Benefits of polyphenols on gut microbiota and implications in human health

The biological properties of dietary polyphenols are greatly dependent on their bioavailability that, in turn, is largely influenced by their degree of polymerization. The gut microbiota play a key role in modulating the production, bioavailability and, thus, the biological activities of phenolic metabolites, particularly after the intake of food containing high-molecular-weight polyphenols. In addition, evidence is emerging on the activity of dietary polyphenols on the modulation of the colonic microbial population composition or activity. However, although the great range of health-promoting activities of dietary polyphenols has been widely investigated, their effect on the modulation of the gut ecology and the two-way relationship 'polyphenols ↔ microbiota' are still poorly understood. Only a few studies have examined the impact of dietary polyphenols on the human gut microbiota, and most were focused on single polyphenol molecules and selected bacterial populations. This review focuses on the reciprocal interactions between the gut microbiota and polyphenols, the mechanisms of action and the consequences of these interactions on human health

Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites.

Flavan-3-ols, occurring in monomeric, as well as in oligomeric and polymeric forms (also known as condensed tannins or proanthocyanidins), are among the most abundant and bioactive dietary polyphenols, but their in vivo health effects in humans may be limited because of their recognition as xenobiotics. Bioavailability of flavan-3-ols is largely influenced by their degree of polymerization; while monomers are readily absorbed in the small intestine, oligomers and polymers need to be biotransformed by the colonic microbiota before absorption. Therefore, phenolic metabolites, rather than the original high molecular weight compounds found in foods, may be responsible for the health effects derived from flavan-3-ol consumption. Flavan-3-ol phenolic metabolites differ in structure, amount and excretion site. Phase II or tissular metabolites derived from the small intestine and hepatic metabolism are presented as conjugated derivatives (glucuronic acid or sulfate esters, methyl ether, or their combined forms) of monomeric flavan-3-ols and are preferentially eliminated in the bile, whereas microbial metabolites are rather simple conjugated lactones and phenolic acids that are largely excreted in urine. Although the colon is seen as an important organ for the metabolism of flavan-3-ols, the microbial catabolic pathways of these compounds are still under consideration, partly due to the lack of identification of bacteria with such capacity. Studies performed with synthesized or isolated phase II conjugated metabolites have revealed that they could have an effect beyond their antioxidant properties, by interacting with signalling pathways implicated in important processes involved in the development of diseases, among other bioactivities. However, the biological properties of microbe-derived metabolites in their actual conjugated forms remain largely unknown. Currently, there is an increasing interest in their effects on intestinal infections, inflammatory intestinal diseases and overall gut health. The present review will give an insight into the metabolism and microbial biotransformation of flavan-3-ols, including tentative catabolic pathways and aspects related to the identification of bacteria with the ability to catabolize these kinds of polyphenols. Also, the in vitro bioactivities of phase II and microbial phenolic metabolites will be covered in detail

Red wine polyphenols modulate fecal microbiota and reduce markers of the metabolic syndrome in obese patients.

This study evaluated the possible prebiotic effect of a moderate intake of red wine polyphenols on the modulation of the gut microbiota composition and the improvement in the risk factors for the metabolic syndrome in obese patients. Ten metabolic syndrome patients and ten healthy subjects were included in a randomized, crossover, controlled intervention study. After a washout period, the subjects consumed red wine and de-alcoholized red wine over a 30 day period for each. The dominant bacterial composition did not differ significantly between the study groups after the two red wine intake periods. In the metabolic syndrome patients, red wine polyphenols significantly increased the number of fecal bifidobacteria and Lactobacillus (intestinal barrier protectors) and butyrate-producing bacteria (Faecalibacterium prausnitzii and Roseburia) at the expense of less desirable groups of bacteria such as LPS producers (Escherichia coli and Enterobacter cloacae). The changes in gut microbiota in these patients could be responsible for the improvement in the metabolic syndrome markers. Modulation of the gut microbiota by using red wine could be an effective strategy for managing metabolic diseases associated with obesity

Endotoxin increase after fat overload is related to postprandial hypertriglyceridemia in morbidly obese patients.

The low-grade inflammation observed in obesity has been associated with a high-fat diet, though this relation is not fully understood. Bacterial endotoxin, produced by gut microbiota, may be the linking factor. However, this has not been confirmed in obese patients. To study the relationship between a high-fat diet and bacterial endotoxin, we analyzed postprandial endotoxemia in morbidly obese patients after a fat overload. The endotoxin levels were determined in serum and the chylomicron fraction at baseline and 3 h after a fat overload in 40 morbidly obese patients and their levels related with the degree of insulin resistance and postprandial hypertriglyceridemia. The morbidly obese patients with the highest postprandial hypertriglyceridemia showed a significant increase in lipopolysaccharide (LPS) levels in serum and the chylomicron fraction after the fat overload. Postprandial chylomicron LPS levels correlated positively with the difference between postprandial triglycerides and baseline triglycerides. There were no significant correlations between C-reactive protein (CRP) and LPS levels. The main variables contributing to serum LPS levels after fat overload were baseline and postprandial triglyceride levels but not glucose or insulin resistance. Additionally, superoxide dismutase activity decreased significantly after the fat overload. Postprandial LPS increase after a fat overload is related to postprandial hypertriglyceridemia but not to degree of insulin resistance in morbidly obese patients

Endotoxin increase after fat overload is related to postprandial hypertriglyceridemia in morbidly obese patients

The low-grade inflammation observed in obesity has been associated with a high-fat diet, though this relation is not fully understood. Bacterial endotoxin, produced by gut microbiota, may be the linking factor. However, this has not been confirmed in obese patients. To study the relationship between a high-fat diet and bacterial endotoxin, we analyzed postprandial endotoxemia in morbidly obese patients after a fat overload. The endotoxin levels were determined in serum and the chylomicron fraction at baseline and 3 h after a fat overload in 40 morbidly obese patients and their levels related with the degree of insulin resistance and postprandial hypertriglyceridemia. The morbidly obese patients with the highest postprandial hypertriglyceridemia showed a significant increase in lipopolysaccharide (LPS) levels in serum and the chylomicron fraction after the fat overload. Postprandial chylomicron LPS levels correlated positively with the difference between postprandial triglycerides and baseline triglycerides. There were no significant correlations between C-reactive protein (CRP) and LPS levels. The main variables contributing to serum LPS levels after fat overload were baseline and postprandial triglyceride levels but not glucose or insulin resistance. Additionally, superoxide dismutase activity decreased significantly after the fat overload. Postprandial LPS increase after a fat overload is related to postprandial hypertriglyceridemia but not to degree of insulin resistance in morbidly obese patients.This study was funded by the Fondo de Investigación Sanitaria “Centros de Investigación En Red” (CIBER, CB06/03/0018) of the “Instituto de Salud Carlos III”, FIS PS09/00997, FIS 08/1655 and CP07/00095 of the “Instituto de Salud Carlos III”, Madrid, Spain. SAS 08/325 and SAS 10/0696 Consejería de Salud, Junta de Andalucía. M.C.P. was a recipient of a FPU grant from Educa- tion Ministry, Madrid, Spain [AP2009-4537]

Metabolomic pattern analysis after Mediterranean diet intervention in non-diabetic population: a 1- and 3-year follow-up in the PREDIMED study

The Mediterranean diet (MD) is considered a dietary pattern with beneficial effects on human health. The aim of this study was to assess the effect of an MD on urinary metabolome by comparing subjects at 1 and 3 years of follow-up, after an MD supplemented with either extra-virgin olive oil (MD + EVOO) or nuts (MD + Nuts), to those on advice to follow a control low-fat diet (LFD). Ninety-eight nondiabetic volunteers were evaluated, using metabolomic approaches, corresponding to MD + EVOO (n = 41), MD + Nuts (n = 27), or LFD (n = 30) groups. The 1H NMR urinary profiles were examined at baseline and after 1 and 3 years of follow-up. Multivariate data analysis (OSC-PLS-DA and HCA) methods were used to identify the potential biomarker discriminating groups, exhibiting a urinary metabolome separation between MD groups against baseline and LFD. Results revealed that the most prominent hallmarks concerning MD groups were related to the metabolism of carbohydrates (3-hydroxybutyrate, citrate, and cis-aconitate), creatine, creatinine, amino acids (proline, N-acetylglutamine, glycine, branched-chain amino acids, and derived metabolites), lipids (oleic and suberic acids), and microbial cometabolites (phenylacetylglutamine and p-cresol). Otherwise, hippurate, trimethylamine-N-oxide, histidine and derivates (methylhistidines, carnosine, and anserine), and xanthosine were predominant after LFD. The application of NMR-based metabolomics enabled the classification of individuals regarding their dietary pattern and highlights the potential of this approach for evaluating changes in the urinary metabolome at different time points of follow-up in response to specific dietary interventions

Biomarkers of Morbid Obesity and Prediabetes by Metabolomic Profiling of Human Discordant Phenotypes

Metabolomic studies aimed to dissect the connection between the development of type 2 diabetes and obesity are still scarce. In the present study, fasting serum from sixty-four adult individuals classified into four sex-matched groups by their BMI [non-obese versus morbid obese] and the increased risk of developing diabetes [prediabetic insulin resistant state versus non-prediabetic non-insulin resistant] was analyzed by LC- and FIA-ESI-MS/MS-driven metabolomic approaches. Altered levels of [lyso]glycerophospholipids was the most specific metabolic trait associated to morbid obesity, particularly lysophosphatidylcholines acylated with margaric, oleic and linoleic acids [lysoPC C17:0: R=-0.56, p=0.0003; lysoPC C18:1: R=-0.61, p=0.0001; lysoPC C18:2 R=-0.64, p<0.0001]. Several amino acids were biomarkers of risk of diabetes onset associated to obesity. For instance, glutamate significantly associated with fasting insulin [R=0.5, p=0.0019] and HOMA-IR [R=0.46, p=0.0072], while glycine showed negative associations [fasting insulin: R=-0.51, p=0.0017; HOMA-IR: R=-0.49, p=0.0033], and the branched chain amino acid valine associated to prediabetes and insulin resistance in a BMI-independent manner [fasting insulin: R=0.37, p=0.0479; HOMA-IR: R=0.37, p=0.0468]. Minority sphingolipids including specific [dihydro]ceramides and sphingomyelins also associated with the prediabetic insulin resistant state, hence deserving attention as potential targets for early diagnosis or therapeutic intervention

Effect of acute and chronic red wine consumption on lipopolysaccharide concentrations

Background: Chronic red wine (RW) consumption has been associated with decreased cardiovascular disease risk, mainly attributed to an improvement in lipid profile. RW intake is also able to change the composition of gut microbiota. High fat intake has recently been reported to increase metabolic endotoxemia. The gut microbiota has been proposed as the main resource of plasma lipopolysaccharides (LPSs) in metabolic endotoxemia. Objective: We analyzed the effect on LPS concentrations of chronic RW consumption and acute RW intake in relation to high fat intake in middle-aged men. Design: For the chronic study, 10 middle-aged male volunteers were randomly assigned in a crossover trial, and after a washout period, all subjects received RW, dealcoholized red wine (DRW), or gin for 20 d. Serum endotoxin and LPS-binding protein (LBP) concentrations were determined after the washout period and after each of the treatments, and changes in fecal microbiota were quantified. For the acute study, 5 adult men underwent a fat overload or a fat overload together with the consumption of RW, DRW, or gin. Baseline and postprandial serum LPS and LBP concentrations and postprandial chylomicron LPS concentrations were measured. Results: There were no significant differences in the change in LPS or LBP concentrations between chronic RW, DRW, and gin consumption. Bifidobacterium and Prevotella amounts were significantly increased by RW and correlated negatively with LPS concentrations. There were no differences in postprandial serum LPS, LBP, or chylomicron LPS concentrations between acute RW, DRW, or gin intake together with a fatty meal. Conclusion: Chronic RW consumption increases Bifidobacterium and Prevotella amounts, which may have beneficial effects by leading to lower LPS concentrations. This trial was registered at controlled-trials.CIBER, CB06/03/0018 of the Instituto de Salud Carlos III (ISCIII), the ISCIII FIS PS09/00997, “Consejeria de Innovación (Junta de Andalucia)” CTS04369, “Consejeria de Salud” (Junta de Andalucia) PI696/2010; in part by the INGENIO-CONSOLIDER Program, Fun-C-Food CSD2007-063 and AGL2006-14228-C03-02 from the Spanish Ministry; and by Programa de Formación de Profesorado Universitario (FPU) grants from Education Ministry, Madrid, Spain [AP2009-4537 (to MC-P) and AP2008-01922 (MB-O)]. Torres SA provided the red wine and dealcoholized red wine used in the study, and Gin Xoriguer provided the gin used in the study

Untargeted profiling of concordant/discordant phenotypes of high insulin resistance and obesity to predict the risk of developing diabetes

This study explores the metabolic profiles of concordant/discordant phenotypes of high insulin resistance (IR) and obesity. Through untargeted metabolomics (LC-ESI-QTOF-MS), we analyzed the fasting serum of subjects with high IR and/or obesity ( n = 64). An partial least-squares discriminant analysis with orthogonal signal correction followed by univariate statistics and enrichment analysis allowed exploration of these metabolic profiles. A multivariate regression method (LASSO) was used for variable selection and a predictive biomarker model to identify subjects with high IR regardless of obesity was built. Adrenic acid and a dyglyceride (DG) were shared by high IR and obesity. Uric and margaric acids, 14 DGs, ketocholesterol, and hydroxycorticosterone were unique to high IR, while arachidonic, hydroxyeicosatetraenoic (HETE), palmitoleic, triHETE, and glycocholic acids, HETE lactone, leukotriene B4, and two glutamyl-peptides to obesity. DGs and adrenic acid differed in concordant/discordant phenotypes, thereby revealing protective mechanisms against high IR also in obesity. A biomarker model formed by DGs, uric and adrenic acids presented a high predictive power to identify subjects with high IR [AUC 80.1% (68.9-91.4)]. These findings could become relevant for diabetes risk detection and unveil new potential targets in therapeutic treatments of IR, diabetes, and obesity. An independent validated cohort is needed to confirm these results

Predictors Of Positivity Of [F-18]F-Choline PET-CT In Prostate Cancer Recurrence. Preliminary Results

EP-173 Aim/Introduction: To analyze the validity of [18F]F-Choline PET-CT results in prostate cancer recurrence in our daily practice, based on theoretical cut-off points of prostatespecific antigen (PSA), its kinetic, and PSA doubling time (PSADT), to identify predictors of positivity and modify the indication criteria. Materials and Methods: Prior to the validity analysis, a descriptive, prospective analysis of consecutive patients with prostate cancer treated with curative intent by radical prostatectomy (RP) or radiotherapy (RT), who underwent PET-CT scan with recurrence criteria: PSA =1 or PSA 0.4-1 with PSADT Nadir + 2 after RT, was performed. Results: From April to December 2019, 69 patients were included, 40 were treated with RP (58%) and 29 with RT (42%). In 45 patients (65%) PET-CT was able to identify recurrence of the disease (positive PET) and in 24 it was not (negative PET). Of patients treated with RP, 82, 5% (33/40) had PSA>1, and of those, 61% were positive PET. 17, 5% (7/40) had PSA6months (28/69), in 71% if PSADT6 months, in 61% and 92% if PSADT<6 months and in 77% and 100% if PSADT<3 months. Conclusion: Preliminarily and awaiting validation, it seems that PSA>1 after RP or Nadir +2 after RT is an indicator of PET-CT. There seems to be a tendency that shows that PSA<1 after RP is an indicator of PET-CT if PSADT<3 months. PSADT <3 or <6 months could be the best predictor of positivity of PET-CT with [18F]F-Choline in recurrent prostate cancer