The tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or Krebs cycle) is a series of reactions forming a loop that ultimately generate energy, mainly by oxidation of acetyl-CoA generated from glycolysis, and catabolism of fatty acids and amino acids. The energy is stored in guanosine triphosphate (GTP), NADH and FADH2 (Figure 1). The citric acid cycle also provides precursors for many compounds, including certain amino acids. Recent basic research have demonstrated roles of Krebs cycle intermediates in intra- and intercellular signalling affecting physiology and pathogenesis ( 1 ). Krebs cycle intermediates have been linked to DNA and histone methylation (α-ketoglutarate and α-hydroxyglutarate), immune modulation (acetyl-CoA, itaconate, fumarate and succinate), thermogenesis (succinate), inhibition of hypoxia state and HIF-α stabilization (succinate, fumarate and α-hydroxyglutarate), and some are considered as “oncometabolites” defined as conventional metabolites that, when aberrantly accumulated, have pro-oncogenic functions (α-hydroxyglutarate, succinate ( 1 ), fumarate ( 2 ) and lactate ( 3 )). Studies on metabolomics involving Krebs cycle intermediates in relation to human health and disease usually include few patients and have been performed only recently. These metabolites have been related to BMI, cardiovascular disease (pyruvate, citrate, succinate), diabetes (pyruvate, isocitrate, succinate), NAFLD (isocitrate and citrate), longevity (isocitrate), asthma (succinate), disease activity in rheumatoid arthritis patients (itaconate), and worsening of clinical outcome in cancer patients (succinate, fumarate and α-hydroxyglutarate).

α-Ketoglutaric acid (α-ketoglutarate) is a keto acid of the Krebs cycle formed from isocitrate in a reaction catalyzed by isocitrate dehydrogenase (IDH), and further metabolized to succinate through the action of the thiamine pyrophosphate (TPP)-dependent enzyme, α-ketoglutarate dehydrogenase. About 60 α-ketoglutarate-dependent dioxygenases have been identified in humans. These iron-dependent enzymes are involved in a variety of processes, including collagen stabilization, hypoxia, epigenetic regulation and DNA repair ( 2 ). Circulating α-ketoglutarate has been associated with heart failure, obesity, diabetes and ageing.

The tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or Krebs cycle) is a series of reactions forming a loop that ultimately generate energy, mainly by oxidation of acetyl-CoA generated from glycolysis, and catabolism of fatty acids and amino acids. The energy is stored in guanosine triphosphate (GTP), NADH and FADH2 (Figure 1). The citric acid cycle also provides precursors for many compounds, including certain amino acids. Recent basic research have demonstrated roles of Krebs cycle intermediates in intra- and intercellular signalling affecting physiology and pathogenesis ( 1 ). Krebs cycle intermediates have been linked to DNA and histone methylation (α-ketoglutarate and α-hydroxyglutarate), immune modulation (acetyl-CoA, itaconate, fumarate and succinate), thermogenesis (succinate), inhibition of hypoxia state and HIF-α stabilization (succinate, fumarate and α-hydroxyglutarate), and some are considered as “oncometabolites” defined as conventional metabolites that, when aberrantly accumulated, have pro-oncogenic functions (α-hydroxyglutarate, succinate ( 1 ), fumarate ( 2 ) and lactate ( 3 )). Studies on metabolomics involving Krebs cycle intermediates in relation to human health and disease usually include few patients and have been performed only recently. These metabolites have been related to BMI, cardiovascular disease (pyruvate, citrate, succinate), diabetes (pyruvate, isocitrate, succinate), NAFLD (isocitrate and citrate), longevity (isocitrate), asthma (succinate), disease activity in rheumatoid arthritis patients (itaconate), and worsening of clinical outcome in cancer patients (succinate, fumarate and α-hydroxyglutarate).

Formation of α-hydroxyglutaric acid (α-hydroxyglutarate, aHG) from α-ketoglutarate is catalyzed by several enzymes. Gain-of-function neomorphic activity of mutated isocitrate dehydrogenase 1 (IDH1) or IDH2 leads to accumulation of d-aHG, whereas promiscuous activity of malate dehydrogenase (MDH) and/or lactate dehydrogenase (LDH) results in the accumulation of l-aHG. Mutated isocitrate dehydrogenase (IDH) has been reported in a wide range of tumours, including acute myeloid leukemia (AML), intrahepatic cholangiocarcinoma, breast carcinoma and glioma. Some effect of aHB on cellular metabolism that promote carcinogenesis (hypermethylated state of DNA and histones, induction of pseudohypoxia) are mediated by inhibition of α-ketoglutarate-dependent dioxygenases. Thus, α-hydroxyglutaric acid has been regarded as an “oncometabolite”, the circulating levels of which may provide diagnostic and prognostic information ( 2 ).

The tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or Krebs cycle) is a series of reactions forming a loop that ultimately generate energy, mainly by oxidation of acetyl-CoA generated from glycolysis, and catabolism of fatty acids and amino acids. The energy is stored in guanosine triphosphate (GTP), NADH and FADH2 (Figure 1). The citric acid cycle also provides precursors for many compounds, including certain amino acids. Recent basic research have demonstrated roles of Krebs cycle intermediates in intra- and intercellular signalling affecting physiology and pathogenesis ( 1 ). Krebs cycle intermediates have been linked to DNA and histone methylation (α-ketoglutarate and α-hydroxyglutarate), immune modulation (acetyl-CoA, itaconate, fumarate and succinate), thermogenesis (succinate), inhibition of hypoxia state and HIF-α stabilization (succinate, fumarate and α-hydroxyglutarate), and some are considered as “oncometabolites” defined as conventional metabolites that, when aberrantly accumulated, have pro-oncogenic functions (α-hydroxyglutarate, succinate ( 1 ), fumarate ( 2 ) and lactate ( 3 )). Studies on metabolomics involving Krebs cycle intermediates in relation to human health and disease usually include few patients and have been performed only recently. These metabolites have been related to BMI, cardiovascular disease (pyruvate, citrate, succinate), diabetes (pyruvate, isocitrate, succinate), NAFLD (isocitrate and citrate), longevity (isocitrate), asthma (succinate), disease activity in rheumatoid arthritis patients (itaconate), and worsening of clinical outcome in cancer patients (succinate, fumarate and α-hydroxyglutarate).

About 5 % of tryptophan is catabolized by the gut microbome, generating so-called microbiome-derived tryptophan metabolites, which include indole (IND), 3-indoxyl sulfate (3IS), and indole derivatives, such as indole-3-acetamide (IAM), indole-3-acetate (IAA), indole-3-acetaldehyde (IAAld), indole-3-aldehyde (IAld), indole-3-acrylate (IacA) and indole-3-propionate (IPA). Microbiome-derived tryptophan metabolites have diverse biological roles affecting health (Figure 1). Some are ligands of the aryl hydrocarbon receptor (AhR) thereby modulating the immune response, others have anti-inflammatory and anti-oxidative effects, enhance the intestinal epithelial barrier, increase secretion of gut hormones and stimulate intestinal motility. Indoles are generally thought to mediate beneficial health effects, with the exception of 3IS, a host-microbial co-metabolite generated from indole in the liver; 3IS is toxic at high concentrations and associated with vascular disease and renal dysfunction. 3IS is considered as uremic toxin, which is highly (90 %) bound to albumin, and therefore accumulates despite regular hemodialysis ( 2 ).

About 5 % of tryptophan is catabolized by the gut microbome, generating so-called microbiome-derived tryptophan metabolites, which include indole (IND), 3-indoxyl sulfate (3IS), and indole derivatives, such as indole-3-acetamide (IAM), indole-3-acetate (IAA), indole-3-acetaldehyde (IAAld), indole-3-aldehyde (IAld), indole-3-acrylate (IacA) and indole-3-propionate (IPA). Microbiome-derived tryptophan metabolites have diverse biological roles affecting health (Figure 1). Some are ligands of the aryl hydrocarbon receptor (AhR) thereby modulating the immune response, others have anti-inflammatory and anti-oxidative effects, enhance the intestinal epithelial barrier, increase secretion of gut hormones and stimulate intestinal motility. Indoles are generally thought to mediate beneficial health effects, with the exception of 3IS, a host-microbial co-metabolite generated from indole in the liver; 3IS is toxic at high concentrations and associated with vascular disease and renal dysfunction. 3IS is considered as uremic toxin, which is highly (90 %) bound to albumin, and therefore accumulates despite regular hemodialysis ( 2 ).

About 5 % of tryptophan is catabolized by the gut microbome, generating so-called microbiome-derived tryptophan metabolites, which include indole (IND), 3-indoxyl sulfate (3IS), and indole derivatives, such as indole-3-acetamide (IAM), indole-3-acetate (IAA), indole-3-acetaldehyde (IAAld), indole-3-aldehyde (IAld), indole-3-acrylate (IacA) and indole-3-propionate (IPA). Microbiome-derived tryptophan metabolites have diverse biological roles affecting health (Figure 1). Some are ligands of the aryl hydrocarbon receptor (AhR) thereby modulating the immune response, others have anti-inflammatory and anti-oxidative effects, enhance the intestinal epithelial barrier, increase secretion of gut hormones and stimulate intestinal motility. Indoles are generally thought to mediate beneficial health effects, with the exception of 3IS, a host-microbial co-metabolite generated from indole in the liver; 3IS is toxic at high concentrations and associated with vascular disease and renal dysfunction. 3IS is considered as uremic toxin, which is highly (90 %) bound to albumin, and therefore accumulates despite regular hemodialysis ( 2 ).

About 5 % of tryptophan is catabolized by the gut microbome, generating so-called microbiome-derived tryptophan metabolites, which include indole (IND), 3-indoxyl sulfate (3IS), and indole derivatives, such as indole-3-acetamide (IAM), indole-3-acetate (IAA), indole-3-acetaldehyde (IAAld), indole-3-aldehyde (IAld), indole-3-acrylate (IacA) and indole-3-propionate (IPA). Microbiome-derived tryptophan metabolites have diverse biological roles affecting health (Figure 1). Some are ligands of the aryl hydrocarbon receptor (AhR) thereby modulating the immune response, others have anti-inflammatory and anti-oxidative effects, enhance the intestinal epithelial barrier, increase secretion of gut hormones and stimulate intestinal motility. Indoles are generally thought to mediate beneficial health effects, with the exception of 3IS, a host-microbial co-metabolite generated from indole in the liver; 3IS is toxic at high concentrations and associated with vascular disease and renal dysfunction. 3IS is considered as uremic toxin, which is highly (90 %) bound to albumin, and therefore accumulates despite regular hemodialysis ( 2 ).

About 5 % of tryptophan is catabolized by the gut microbome, generating so-called microbiome-derived tryptophan metabolites, which include indole (IND), 3-indoxyl sulfate (3IS), and indole derivatives, such as indole-3-acetamide (IAM), indole-3-acetate (IAA), indole-3-acetaldehyde (IAAld), indole-3-aldehyde (IAld), indole-3-acrylate (IacA) and indole-3-propionate (IPA). Microbiome-derived tryptophan metabolites have diverse biological roles affecting health (Figure 1). Some are ligands of the aryl hydrocarbon receptor (AhR) thereby modulating the immune response, others have anti-inflammatory and anti-oxidative effects, enhance the intestinal epithelial barrier, increase secretion of gut hormones and stimulate intestinal motility. Indoles are generally thought to mediate beneficial health effects, with the exception of 3IS, a host-microbial co-metabolite generated from indole in the liver; 3IS is toxic at high concentrations and associated with vascular disease and renal dysfunction. 3IS is considered as uremic toxin, which is highly (90 %) bound to albumin, and therefore accumulates despite regular hemodialysis ( 2 ).