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Short chain fatty acids (SCFAs) derived from dietary fiber fermentation by gut microbiota have been identified as one of the mechanisms behind the association between habitual whole-grain intake and a lower risk of cardiometabolic diseases. The aims of the present work are: (1) to evaluate whether a whole-grain wheat-based diet may increase SCFAs concentration, and (2) to identify possible associations between SCFAs and metabolic changes observed after the nutritional intervention. Fifty-four subjects participated in the trial. They underwent a 12-wk dietary intervention based on whole-grain or refined cereal products. At baseline and after the intervention, glucose, insulin, triacylglycerol, inflammatory markers (hs-CRP, IL-1 ra, IL-6, and TNF-α), and SCFAs plasma concentrations were evaluated. After the intervention, in the whole-grain group fasting plasma propionate concentrations were higher than at baseline, whereas a reduction was detected in the control group. The absolute changes (end of trial minus baseline) in fasting plasma propionate concentrations were significantly different between the two groups (P = 0.048). The absolute changes of fasting propionate correlated with cereal fiber intake (r = 0.358, P = 0.023), but no significant correlations with clinical outcomes were found. However, postprandial insulin was significantly decreased in the group having the absolute changes of fasting propionate concentration above the median value (P = 0.022 versus subjects with fasting propionate changes below the median value). A 12-wk whole-grain wheat-based diet increases fasting plasma propionate. This increase correlates with the cereal fiber intake and is associated with lower postprandial insulin concentrations. •Participants underwent a 12-wk dietary intervention based on whole-grain or refined cereal products.•Higher propionate plasma levels were observed after the whole grain diet.•The increase in fasting plasma propionate correlates with the mean intake of cereal fiber during the intervention.•Subjects with greater changes in fasting plasma propionate between the end of the trial and baseline (above the median value) had lower postprandial insulin than subjects below the median.

This study aimed to investigate whether psychological distress, whole-grain consumption and tryptophan metabolism are associated with participants undergoing weight management intervention. Seventy-nine women and men (mean age 49·7 (sd 9·0) years; BMI 34·2(sd 2·5) kg/m2) participated in a 7-week weight-loss (WL) period and in a 24-week weight maintenance (WM) intervention period. Whole-grain consumption was measured using 4 d food diaries. Psychological distress was assessed with the General Health Questionnaire-12 (GHQ), and participants were divided into three GHQ groups based on the GHQ scores before WL. Tryptophan metabolites were determined from the participants’ fasting plasma using liquid chromatography-MS. GHQ scores were not associated with the whole-grain consumption. A positive association was observed between the whole-grain consumption and indole propionic acid (IPA) during the WM (P = 0·033). Serotonin levels were higher after the WL in the lowest GHQ tertile (P = 0·033), while the level at the end of the WM was higher compared with other timepoints in the highest GHQ tertile (P = 0·015 and P = 0·001). This difference between groups was not statistically significant. Furthermore, levels of several tryptophan metabolites changed within the groups during the study. Tryptophan metabolism changed during the study in the whole study group, independently from the level of psychological distress. The association between whole-grain consumption and IPA is possibly explained by the effects of dietary fibre on gut microbiota. This broadens the understanding of the pathways behind the health benefits associated with the intake of whole grains.

(1) Background: Dyslipidemia represents a major risk factor for atherosclerosis-driven cardiovascular disease. Emerging evidence suggests a close relationship between cholesterol metabolism and gut microbiota. Recently, we demonstrated that the short-chain fatty acid (SCFA) propionate (PA) reduces serum cholesterol levels through an immunomodulatory mechanism. Here, we investigated the effects of oral PA supplementation on the human serum metabolome and analyzed changes in the serum metabolome in relation to the cholesterol-lowering properties of PA. (2) Methods: The serum metabolome of patients supplemented with either placebo or propionate orally for 8 weeks was assessed using a combination of flow injection analysis-tandem (FIA-MS/MS) as well as liquid chromatography (LC-MS/MS) and mass spectrometry using a targeted metabolomics kit (MxP®Quant 500 kit: BIOCRATES Life Sciences AG, Innsbruck, Austria). A total of 431 metabolites were employed for further investigation in this study. (3) Results: We observed a significant increase in distinct bile acids (GCDCA: fold change = 1.41, DCA: fold change = 1.39, GUDCA: fold change = 1.51) following PA supplementation over the study period, with the secondary bile acid DCA displaying a significant negative correlation with the serum cholesterol levels. (4) Conclusions: Oral supplementation with PA modulates the serum metabolome with a particular impact on the circulatory bile acid profile. Since cholesterol and bile acid metabolism are interconnected, the elevation of the secondary bile acid DCA may contribute to the cholesterol-lowering effect of PA.

Gut microbial-derived short-chain fatty acids (SCFAs) may regulate energy homeostasis and exert anti-carcinogenic, immunomodulatory and anti-inflammatory effects. Smaller trials indicate that dietary weight loss may lead to decreased SCFA production, but findings have been inconclusive. SCFA concentrations were measured by HPLC-MS/MS in plasma samples of 150 overweight or obese adults in a trial initially designed to evaluate the metabolic effects of intermittent (ICR) versus continuous (CCR) calorie restriction (NCT02449148). For the present post hoc analyses, participants were classified by quartiles of weight loss, irrespective of the dietary intervention. Linear mixed models were used to analyze weight-loss-induced changes in SCFA concentrations after 12, 24 and 50 weeks. There were no differential changes in SCFA levels across the initial study arms (ICR versus CCR versus control) after 12 weeks, but acetate concentrations significantly decreased with overall weight loss (mean log-relative change of −0.7 ± 1.8 in the lowest quartile versus. −7.6 ± 2 in the highest, p = 0.026). Concentrations of propionate, butyrate and other SCFAs did not change throughout the study. Our results show that weight-loss, achieved through calorie restriction, may lead to smaller initial decreases in plasma acetate, while plasma SCFAs generally remain remarkably stable over time.

We aimed to investigate the change of serum metabolomics in response to n-3 fatty acid supplements in Chinese patients with type 2 diabetes (T2D). In a double-blind parallel randomised controlled trial, 59 Chinese T2D patients were randomised to receive either fish oil (FO), flaxseed oil (FSO) or corn oil capsules (CO, served as a control group) and followed up for 180 days. An additional 17 healthy non-T2D participants were recruited at baseline for cross-sectional comparison between cases and non-cases. A total of 296 serum metabolites were measured among healthy controls and T2D patients before and after the intervention. Serum 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) ( P -interaction = 1.8 × 10 −7 ) was the most significant metabolite identified by repeated-measures ANOVA, followed by eicosapentaenoate ( P -interaction = 4.6 × 10 −6 ), 1-eicosapentaenoylglycerophosphocholine ( P -interaction = 3.4 × 10 −4 ), docosahexaenoate ( P -interaction = 0.001), linolenate (n-3 or n-6, P -interaction = 0.005) and docosapentaenoate (n-3, P -interaction = 0.021). CMPF level was lower in T2D patients than in the healthy controls ( P  = 0.014) and it was significantly increased in the FO compared with CO group ( P  = 1.17 × 10 −7 ). Furthermore, change of CMPF during the intervention was negatively correlated with change of serum triglycerides ( P  = 0.016). In conclusion, furan fatty acid metabolite CMPF was the strongest biomarker of fish oil intake. The association of CMPF with metabolic markers warrants further investigation.

3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) is a metabolite produced endogenously from dietary sources of furan fatty acids. The richest source of furan fatty acids in human diet is fish. CMPF was recently shown to be elevated in fasting plasma in individuals with gestational diabetes and type 2 diabetes, and mechanistically high level of CMPF was linked to β cell dysfunction. Here we aimed to study the association between plasma CMPF level and glucose metabolism in persons with impaired glucose metabolism. Plasma CMPF concentration was measured from plasma samples of the study participants in an earlier controlled dietary intervention. All of them had impaired glucose metabolism and two other characteristics of the metabolic syndrome. Altogether 106 men and women were randomized into three groups for 12 weeks with different fish consumption (either three fatty fish meals per week, habitual fish consumption or maximum of one fish meal per week). Associations between concentration of CMPF and various glucose metabolism parameters at an oral glucose tolerance test at baseline and at the end of the study were studied. Fasting plasma CMPF concentration was significantly increased after a 12-week consumption of fatty fish three times per week, but the concentration remained much lower compared to concentrations reported in diabetic patients. Increases of plasma CMPF concentrations mostly due to increased fish consumption were not associated with impaired glucose metabolism in this study. Instead, elevated plasma CMPF concentration was associated with decreased 2-hour insulin concentration in OGTT. Moderately elevated concentration of CMPF in plasma resulting from increased intake of fish is not harmful to glucose metabolism. Further studies are needed to fully explore the role of CMPF in the pathogenesis of impaired glucose metabolism. ClinicalTrials.gov NCT00573781.

The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regenerative rate 1 . Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms 2 . Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration 3 . Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and the release of neurotrophins, can be activated by intermittent fasting (IF) 4 , 5 . However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by Clostridium sporogenes is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating the recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-dependent regenerative phenotype, which was confirmed by inhibition of neutrophil chemotaxis. Our results demonstrate the ability of a microbiome-derived metabolite, such as IPA, to facilitate regeneration and functional recovery of sensory axons through an immune-mediated mechanism.

To our knowledge, there are no studies on advanced chronic kidney disease (CKD) analysing the impact of ageing on serum concentrations of uraemic toxins while adjusting for renal function. Knowledge of this feature, however, could influence prognostic assessment and therapeutic decision-making, e.g. about when to start dialysis or how intensive it should be. Indeed, the slowing down of metabolism with age may result in lower uraemic toxin concentrations, hence reducing their toxic effects. In this case, a later start of dialysis or less intensive dialysis may become justified in an already fragile population that might enjoy a better quality of life without a survival disadvantage with conservative treatment. We assessed the impact of advancing age on uraemic solute concentrations [blood, urea, nitrogen (BUN), uric acid, creatinine, asymmetric and symmetric dimethylarginine (ADMA and SDMA), β 2 -microglobulin and a large array of protein-bound solutes] by matching 126 maintenance haemodialysis patients subdivided into two age-groups, younger vs. older (using the median as cut-off: 72 years). Concentrations were compared after age stratification and were matched with patient and dialysis characteristics. In addition, 93 non-dialysed CKD patients (median as cut-off: 70 years), with a comparable average estimated glomerular filtration rate (eGFR) between younger and older age-groups, were analysed. In haemodialysis patients, carboxy-methyl-furanpropionic acid (CMPF) levels were markedly higher and BUN and uric acid borderline lower in the older age-group. All other solutes showed no difference. At multifactor analysis, the concentration of several uraemic toxins was associated with residual renal function and protein intake in the overall haemodialysis group and the younger group, but the association with most solutes, especially those protein-bound, was lost in the older age-group. No differences were found in non-dialysed CKD patients. It was concluded that in this CKD population concentrations of uraemic toxins did not change substantially with calendar age.

Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.

As a synthetic polymer, methoxy-polyethylene glycol propionic acid (M-PEG-PA) is widely used in the biomedicine field. Unraveling the pharmacokinetic behavior of M-PEG 6 -PA in vivo is crucial for evaluating the safety and efficiency of M-PEG-PA-related polymers or drug delivery systems. A high-throughput and green ultra-performance convergence chromatography-tandem mass spectrometry (UPC 2 -MS/MS) assay was firstly developed and validated for the determination of M-PEG 6 -PA polymers in a biological matrix. The MRM transition (mass to charge ratio, precursor ions→fragment ions) of m / z 367.2→118.9 was used to quantify M-PEG 6 -PA in this study. The throughput of the assay is high and the total running time for each sample was only 2 min. The linear range of the developed UPC 2 -MS/MS assay for quantification of M-PEG 6 -PA in a biological matrix is 0.05 to 30 μg/mL ( R ≥0.995). Intra-day and inter-day precisions for the determination of M-PEG 6 -PA by this analytical assay were <6.99%. The absolute recoveries and matrix effects of M-PEG 6 -PA ranged from 79.50 to 92.47% and 68.72 to 81.73%, respectively. The UPC 2 -MS/MS assay was successfully applied to quantify the concentrations of M-PEG 6 -PA polymers in rat plasma samples. Graphical Abstract