Search

The aging phenotype in humans has been thoroughly studied but a detailed metabolic profiling capable of shading light on the underpinning biological processes of longevity is still missing. Here using a combined metabonomics approach compromising holistic (1)H-NMR profiling and targeted MS approaches, we report for the first time the metabolic phenotype of longevity in a well characterized human aging cohort compromising mostly female centenarians, elderly, and young individuals. With increasing age, targeted MS profiling of blood serum displayed a marked decrease in tryptophan concentration, while an unique alteration of specific glycerophospholipids and sphingolipids are seen in the longevity phenotype. We hypothesized that the overall lipidome changes specific to longevity putatively reflect centenarians' unique capacity to adapt/respond to the accumulating oxidative and chronic inflammatory conditions characteristic of their extreme aging phenotype. Our data in centenarians support promotion of cellular detoxification mechanisms through specific modulation of the arachidonic acid metabolic cascade as we underpinned increased concentration of 8,9-EpETrE, suggesting enhanced cytochrome P450 (CYP) enzyme activity. Such effective mechanism might result in the activation of an anti-oxidative response, as displayed by decreased circulating levels of 9-HODE and 9-oxoODE, markers of lipid peroxidation and oxidative products of linoleic acid. Lastly, we also revealed that the longevity process deeply affects the structure and composition of the human gut microbiota as shown by the increased extrection of phenylacetylglutamine (PAG) and p-cresol sulfate (PCS) in urine of centenarians. Together, our novel approach in this representative Italian longevity cohort support the hypothesis that a complex remodeling of lipid, amino acid metabolism, and of gut microbiota functionality are key regulatory processes marking exceptional longevity in humans.

Health is influenced by genetic, lifestyle, and diet determinants; therefore, nutrition plays an essential role in health management. Still, the substantiation of nutritional health benefits is challenged by the intrinsic macro- and micronutrient complexity of foods and individual responses. Evidence of healthy effects of food requires new strategies not only to stratify populations according to their metabolic requirements but also to predict and measure individual responses to dietary intakes. The influence of the gut microbiome and its interaction with the host is pivotal to understand nutrition and metabolism. Thus, the modulation of the gut microbiome composition by alteration of food habits has potentialities in health improvement or even disease prevention. Dietary polyphenols are naturally occurring constituents in vegetables and fruits, including coffee and cocoa. They are commonly associated to health benefits, although mechanistic evidence in vivo is not yet fully understood. Polyphenols are extensively metabolized by gut bacteria into a complex series of end-products that support a significant effect on the functional ecology of symbiotic partners that can affect the host physiology. This review reports recent nutritional metabolomics inspections of gut microbiota-host metabolic interactions with a particular focus on the cometabolism of cocoa and coffee polyphenols.

A two by two experimental study has been designed to determine the effect of gut microbiota on energy metabolism in mouse models. The metabolic phenotype of germ-free (GF, n = 20) and conventional (n = 20) mice was characterized using a NMR spectroscopy-based metabolic profiling approach, with a focus on sexual dimorphism (20 males, 20 females) and energy metabolism in urine, plasma, liver, and brown adipose tissue (BAT). Physiological data of age-matched GF and conventional mice showed that male animals had a higher weight than females in both groups. In addition, conventional males had a significantly higher total body fat content (TBFC) compared to conventional females, whereas this sexual dimorphism disappeared in GF animals (i.e., male GF mice had a TBFC similar to those of conventional and GF females). Profiling of BAT hydrophilic extracts revealed that sexual dimorphism in normal mice was absent in GF animals, which also displayed lower BAT lactate levels and higher levels of (D)-3-hydroxybutyrate in liver, plasma, and BAT, together with lower circulating levels of VLDL. These data indicate that the gut microbiota modulate the lipid metabolism in BAT, as the absence of gut microbiota stimulated both hepatic and BAT lipolysis while inhibiting lipogenesis. We also demonstrated that (1)H NMR metabolic profiles of BAT were excellent predictors of BW and TBFC, indicating the potential of BAT to fight against obesity.

Dietary preferences influence basal human metabolism and gut microbiome activity that in turn may have long-term health consequences. The present study reports the metabolic responses of free living subjects to a daily consumption of 40 g of dark chocolate for up to 14 days. A clinical trial was performed on a population of 30 human subjects, who were classified in low and high anxiety traits using validated psychological questionnaires. Biological fluids (urine and blood plasma) were collected during 3 test days at the beginning, midtime and at the end of a 2 week study. NMR and MS-based metabonomics were employed to study global changes in metabolism due to the chocolate consumption. Human subjects with higher anxiety trait showed a distinct metabolic profile indicative of a different energy homeostasis (lactate, citrate, succinate, trans-aconitate, urea, proline), hormonal metabolism (adrenaline, DOPA, 3-methoxy-tyrosine) and gut microbial activity (methylamines, p-cresol sulfate, hippurate). Dark chocolate reduced the urinary excretion of the stress hormone cortisol and catecholamines and partially normalized stress-related differences in energy metabolism (glycine, citrate, trans-aconitate, proline, beta-alanine) and gut microbial activities (hippurate and p-cresol sulfate). The study provides strong evidence that a daily consumption of 40 g of dark chocolate during a period of 2 weeks is sufficient to modify the metabolism of free living and healthy human subjects, as per variation of both host and gut microbial metabolism.

Symbiotic gut microbes can have a significant influence on host health and disease etiology. Here, we assessed the effects of inoculating germfree mice with human baby microbiota (HBM, n=17) on the biochemical composition of intact intestinal tissues (duodenum, jejunum, ileum, proximal and distal colon) using magic-angle-spinning 1H NMR spectroscopy. We compared the HBM tissue metabolite profiles with those from conventional (n=9) and conventionalized (n=10) mice. Each topographical intestinal region showed a specific metabolic profile that was altered differentially by the various microbiomes, especially for osmolytes. In each animal model, duodenum had higher ethanolamine and myo-inositol, and ileum higher taurine and betaine than other gut regions. HBM mice showed lower taurine and myo-inositol in the colon, and all ex-germfree animals had higher taurine, choline and ethanolamine in the jejunum. Interestingly, the jejunum of HBM mice was marked by a higher glutathione level and lower concentrations of its precursor methionine when compared to other groups. Proximal and distal colon tissues were differentiated in the different microbiome models by the concentrations of bacterial products (higher in conventional animals). These studies show the depth of gut microbiome modulations of the intestinal biochemistry.

Coevolution shapes interorganismal crosstalk leading to profound and diverse cellular and metabolic changes as observed in gut dysbiosis in human diseases. Here, we modulated a simplified gut microbiota using pro-, pre-, and synbiotics to assess the depth of systemic metabolic exchanges in mice, using a multicompartmental modeling approach with metabolic signatures from 10 tissue/fluid compartments. The nutritionally induced microbial changes modulated host lipid, carbohydrate, and amino acid metabolism at a panorganismal scale. Galactosyl-oligosaccharides reduced lipogenesis, triacylglycerol incorporation into lipoproteins and triglyceride concentration in the liver and the kidney. Those changes were not correlated with decreased plasma lipoproteins that were specifically induced by L. rhamnosus supplementation. Additional alteration of transmethylation metabolic pathways (homocysteine-betaine) was observed in the liver and the pancreas following pre- and synbiotic microbial modulation, which may be of interest for control of glucose metabolism and insulin sensitivity. Probiotics also reduced hepatic glycogen and glutamine and adrenal ascorbate with inferred effects on energy homeostasis, antioxidation, and steroidogenesis. These studies show the breadth and the depth of gut microbiome modulations of host biochemistry and reveal that major mammalian metabolic processes are under symbiotic homeostatic control.

Metabonomics is a well established analytical approach for the analysis of physiological regulatory processes via the metabolic profiling of biofluids and tissues in living organisms. Its potential is fully exploited in the field of "nutrimetabonomics" that aims at assessing the metabolic effects of active ingredients and foods in individuals. Yet, one of the greatest challenges in nutrition research is to decipher the critical interactions between mammalian organisms and environmental factors, including the gut microbiota. "Nutrimetabonomics" is today foreseen as a powerful approach for future nutritional programs tailored at health maintenance and disease prevention.

To characterize the impact of gut microbiota on host metabolism, we investigated the multicompartmental metabolic profiles of a conventional mouse strain (C3H/HeJ) (n=5) and its germ-free (GF) equivalent (n=5). We confirm that the microbiome strongly impacts on the metabolism of bile acids through the enterohepatic cycle and gut metabolism (higher levels of phosphocholine and glycine in GF liver and marked higher levels of bile acids in three gut compartments). Furthermore we demonstrate that (1) well-defined metabolic differences exist in all examined compartments between the metabotypes of GF and conventional mice: bacterial co-metabolic products such as hippurate (urine) and 5-aminovalerate (colon epithelium) were found at reduced concentrations, whereas raffinose was only detected in GF colonic profiles. (2) The microbiome also influences kidney homeostasis with elevated levels of key cell volume regulators (betaine, choline, myo-inositol and so on) observed in GF kidneys. (3) Gut microbiota modulate metabotype expression at both local (gut) and global (biofluids, kidney, liver) system levels and hence influence the responses to a variety of dietary modulation and drug exposures relevant to personalized health-care investigations.

The transgenomic metabolic effects of exposure to either Lactobacillus paracasei or Lactobacillus rhamnosus probiotics have been measured and mapped in humanized extended genome mice (germ-free mice colonized with human baby flora). Statistical analysis of the compartmental fluctuations in diverse metabolic compartments, including biofluids, tissue and cecal short-chain fatty acids (SCFAs) in relation to microbial population modulation generated a novel top-down systems biology view of the host response to probiotic intervention. Probiotic exposure exerted microbiome modification and resulted in altered hepatic lipid metabolism coupled with lowered plasma lipoprotein levels and apparent stimulated glycolysis. Probiotic treatments also altered a diverse range of pathways outcomes, including amino-acid metabolism, methylamines and SCFAs. The novel application of hierarchical-principal component analysis allowed visualization of multicompartmental transgenomic metabolic interactions that could also be resolved at the compartment and pathway level. These integrated system investigations demonstrate the potential of metabolic profiling as a top-down systems biology driver for investigating the mechanistic basis of probiotic action and the therapeutic surveillance of the gut microbial activity related to dietary supplementation of probiotics.