplying essential metabolites, and contributing to modulate its immune system. Advances in sequencing technologies have enabled structural analysis of the human gut microbiota and allowed detection of changes in gut bacterial composition in several common diseases, including cardiometabolic disorders. Biological signals sent by the gut microbiota to the host, including microbial metabolites and pro-inflammatory molecules, mediate microbiome—host genome cross-talk.

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