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Background: Vitamin A is essential for physiological processes like vision and immunity. Vitamin A's effect on gut microbiome composition, which affects absorption and metabolism of other vitamins, is still unknown. Here we examined the relationship between gut metagenome composition and six vitamin A-related metabolites (two retinoid: -retinol, 4 oxoretinoic acid (oxoRA) and four carotenoid metabolites, including beta-cryptoxanthin and three carotene diols). Methods: We included 1053 individuals from the TwinsUK cohort with vitamin A-related metabolites measured in serum and faeces, diet history, and gut microbiome composition assessed by shotgun metagenome sequencing. Results were replicated in 327 women from the ZOE PREDICT-1 study. Results: Five vitamin A-related serum metabolites were positively correlated with microbiome alpha diversity (r = 0.15 to r = 0.20, p < 4 × 10−6). Carotenoid compounds were positively correlated with the short-chain fatty-acid-producing bacteria Faecalibacterium prausnitzii and Coprococcus eutactus. Retinol was not associated with any microbial species. We found that gut microbiome composition could predict circulating levels of carotenoids and oxoretinoic acid with AUCs ranging from 0.66 to 0.74 using random forest models, but not retinol (AUC = 0.52). The healthy eating index (HEI) was strongly associated with gut microbiome diversity and with all carotenoid compounds, but not retinoids. We investigated the mediating role of carotenoid compounds on the effect of a healthy diet (HEI) on gut microbiome diversity, finding that carotenoids significantly mediated between 18 and 25% of the effect of HEI on gut microbiome alpha diversity. Conclusions: Our results show strong links between circulating carotene compounds and gut microbiome composition and potential links to a healthy diet pattern. [ABSTRACT FROM AUTHOR]

Metabolomics can uncover physiological responses to prebiotic fibre and omega-3 fatty acid supplements with known health benefits and identify response-specific metabolites. We profiled 534 stool and 799 serum metabolites in 64 healthy adults following a 6-week randomised trial comparing daily omega-3 versus inulin supplementation. Elastic net regressions were used to separately identify the serum and stool metabolites whose change in concentration discriminated between the two types of supplementations. Random forest was used to explore the gut microbiome's contribution to the levels of the identified metabolites from matching stool samples. Changes in serum 3-carboxy-4-methyl-5-propyl-2-furanpropanoate and indoleproprionate levels accurately discriminated between fibre and omega-3 (area under the curve (AUC) = 0.87 [95% confidence interval (CI): 0.63–0.99]), while stool eicosapentaenoate indicated omega-3 supplementation (AUC = 0.86 [95% CI: 0.64–0.98]). Univariate analysis also showed significant increases in indoleproprionate with fibre, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate, and eicosapentaenoate with omega-3. Out of these, only the change in indoleproprionate was partly explained by changes in the gut microbiome composition (AUC = 0.61 [95% CI: 0.58–0.64] and Rho = 0.21 [95% CI: 0.08–0.34]) and positively correlated with the increase in the abundance of the genus Coprococcus (p = 0.005). Changes in three metabolites discriminated between fibre and omega-3 supplementation. The increase in indoleproprionate with fibre was partly explained by shifts in the gut microbiome, particularly Coprococcus, previously linked to better health. [ABSTRACT FROM AUTHOR]

Aims: The current study investigates the role of diet in mediating the gut microbiome-cardiovascular association which has not yet been explored in humans.Methods and Results: Using a two-arm dietary intervention study in healthy participants (N = 70), we assessed the effects of omega-3 and fibre supplementation on gut microbiome composition and short-chain fatty acid (SCFA) production. We then investigated how changes in gut microbiome composition correlated with changes in traditional cardiovascular risk factors (cholesterol, triglycerides, blood pressure), cytokines, and novel validated markers such as GlycA and ceramides, previously linked to CVD incidence and mortality. Both interventions resulted in significant drops in blood pressure, cholesterol, proinflammatory cytokines, GlycA and ceramides (all P < 0.05). Decreases in the atherogenic low-density lipoprotein triglyceride fraction, in total serum cholesterol were correlated with increases in butyric acid-production [β(SE) = −0.58 (0.06), P < 0.001; −0.53 (0.04), P < 0.001] and nominally associated with increases in some butyrogenic bacteria. Drops in GlycA were linked to increases in Bifidobacterium [β(SE) = −0.32 (0.04), P = 0.02] and other SCFAs including acetic acid [β(SE) = −0.28 (0.04), P = 0.02] and propionic acid [β(SE) = −0.3 (0.04), P = 0.02]. Additionally, we report for the first-time reductions in specific ceramide ratios that have been shown to predict CVD mortality and major adverse cardiovascular events such as d18:1/16:0, d18:0/24:0, and d18:1/24:1 which were associated with the reduction in the abundance in Colinsella and increases in Bifidobacteriuim and Coprococcus 3 and SCFAs (all P < 0.05).Conclusion: Overall, these findings support the potential of using simple dietary interventions to alter validated biomarkers linked to cardiovascular risk via the gut microbiome composition and its metabolic functions.

Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicotinate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02–5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16–1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97–8], P = 0.0002). Although these are host-produced metabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset. Article Highlights: Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. We investigated whether there is a fecal metabolite signature of impaired fasting glucose (IFG) and the possible underlying mechanisms of action. We identified a fecal metabolite signature of IFG associated with prevalent IFG in two independent cohorts and incident type 2 diabetes in a subanalysis. Although the signature consists of metabolites of nonmicrobial origin, it is strongly correlated with gut microbiome composition. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes by affecting intestinal absorption or excretion of host compounds and xenobiotics. [ABSTRACT FROM AUTHOR]

Background: Acetate is a short-chain fatty acid (SCFA) produced by gut bacteria, which has been implicated in cardio-metabolic health. Here we examine the relationships of circulating acetate levels with gut microbiome composition and diversity and with visceral fat in a large population-based cohort. Results: Microbiome alpha-diversity was positively correlated with circulating acetate levels (Shannon, Beta [95%CI] = 0.12 [0.06, 0.18], P = 0.002) after adjustment for covariates. Six serum acetate-associated bacterial genera were also identified, including positive correlations with Coprococcus , Barnesiella , Ruminococcus , and Ruminococcaceae NK4A21 and negative correlations were observed with Lachnoclostridium and Bacteroides. We also identified a correlation between visceral fat and serum acetate levels (Beta [95%CI] = −0.07 [−0.11, −0.04], P = 2.8 × 10–4) and between visceral fat and Lachnoclostridium (Beta [95%CI] = 0.076 [0.042, 0.11], P = 1.44 × 10–5). Formal mediation analysis revealed that acetate mediates ∼10% of the total effect of Lachnoclostridium on visceral fat. The taxonomic diversity showed that Lachnoclostridium and Coprococcus comprise at least 18 and 9 species, respectively, including novel bacterial species. By predicting the functional capabilities, we found that Coprococcus spp. present pathways involved in acetate production and metabolism of vitamins B, whereas we identified pathways related to the biosynthesis of trimethylamine (TMA) and CDP-diacylglycerol in Lachnoclostridium spp. Conclusions: Our data indicates that gut microbiota composition and diversity may influence circulating acetate levels and that acetate might exert benefits on certain cardio-metabolic disease risk by decreasing visceral fat. Coprococcus may play an important role in host health by its production of vitamins B and SCFAs, whereas Lachnoclostridium might have an opposing effect by influencing negatively the circulating levels of acetate and being involved in the biosynthesis of detrimental lipid compounds. [ABSTRACT FROM AUTHOR]

Epidemiologic and genomic studies have progressively improved our understanding of the causation of hypertension and the complex relationship with diet and environment. The majority of Mendelian forms of syndromic hypotension and hypertension (HTN) have all been linked to mutations in genes whose encoded proteins regulate salt–water balance in the kidney, supporting the primacy of the kidneys in blood pressure regulation. There are more than 1,477 single nucleotide polymorphisms associated with blood pressure and hypertension and the challenge is establishing a causal role for these variants. Hypertension is a complex multifactorial phenotype and it is likely to be influenced by multiple factors including interactions between diet and lifestyle factors, microbiome, and epigenetics. Given the finite genetic variability that is possible in humans, it is likely that incremental gains from single marker analyses have now plateaued and a greater leap in our understanding of the genetic basis of disease will come from integration of other omics and the interacting environmental factors. In this review, we focus on emerging results from the microbiome and metabolomics and discuss how leveraging these findings may facilitate a deeper understanding of the interrelationships between genomics, diet, and microbial ecology in humans in the causation of essential hypertension. [ABSTRACT FROM AUTHOR]

The optimal dietary pattern to improve metabolic function remains elusive. In a 21-day randomized controlled inpatient crossover feeding trial of 20 insulin-resistant obese women, we assessed the extent to which two isocaloric dietary interventions—Mediterranean (M) and high protein (HP)—improved metabolic parameters. Obese women were assigned to one of the following dietary sequences: M–HP or HP–M. Cardiometabolic parameters, body weight, glucose monitoring and gut microbiome composition were assessed. Sixteen women completed the study. Compared to the M diet, the HP diet was more effective in (i) reducing insulin resistance (insulin: Beta (95% CI) = −6.98 (−12.30, −1.65) µIU/mL, p = 0.01; HOMA-IR: −1.78 (95% CI: −3.03, −0.52), p = 9 × 10−3); and (ii) improving glycemic variability (−3.13 (−4.60, −1.67) mg/dL, p = 4 × 10−4), a risk factor for T2D development. We then identified a panel of 10 microbial genera predictive of the difference in glycemic variability between the two diets. These include the genera Coprococcus and Lachnoclostridium, previously associated with glucose homeostasis and insulin resistance. Our results suggest that morbidly obese women with insulin resistance can achieve better control of insulin resistance and glycemic variability on a high HP diet compared to an M diet. [ABSTRACT FROM AUTHOR]