Jordi Mayneris-Perxachs

Plasma fatty acid composition, estimated desaturase activities, and their relation with the metabolic syndrome in a population at high risk of cardiovascular disease

BACKGROUND & AIMS The metabolic syndrome (MetS) is a clustering of various metabolic abnormalities which is associated with increased risk of cardiovascular disease (CVD) and type 2 diabetes mellitus. Due to its increasing prevalence, it has become an important public health concern. Altered fatty acid (FA) composition and desaturase activities have been associated with several metabolic diseases, including MetS. The aim of the present study was to evaluate the relationship of the plasma FA profile and desaturase activities with the MetS in a Mediterranean population at high risk of CVD. METHODS Baseline data from 427 participants aged 55-80 years who took part in the interventional PREDIMED study were obtained. Individual FA was determined in plasma and desaturase activities were estimated from product/precursor ratios. Odds ratios (OR) and partial correlation coefficients were used to examine these relations with MetS and its components, respectively. RESULTS We found higher levels of C14:0, C16:0, C16:1n-7, estimated Δ(9)- or stearoyl-CoA desaturase (SCD), and estimated Δ(6) desaturase (D6D), and lower levels of C18:2n-6 in people with MetS compared to those without it. After adjustment for several confounders, only higher quartiles of C14:0, C16:0, C16:1n-7, and D6D were found to be associated with an increasing prevalence of MetS, while higher quartiles of C18:2n-6 were inversely associated with MetS. High proportions of C14:0, C16:0, C16:1n-7, C20:3n-6, SCD, and D6D, and decreased proportions of C18:2n-6 and estimated Δ(5)-desaturase (D5D) were associated with adverse profiles of several metabolic risk factors. Women showed more unhealthy FA pattern and lipid profiles than men, but only among those with MetS. CONCLUSION A FA composition and estimated desaturase activities consisting in high levels of SFA, SCD and D6D, and low levels of PUFA and D5D are associated with increased MetS probability and are characteristic of people presenting MetS, especially women. These findings support those observed in non-Mediterranean populations in which an altered FA profile and estimated desaturase activities are associated with MetS.

Biomarkers of environmental enteropathy, inflammation, stunting, and impaired growth in children in Northeast Brazil

Critical to the design and assessment of interventions for enteropathy and its developmental consequences in children living in impoverished conditions are non-invasive biomarkers that can detect intestinal damage and predict its effects on growth and development. We therefore assessed fecal, urinary and systemic biomarkers of enteropathy and growth predictors in 375 6–26 month-old children with varying degrees of malnutrition (stunting or wasting) in Northeast Brazil. 301 of these children returned for followup anthropometry after 2-6m. Biomarkers that correlated with stunting included plasma IgA anti-LPS and anti-FliC, zonulin (if >12m old), and intestinal FABP (I-FABP, suggesting prior barrier disruption); and with citrulline, tryptophan and with lower serum amyloid A (SAA) (suggesting impaired defenses). In contrast, subsequent growth was predicted in those with higher fecal MPO or A1AT and also by higher L/M, plasma LPS, I-FABP and SAA (showing intestinal barrier disruption and inflammation). Better growth was predicted in girls with higher plasma citrulline and in boys with higher plasma tryptophan. Interactions were also seen with fecal MPO and neopterin in predicting subsequent growth impairment. Biomarkers clustered into markers of 1) functional intestinal barrier disruption and translocation, 2) structural intestinal barrier disruption and inflammation and 3) systemic inflammation. Principle components pathway analyses also showed that L/M with %L, I-FABP and MPO associate with impaired growth, while also (like MPO) associating with a systemic inflammation cluster of kynurenine, LBP, sCD14, SAA and K/T. Systemic evidence of LPS translocation associated with stunting, while markers of barrier disruption or repair (A1AT and Reg1 with low zonulin) associated with fecal MPO and neopterin. We conclude that key noninvasive biomarkers of intestinal barrier disruption, LPS translocation and of intestinal and systemic inflammation can help elucidate how we recognize, understand, and assess effective interventions for enteropathy and its growth and developmental consequences in children in impoverished settings.

Effects of 1-year intervention with a Mediterranean diet on plasma fatty acid composition and metabolic syndrome in a population at high cardiovascular risk.

Background & Aims Metabolic syndrome (MetS) has become an important public concern due to its increasing prevalence. An altered fatty acid composition has been associated with MetS, but the Mediterranean diet has been shown to have a protective effect. The aim of the present study was to analyze the influence of a Mediterranean dietary pattern, as assessed by the biomarkers of food supplied, on the plasma fatty acid composition and its relation with MetS after 1 year of intervention. Methods A total of 424 subjects were randomly selected from the PREDIMED randomized dietary trial after completing a 1-year intervention program. Participants aged 55 to 80 years and at high risk of cardiovascular disease were randomly assigned to three dietary interventions: Mediterranean diet supplemented with virgin olive oil or nuts, or a low-fat diet. Results After 1 year of intervention participants in the virgin olive oil group showed significantly increased plasma concentrations of palmitic and oleic acids, but reduced proportions of margaric, stearic, and linoleic acids. In turn, subjects in the nut group showed significantly increased levels of palmitic, linoleic, and α-linolenic acids, but reduced proportions of myristic, margaric, palmitoleic, and dihommo-γ-linoleic acids. Increases in the biomarkers of foods supplied to the Mediterranean diet groups, i.e., oleic and α-linolenic acids, were beneficially associated with the incidence, reversion and prevalence of MetS. No weight changes were observed among participants. Conclusions The nut and olive oil diets induced a fatty acid composition that has been shown to be beneficial in the face of MetS. Therefore, a Mediterranean diet rich in fats of vegetable origin may be a useful tool for the management of MetS without the need for concerns over weight gain due to its high fat content. Trial Registration Controlled-Trials.com ISRCTN35739639

Urinary N -methylnicotinamide and β-aminoisobutyric acid predict catch-up growth in undernourished Brazilian children

Enteric infections, enteropathy and undernutrition in early childhood are preventable risk factors for child deaths, impaired neurodevelopment, and later life metabolic diseases. However, the mechanisms linking these exposures and outcomes remain to be elucidated, as do biomarkers for identifying children at risk. By examining the urinary metabolic phenotypes of nourished and undernourished children participating in a case-control study in Semi-Arid Brazil, we identified key differences with potential relevance to mechanisms, biomarkers and outcomes. Undernutrition was found to perturb several biochemical pathways, including choline and tryptophan metabolism, while also increasing the proteolytic activity of the gut microbiome. Furthermore, a metabolic adaptation was observed in the undernourished children to reduce energy expenditure, reflected by increased N-methylnicotinamide and reduced β-aminoisobutyric acid excretion. Interestingly, accelerated catch-up growth was observed in those undernourished children displaying a more robust metabolic adaptation several months earlier. Hence, urinary N-methylnicotinamide and β-aminoisobutyric acid represent promising biomarkers for predicting short-term growth outcomes in undernourished children and for identifying children destined for further growth shortfalls. These findings have important implications for understanding contributors to long-term sequelae of early undernutrition, including cognitive, growth, and metabolic functions.

Protein- and zinc-deficient diets modulate the murine microbiome and metabolic phenotype

Background: Environmental enteropathy, which is linked to undernutrition and chronic infections, affects the physical and mental growth of children in developing areas worldwide. Key to understanding how these factors combine to shape developmental outcomes is to first understand the effects of nutritional deficiencies on the mammalian system including the effect on the gut microbiota. Objective: We dissected the nutritional components of environmental enteropathy by analyzing the specific metabolic and gut-microbiota changes that occur in weaned-mouse models of zinc or protein deficiency compared with well-nourished controls. Design: With the use of a 1H nuclear magnetic resonance spectroscopy–based metabolic profiling approach with matching 16S microbiota analyses, the metabolic consequences and specific effects on the fecal microbiota of protein and zinc deficiency were probed independently in a murine model. Results: We showed considerable shifts within the intestinal microbiota 14–24 d postweaning in mice that were maintained on a normal diet (including increases in Proteobacteria and striking decreases in Bacterioidetes). Although the zinc-deficient microbiota were comparable to the age-matched, well-nourished profile, the protein-restricted microbiota remained closer in composition to the weaned enterotype with retention of Bacteroidetes. Striking increases in Verrucomicrobia (predominantly Akkermansia muciniphila) were observed in both well-nourished and protein-deficient mice 14 d postweaning. We showed that protein malnutrition impaired growth and had major metabolic consequences (much more than with zinc deficiency) that included altered energy, polyamine, and purine and pyrimidine metabolism. Consistent with major changes in the gut microbiota, reductions in microbial proteolysis and increases in microbial dietary choline processing were observed. Conclusions: These findings are consistent with metabolic alterations that we previously observed in malnourished children. The results show that we can model the metabolic consequences of malnutrition in the mouse to help dissect relevant pathways involved in the effects of undernutrition and their contribution to environmental enteric dysfunction.

Time-Dependent Quantum Dynamics Study of the Ne + H2+ (v = 0−9) and D2+ (v = 0−12) Proton Transfer Reactions at Thermal Collision Energies†

The Ne + H2+ and D2+ proton transfer reactions were studied (reaction probabilities (P) and cross sections (sigma)) using the time-dependent real wave packet quantum dynamics method at the centrifugal sudden level (CS-RWP method). This was made considering the influence of vibrational excitation of H2+ and D2+ on the dynamics ((v = 0-9, j = 0) and (v = 0-12, j = 0) vibrorotational states, respectively) at thermal collision energies (Ecol = 0.010 to 0.14 eV). The CS-RWP relative cross sections at thermal collision energy (300 K) for Ne + H2+ and Ne + D2+ are in good agreement with the experimental data. The present results suggest the adequacy of the approach used here in describing these and related systems at thermal collision energies and from low to high vibrational excitation of reactants.

Diet quality of a population sample from coastal north-east Spain evaluated by a Mediterranean adaptation of the Diet Quality Index (DQI)

OBJECTIVE To assess the adherence to the Mediterranean dietary pattern in the population from a coastal region from north-east Spain and its relationship to diseases, applying the Mediterranean Diet Quality Index (M-DQI) validated by the use of several biomarkers. DESIGN Cross-sectional nutrition survey. SETTING Population-based random sample derived from the Catalan Nutrition Survey. SUBJECTS A total of 621 healthy adults. RESULTS The Catalan representative sample presented a mean M-DQI score of 6.6 (sd 2.3, median 7, range 0-14). The percentage of adherence to the Mediterranean diet was 53 %; 10 % of subjects showed high adherence to the Mediterranean diet, while only 2 % were categorized as poorest adherence. The plasma fatty acid profile of the Catalan sample progressed with perfect regularity throughout the index ranges. Both EPA and DHA presented a significant correlation to the M-DQI (r = -0.410 for EPA and -0.360 for DHA). A significant increase in palmitic, oleic and alpha-linolenic acids and a significant decrease in stearic, linoleic and arachidonic acids content were also observed. The mean values for the M-DQI according to the clinical characteristics of the Catalan sample were also calculated. CONCLUSIONS The M-DQI has been demonstrated a suitable tool for assessment of an individuals nutritional status according to the Mediterranean dietary pattern and for clinical purposes. Although the current diet followed in Catalonia seems to agree with the main characteristics of the Mediterranean diet, the promotion of the Mediterranean pattern should be reinforced in the Catalan population, especially among young people.

Cross-modulation of pathogen-specific pathways enhances malnutrition during enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli

Diverse enteropathogen exposures associate with childhood malnutrition. To elucidate mechanistic pathways whereby enteric microbes interact during malnutrition, we used protein deficiency in mice to develop a new model of co-enteropathogen enteropathy. Focusing on common enteropathogens in malnourished children, Giardia lamblia and enteroaggregative Escherichia coli (EAEC), we provide new insights into intersecting pathogen-specific mechanisms that enhance malnutrition. We show for the first time that during protein malnutrition, the intestinal microbiota permits persistent Giardia colonization and simultaneously contributes to growth impairment. Despite signals of intestinal injury, such as IL1α, Giardia-infected mice lack pro-inflammatory intestinal responses, similar to endemic pediatric Giardia infections. Rather, Giardia perturbs microbial host co-metabolites of proteolysis during growth impairment, whereas host nicotinamide utilization adaptations that correspond with growth recovery increase. EAEC promotes intestinal inflammation and markers of myeloid cell activation. During co-infection, intestinal inflammatory signaling and cellular recruitment responses to EAEC are preserved together with a Giardia-mediated diminishment in myeloid cell activation. Conversely, EAEC extinguishes markers of host energy expenditure regulatory responses to Giardia, as host metabolic adaptations appear exhausted. Integrating immunologic and metabolic profiles during co-pathogen infection and malnutrition, we develop a working mechanistic model of how cumulative diet-induced and pathogen-triggered microbial perturbations result in an increasingly wasted host.

Increased Urinary Trimethylamine N-Oxide Following Cryptosporidium Infection and Protein Malnutrition Independent of Microbiome Effects

Cryptosporidium infections have been associated with growth stunting, even in the absence of diarrhea. Having previously detailed the effects of protein deficiency on both microbiome and metabolome in this model, we now describe the specific gut microbial and biochemical effects of Cryptosporidium infection. Protein-deficient mice were infected with Cryptosporidium parvum oocysts for 6-13 days and compared with uninfected controls. Following infection, there was an increase in the urinary excretion of choline- and amino-acid-derived metabolites. Conversely, infection reduced the excretion of the microbial-host cometabolite (3-hydroxyphenyl)propionate-sulfate and disrupted metabolites involved in the tricarboxylic acid (TCA) cycle. Correlation analysis of microbial and biochemical profiles resulted in associations between various microbiota members and TCA cycle metabolites, as well as some microbial-specific degradation products. However, no correlation was observed between the majority of the infection-associated metabolites and the fecal bacteria, suggesting that these biochemical perturbations are independent of concurrent changes in the relative abundance of members of the microbiota. We conclude that cryptosporidial infection in protein-deficient mice can mimic some metabolic changes seen in malnourished children and may help elucidate our understanding of long-term metabolic consequences of early childhood enteric infections.

Characterizing the metabolic phenotype of intestinal villus blunting in Zambian children with severe acute malnutrition and persistent diarrhea

Background Environmental enteric dysfunction (EED) is widespread throughout the tropics and in children is associated with stunting and other adverse health outcomes. One of the hallmarks of EED is villus damage. In children with severe acute malnutrition (SAM) the severity of enteropathy is greater and short term mortality is high, but the metabolic consequences of enteropathy are unknown. Here, we characterize the urinary metabolic alterations associated with villus health, classic enteropathy biomarkers and anthropometric measurements in severely malnourished children in Zambia. Methods/Principal findings We analysed 20 hospitalised children with acute malnutrition aged 6 to 23 months in Zambia. Small intestinal biopsies were assessed histologically (n = 15), anthropometric and gut function measurements were collected and the metabolic phenotypes were characterized by 1H nuclear magnetic resonance (NMR) spectroscopy. Endoscopy could not be performed on community controls children. Growth parameters were inversely correlated with enteropathy biomarkers (p = 0.011) and parameters of villus health were inversely correlated with translocation and permeability biomarkers (p = 0.000 and p = 0.015). Shorter villus height was associated with reduced abundance of metabolites related to gut microbial metabolism, energy and muscle metabolism (p = 0.034). Villus blunting was also related to increased sucrose excretion (p = 0.013). Conclusions/Significance Intestinal villus blunting is associated with several metabolic perturbations in hospitalized children with severe undernutrition. Such alterations include altered muscle metabolism, reinforcing the link between EED and growth faltering, and a disruption in the biochemical exchange between the gut microbiota and host. These findings extend our understanding on the downstream consequences of villus blunting and provide novel non-invasive biomarkers of enteropathy dysfunction. The major limitations of this study are the lack of comparative control group and gut microbiota characterization.