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PurposeFlavonoid consumption during adolescence could contribute to preventing adult onset of type 2 diabetes mellitus. We investigated the prospective association between habitual intake of flavonoids from fruit and vegetables (FlavFV) during adolescence and risk markers of type 2 diabetes in early adulthood.MethodsThis analysis included participants of the DONALD Study, who had provided a fasting blood sample in adulthood (18–39 years), data on FlavFV-intake during adolescence (females: 9–15 years, males: 10–16 years) and relevant covariates. Habitual FlavFV-intake was either estimated using repeated 3-day weighed dietary records (n = 268), or the validated biomarker hippuric acid (uHA)-excretion in repeated 24-h urine samples (n = 241). Multivariable linear regressions were performed to analyse the prospective associations of FlavFV or uHA with homeostasis model assessment insulin sensitivity (HOMA2-%S), hepatic steatosis index (HSI), fatty liver index (FLI) and a pro-inflammatory score.ResultsHigher FlavFV-intake was independently related to higher HOMA2-%S among females (Ptrend = 0.03), but not among males. Both FlavFV-intake and uHA-excretion were inversely associated with HSI (Ptrend < 0.0001 and Ptrend = 0.02, respectively) and the pro-inflammatory score (Ptrend = 0.02 and Ptrend = 0.008, respectively), but not with FLI.ConclusionsOur data indicate that flavonoid consumption from fruit and vegetables during adolescence is associated with a favourable risk factor profile for type 2 diabetes in early adulthood.

Chronic kidney disease (CKD) is a progressive loss of renal function. The gradual decline in kidney function leads to an accumulation of toxins normally cleared by the kidneys, resulting in uremia. Uremic toxins are classified into three categories: free water-soluble low-molecular-weight solutes, protein-bound solutes, and middle molecules. CKD patients have increased risk of developing cardiovascular disease (CVD), due to an assortment of CKD-specific risk factors. The accumulation of uremic toxins in the circulation and in tissues is associated with the progression of CKD and its co-morbidities, including CVD. Although numerous uremic toxins have been identified to date and many of them are believed to play a role in the progression of CKD and CVD, very few toxins have been extensively studied. The pathophysiological mechanisms of uremic toxins must be investigated further for a better understanding of their roles in disease progression and to develop therapeutic interventions against uremic toxicity. This review discusses the renal and cardiovascular toxicity of uremic toxins indoxyl sulfate, p-cresyl sulfate, hippuric acid, TMAO, ADMA, TNF-α, and IL-6. A focus is also placed on potential therapeutic targets against uremic toxicity.

The human gut microbiota produces dozens of small molecules that circulate in blood, accumulate to comparable levels as pharmaceutical drugs, and influence host physiology. Despite the importance of these metabolites to human health and disease, the origin of most microbially-produced molecules and their fate in the host remains largely unknown. Here, we uncover a host-microbe co-metabolic pathway for generation of hippuric acid, one of the most abundant organic acids in mammalian urine. Combining stable isotope tracing with bacterial and host genetics, we demonstrate reduction of phenylalanine to phenylpropionic acid by gut bacteria; the host re-oxidizes phenylpropionic acid involving medium-chain acyl-CoA dehydrogenase (MCAD). Generation of germ-free male and female MCAD −/− mice enabled gnotobiotic colonization combined with untargeted metabolomics to identify additional microbial metabolites processed by MCAD in host circulation. Our findings uncover a host-microbe pathway for the abundant, non-toxic phenylalanine metabolite hippurate and identify β-oxidation via MCAD as a novel mechanism by which mammals metabolize microbiota-derived metabolites. Here, using a mouse model, the authors report a previously undescribed role for medium-chain acyl-CoA dehydrogenase in host metabolism of gut microbiota metabolites, and show that circulating compounds, including the abundant organic acid hippurate, depend on host-microbe co-metabolism of phenylalanine by Clostridium sporogenes .

This study aimed to assess stress in indoor and free-ranging domestic cats by measuring biomarkers (serotonin, cortisol, dopamine) in serum and urine, along with urinary hippuric acid levels, and to examine their correlation with exposure to industrial substances, particularly toluene-containing materials. A total of 244 cats underwent physical and laboratory assessments, including anamnesis, physical examination, laboratory analyses (urine analysis, urine sediment analysis, urine bacterial culture, venous blood gas analysis, complete blood count (CBC), serum biochemistry), and abdominal ultrasonographic examination. After applying inclusion/exclusion criteria, 16 cats were categorized into two groups: Free-ranging (n = 8) and Indoor (n = 8). Serum and urine serotonin, cortisol, dopamine, and urinary hippuric acid concentrations were measured to assess exposure to indoor materials. Indoor cats had a higher respiratory rate and significantly greater bladder wall thickness (0.28 ± 0.07 cm vs. 0.19 ± 0.02 cm, p = 0.002). Urine pH was lower in indoor cats, and hippuric acid crystals were found in their urine sediment. Serum serotonin levels were lower in free-ranging cats (p = 0.006), while urinary serotonin (p = 0.005), cortisol (p = 0.012), dopamine (p = 0.003), and hippuric acid (p = 0.033) levels were higher in indoor cats. The findings suggest that indoor confinement may be associated with increased physiological stress and greater exposure to toluene-containing materials, which could potentially contribute to stress-related conditions and elevate the risk of toluene-associated effects.

Viral sepsis has been proposed as an accurate term to describe all multisystemic dysregulations and clinical findings in severe and critically ill COVID-19 patients. The adoption of this term may help the implementation of more accurate strategies of early diagnosis, prognosis, and in-hospital treatment. We accurately quantified 110 metabolites using targeted metabolomics, and 13 cytokines/chemokines in plasma samples of 121 COVID-19 patients with different levels of severity, and 37 non-COVID-19 individuals. Analyses revealed an integrated host-dependent dysregulation of inflammatory cytokines, neutrophil activation chemokines, glycolysis, mitochondrial metabolism, amino acid metabolism, polyamine synthesis, and lipid metabolism typical of sepsis processes distinctive of a mild disease. Dysregulated metabolites and cytokines/chemokines showed differential correlation patterns in mild and critically ill patients, indicating a crosstalk between metabolism and hyperinflammation. Using multivariate analysis, powerful models for diagnosis and prognosis of COVID-19 induced sepsis were generated, as well as for mortality prediction among septic patients. A metabolite panel made of kynurenine/tryptophan ratio, IL-6, LysoPC a C18:2, and phenylalanine discriminated non-COVID-19 from sepsis patients with an area under the curve (AUC (95%CI)) of 0.991 (0.986–0.995), with sensitivity of 0.978 (0.963–0.992) and specificity of 0.920 (0.890–0.949). The panel that included C10:2, IL-6, NLR, and C5 discriminated mild patients from sepsis patients with an AUC (95%CI) of 0.965 (0.952–0.977), with sensitivity of 0.993(0.984–1.000) and specificity of 0.851 (0.815–0.887). The panel with citric acid, LysoPC a C28:1, neutrophil-lymphocyte ratio (NLR) and kynurenine/tryptophan ratio discriminated severe patients from sepsis patients with an AUC (95%CI) of 0.829 (0.800–0.858), with sensitivity of 0.738 (0.695–0.781) and specificity of 0.781 (0.735–0.827). Septic patients who survived were different from those that did not survive with a model consisting of hippuric acid, along with the presence of Type II diabetes, with an AUC (95%CI) of 0.831 (0.788–0.874), with sensitivity of 0.765 (0.697–0.832) and specificity of 0.817 (0.770–0.865).

Hippuric acid (HA) is a metabolite resulting from the hepatic glycine conjugation of benzoic acid (BA) or from the gut bacterial metabolism of phenylalanine. BA is generally produced by gut microbial metabolic pathways after the ingestion of foods of vegetal origin rich in polyphenolic compounds, namely, chlorogenic acids or epicatechins. It can also be present in foods, either naturally or artificially added as a preservative. The plasma and urine HA levels have been used in nutritional research for estimating the habitual fruit and vegetable intake, especially in children and in patients with metabolic diseases. HA has also been proposed as a biomarker of aging, since its levels in the plasma and urine can be influenced by the presence of several age-related conditions, including frailty, sarcopenia and cognitive impairment. Subjects with physical frailty generally exhibit reduced plasma and urine levels of HA, despite the fact that HA excretion tends to increase with aging. Conversely, subjects with chronic kidney disease exhibit reduced HA clearance, with HA retention that may exert toxic effects on the circulation, brain and kidneys. With regard to older patients with frailty and multimorbidity, interpreting the HA levels in the plasma and urine may result particularly challenging because HA is at the crossroads between diet, gut microbiota, liver and kidney function. Although these considerations may not make HA the ideal biomarker of aging trajectories, the study of its metabolism and clearance in older subjects may provide valuable information for disentangling the complex interaction between diet, gut microbiota, frailty and multimorbidity.

Background Mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. We explored the effect of the green-MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT). Methods In the 18-month Dietary Intervention Randomized Controlled Trial PoLyphenols UnproceSsed (DIRECT-PLUS) weight-loss trial, 294 participants were randomized to (A) healthy dietary guidelines (HDG), (B) MED, or (C) green-MED diets, all combined with physical activity. Both isocaloric MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green-MED group further consumed green tea (3–4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake. We used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues. Results Participants (age = 51 years; 88% men; body mass index = 31.2 kg/m 2 ; 29% VAT) had an 89.8% retention rate and 79.3% completed eligible MRIs. While both MED diets reached similar moderate weight (MED: − 2.7%, green-MED: − 3.9%) and waist circumference (MED: − 4.7%, green-MED: − 5.7%) loss, the green-MED dieters doubled the VAT loss (HDG: − 4.2%, MED: − 6.0%, green-MED: − 14.1%; p < 0.05, independent of age, sex, waist circumference, or weight loss). Higher dietary consumption of green tea, walnuts, and Wolffia globosa ; lower red meat intake; higher total plasma polyphenols (mainly hippuric acid ), and elevated urine urolithin A polyphenol were significantly related to greater VAT loss ( p < 0.05, multivariate models). Conclusions A green-MED diet, enriched with plant-based polyphenols and lower in red/processed meat, may be a potent intervention to promote visceral adiposity regression. Trial registration ClinicalTrials.gov , NCT03020186

Spot urinary polyphenols have potential as a biomarker of polyphenol-rich food intakes. The aim of this study is to explore the relationship between spot urinary polyphenols and polyphenol intakes from polyphenol-rich food sources. Young adults (18–24 years old) were recruited into a sub-study of an online intervention aimed at improving diet quality. Participants’ intake of polyphenols and polyphenol-rich foods was assessed at baseline and 3 months using repeated 24-h recalls. A spot urine sample was collected at each session, with samples analysed for polyphenol metabolites using LC-MS. To assess the strength of the relationship between urinary polyphenols and dietary polyphenols, Spearman correlations were used. Linear mixed models further evaluated the relationship between polyphenol intakes and urinary excretion. Total urinary polyphenols and hippuric acid (HA) demonstrated moderate correlation with total polyphenol intakes (rs = 0·29–0·47). HA and caffeic acid were moderately correlated with polyphenols from tea/coffee (rs = 0·26–0·46). Using linear mixed models, increases in intakes of total polyphenols or polyphenols from tea/coffee or oil resulted in a greater excretion of HA, whereas a negative relationship was observed between soya polyphenols and HA, suggesting that participants with higher intakes of soya polyphenols had a lower excretion of HA. Findings suggest that total urinary polyphenols may be a promising biomarker of total polyphenol intakes foods and drinks and that HA may be a biomarker of total polyphenol intakes and polyphenols from tea/coffee. Caffeic acid warrants further investigation as a potential biomarker of polyphenols from tea/coffee.

With the widespread application of low-dose computed tomography (LDCT) technology, pulmonary nodules have aroused more attention. Significant alteration in plasma metabolite levels, mainly amino acid and lipid, have been observed in patients of PNs. However, evidence on the association between central carbon metabolism and PNs are largely unknown. The aim of this study was to investigate the underlying association of PNs and plasma central carbon metabolites. We measured the levels of 16 plasma central carbon metabolites in 1954 participants who gained LDCT screening in MALSC cohort. The inverse probability weighting (IPW) technique was used to control for bias due to self-selection for LDCT in the assessed high-risk population. The least absolute shrinkage and selection operator (LASSO) penalized regression was used to deal with the problem of multicollinearity among metabolites and the combined association of central carbon metabolites with PNs was estimated by using quantile g-computation (QgC) models. A quartile increase in 3-hydroxybutyric acid, gluconic acid, succinic acid and hippuric acid was positively associated with the PNs risk, whereas a quartile increase in 2-oxadipic acid and fumaric acid was negatively associated with the risk of PNs in multiple-metabolite models. A positive but insignificant joint associations of the mixture of 16 metabolites with PNs was observed by using QgC models analyses. Further studies are warranted to clarify the association between circulating metabolites and PNs and the biological mechanisms.

Fuel combustion is a major source of volatile organic compounds such as benzene, a known human carcinogen. Benzene is metabolized into intermediate biomarkers that can be used to assess the extent of exposure. This study aimed to investigate the association between urinary concentrations of creatinine (Cr), muconic acid (MA), trans, trans-muconic acid (tt-MA), and hippuric acid (HA) with demographic, lifestyle, and occupational factors among motorcyclists exposed to heavy traffic in the Shiraz metropolis, both before and after shift work. Data on demographic characteristics, lifestyle habits, and working conditions were collected through structured interviews and questionnaires. Urinary biomarkers were extracted using a solid-phase extraction method and analyzed by HPLC with a strong basic anion-exchange cartridge (60 mg/3 mL). The results confirmed a significant increase in biomarker concentrations, particularly HA, after the work shift. Notably, HA levels exceeded the recommended limit in 13.79% of pre-shift samples and 68.97% of post-shift samples. A significant odds ratio (OR) for elevated HA was observed in relation to smoking (OR: 6.37), proximity to traffic, and having a second job. Additionally, riders over the age of 40 were more likely than younger individuals to exceed acceptable tt-MA levels after their shift. Before the work shift, tt-MA levels were partially associated with lifestyle factors such as higher BMI (OR = 2.89; 2.69–19.28), smoking (OR = 1.87; 0.1–11.5), and engagement in a second job. These findings provide evidence of a synergistic effect between demographic and lifestyle factors, increasing the health risks faced by workers during shift-based occupations.