Tryptophan ⇒ Indole {90000233}

Shared Reference Notes

• [1.1] [#Crohn’s disease, #Inflamatory bowel disease] 
  - The blood–brain barrier allows the access of #Tryptophan. - In IBD, especially in CD patients, TRP metabolism increases; consequently, the amino acid levels are reduced with respect to normal healthy individuals, and these changes correlate with the gravity of the disease. - TRP undergoes two major metabolic host pathways, the #kynurenine (KYN) and #Serotonin (5-HT) biosynthetic pathways, and one microbial pathway to produce indole and its derivatives.
• [1.2] 
  - #Tryptophan and #Phenylalanine > Microbiom Catabolism > increased #Phenol and indole derivatives > chronic exposure of cultured neurons to these metabolites impaired their firing rate and induced axonal damage, independent from mitochondrial dysfunction and oxidative stress, thereby identifying a novel pathway of neurotoxicity.
• [1.3] [#Pancreatic Cancer] [#Lactobacillus] [#Tryptophan] [#Probiotic] 
• [1.4] [#Colorectal cancer] [#Tryptophan] 
  - Around 5% of Trp > metabolized by gut bacteria into indole and indolic compounds > can bind to pregnane X receptors (PXR) and aryl hydrocarbon receptor (AhR) > promote intestinal homeostasis, enhance barrier function and tight junctions, reduce permeability, regulate intestinal immune tolerance. - Alteration in Trp metabolism begin at early stages of CRC and allow immune evasion umor microenvironment (i.e. the oncogene c-MYC cab accelerate Trp uptake) with an increase in IDO1 and T cell inactivation. - Reduction in indoles production is observed in CRC and the administration of microbial indolic metabolites, diindolylmethane or I3C (AhR ligands), reduces tumor formation
• [1.5] 
  - #Lactococcus lactis species within Lactococcus can produce TRP 2,3-dioxygenase that metabolizes TRP into KYN, while both #Lactococcus lactis and #Streptococcus thermophilus species can produce aromatic-amino-acid transaminase that metabolizes TRP into indole-3-lactate.
• [1.6] [#Chronic kidney disease] 
  - Bacterial species involved in #Butyrate production, indole synthesis and mucin degradation were also related to CKD.
• [1.7] 
  - #Chronic kidney disease > decreased Indole, indole-3-carboxaldehyde and indole-3-propionic acid
• - #kynurenine and indole derivatives might be associated with neurogenic #Depression
• [#Short Chain Fatty Acid] - SCFAs, #Serotonin, #kynurenine, indole and its derivatives, and #Tryptamine, can bridge the gut and nervous system.
• - indole has antipathogenic potential toward #Salmonella by reducing the expression of virulence genes. - Indole also exerts anti-inflammatory properties by counteracting the lipopolysaccharide (LPS)-induced inflammatory response and inhibiting pro-inflammatory activation of macrophages.
• [1.8] [#Indole-3-propionic acid, #Indole-3-aldehyde] 
  - Most #Tryptophan is transformed in the indole pathway. Intestinal bacteria express the enzyme tryptophanase, leading to the production of indole in the gut. - Indole > metabolized into 3-indolepropionic acid (IPA) > binds to the pregnane X receptor (PXR) in intestinal cells. - IPA is absorbed in the intestine and distributed to the brain > neuroprotective properties. - Indole > metabolized into indole-3-aldehyde (I3A) > triggers immunoprotective effects in the intestine.
• [#Indoxyl-3-sulfate] - In the liver, indole may be metabolized into indoxyl sulfate, which can be toxic in high concentrations.
• [1.9] [#Diabetes Type 2] [#Indole sulfuric acid (ISA), #Indole-3-propionic acid] 
  - The bacterially derived Trp metabolites indoles, IPA and indole sulfuric acid (ISA) are lower in blood samples from subjects with type 2 diabetes as compared to the lean controls. - Higher serum concentrations of IPA are also associated with a reduced prevalence of T2D.
• - Bacterial species such as Bacteroides ovatus, Clostridium limosum, Enterococcus faecalis and Escherichia coli are able to convert Trp into indole. - Indole modulates the secretion of glucagon-like peptide-1 (GLP-1) in mouse colonic enteroendocrine L cells, which is critical in stimulating the insulin secretion of pancreatic β cells, suppressing appetite and slowing gastric emptying.
• [#Indole-3-acetamide (IAM), #Indole-3-acetic acid, #Indole-3-aldehyde, #Indole-3-lactic acid, #Indole-3-propionic acid, #Indole-3-pyruvic acid (IPyA), #Indoleacrylic acid (IA)] - For AhR, the most effective Trp metabolites are indole, #Skatole, IA, #Tryptamine, IPyA and indole-3-acetamide (IAM), whereas IAA, IAID, IPA and ILA are the least active
• [#Serotonin] - #Pu-erh tea could boost the indole and 5-hydroxytryptamine pathways of the Trp metabolism.
• [#Tryptophan] - There are decreased circulating levels of AhR agonists in individuals with #Multiple Sclerosis.
• [#Colorectal cancer] - Indole derivates support gut homeostasis by promoting epithelial barrier function and immune tolerance, which are important to suppress carcinogenesis in the colon
• [#Colorectal cancer] - #Tryptophan metabolism is altered in CRC with a shift towards increased Kyn production by host cells but decreased indole production by gut microbes. - Elevated fecal Kyn to #Tryptophan ratios but decreased indole to tryptophane ratios were found in patients with colorectal neoplastic lesions.
• - Many common gut bacteria are capable of producing indoles and the fecal indole concentration ranges between 1 and 4 mM. - Common indole metabolites include indole-3-pyruvate, indole-3-acetaldehyde, indole-3-lactic acid, indole-3-acetic acid, indole-3-acetamide, and indole-3-propionic acid. - Indoles are recognized by PXR and the acryl hydrocarbon receptor (AhR), which are expressed by various cell types including intestinal epithelial and immune cells. - Dietary indoles, found in cruciferous vegetables, also function as AhR ligands.
• - #Tryptophan metabolites are produced via four different pathways: The #Serotonin pathway, the #Tryptamine pathway, the #kynurenine pathway, and the bacterial indole pathway.
• [#kynurenine] - The host Kyn and bacterial indole pathways each process ~90% and ~5% of the available #Tryptophan, respectively.
• [#Polyamine] - Amino acids that reach the colon are converted by the microbiome to polyamines or indole derivates. - The most common polyamines are #Putrescine, #Spermidine, and #Spermine, which play important roles in cell growth, proliferation, and migration.
• [1.11] [#kynurenine] 
  - #Tryptophan can be metabolized via the indoleamine 2,3-dioxygenase (IDO) or through the enzyme #Tryptophan-2,3-dioxygenase (TDO) to form N-formylkynurenine (Kyn) > Kyn pathway, and accounts for ~95% of dietary #Tryptophan degradation. - The indoles and their derivates can also be transformed into Kyn. - Many components of the Kyn pathway are neuroactive.
• [1.12] [#Phenol] [#High-protein diet] 
  - Excessive fermentation of undigested protein residues in the colon increases the amount of #Ammonia, biogenic amines, indole compounds, and phenols.
• [1.13] [#α-tocopherol] 
  - microbial metabolites such as α-tocopherol, #Tyramine, #p-aminobenzoate, and indole impact #Serotonin 5-HT secretion by enteroendocrine cells in the intestine.
• [1.14] [#Tryptophan] 
  - Indoles, generated by commensal microbes, also serve as #AHR agonists and therefore are likely to influence immune homeostasis as well as anticancer immunity.
• [1.15] 
  - Indole-derived metabolites are produced by fermentation via #Clostridium sporogenes and #Escherichia coli.
• - indole, a #Tryptophan metabolite, has been reported to increase neurogenesis in the hippocampus of adult mice.
• [1.16] 
  - Humans lack this indole pathway and instead rely on exogenous indoles, either from dietary sources or microbial metabolism, which is metabolically straightforward but the resulting bioactivity in the microbiome is complex and can alter biofilm formation, virulence, and host interaction
• - #Tryptophan is mostly shunted into the #kynurenine pathway but is also the primary metabolite for #Serotonin production and the bacterial indole pathway.
• [#Tryptophan] - some gut microbes can synthesize Trp from indole and serine via the Trp synthase enzyme complex
• [1.17] [#CVD] [#Streptococcus] 
  - CACS-associated species was negatively associated with the microbially derived #Tryptophan metabolite indole #Propionate, a metabolite that has been found inversely associated with atherosclerotic coronary disease in humans and reduced progression of #Atherosclerosis in mice.
• [1.18] [#Clostridium botulinum, #Clostridium caloritolerans, #Clostridium paraputrifcum] [#Indole-3-propionic acid, #Tryptophan] 
  - Some gut microbiomes, C. botulinum, C. caloritolerans and C. paraputrifcum converts Trp to indole -3-#Propionic acid (IPA). - Its major contribution is in preserving β-cell function and improving #Glucose metabolism.
• [#Diabetes Type 2] [#Bacteroides ovatus, #Paraclostridium bifermentans] - Various gut bacterial species, like #Bacteroides thetaiotaomicron, B. ovatus, #Clostridium limosum, and C. bifermentans metabolize amino acid #Tryptophan (Trp) to indole. - It helps to secret glucagon-like-peptide-1 (GLP-1), which has an important role to increase insulin secretion and inhibit glucagon secretion.
• [1.19] [#Indole-3-carbinole] 
  - I3C is converted in the stomach by acid-mediated condensation into various byproducts, including high affinity #AHR ligands DIM and indole[3,2-b] carbazole (ICZ)
• [#Indole-3-carbinole] - The main class of dietary #AHR ligands is indoles, including Indole-3-acetonitrile, Indole-3-carbinole (I3C), 3,3’-diindolylmethane (DIM) and Indolo(3,4)bicarbazole, which are found mainly in cruciferous vegetables like #Broccoli or Brussel sprouts
• [#Indole-3-acetic acid] - #Lactobacillus can use #Tryptophan instead of #Glucose as a source of energy, and produce #AHR ligands such as indole-3-acetic acid (IAA), #Tryptamine (TA) and 3-methyl indole
• [#Pancreatic Cancer] - The microbial-related metabolite panel includes indoleacyrlic acid, an indole-derivative, and #TMAO. - #TMAO- and indoleacrylic-acid-producing #Bacteria include those in the phyla of #Bacillota, #Bacteroidota, #Actinomycetota, and Pseudomonadota. - #Bacillota species such as Cs and Er and Bacteriodota species including Bt and Pd have been shown to be increased in fecal samples of patients with PDAC compared with control subjects. - Relative abundances of fecal #Collinsella aeofaciens, a species of #Actinomycetota, is associated with poor prognosis in PDAC.
• [1.21] 
  - #Bacteroides and #Clostridium have been reported to be capable of converting #Tryptophan into indole and indole derivatives
• [#Indole-3-lactic acid, #Indole-3-propionic acid] - #Clostridium sporogenes, for example, converts #Tryptophan into #Tryptamine, indoleacetic acid (ILA), and indole #Propionic acid (IPA)
• [#Antibiotic Therapy] - Indole is a bacterial signaling molecule that has been shown to influence bacterial movement, biofilm formation, antibiotic resistance, and the colonization of #Staphylococcus aureus, #Salmonella enterica, and #Lactobacillus plantarum
• [1.22] [#Para-cresol] 
  - The absence of gut microbiota also reduces the production of amino acid-derived microbial metabolites (e.g., indole and p-cresol), which are reported to modulate #GLP-1 expression and secretion, and gut motility. - supplementing mice with the tyrosine-derived microbial metabolite p-cresol reversed the enteropeptidase inhibition mediated effects on Gcg expression and small intestinal transit.
• [1.23] 
  - By lowering #Oxidative stress, indoles, another byproduct of #Tryptophan metabolism, have shown neuroprotective benefits
• [1.24] [#Depression] 
  - subjects whose GM is highly inclined to produce indole could be more likely to develop #Anxiety or depressive disorders
• [#Autism] [#Butanoic acid, #Propanoic acid] - GM core volatilome for all ASD patients was characterized by over-production of 1-pentanol, 1-butanol, phenyl ethyl alcohol; benzeneacetaldehyde, octadecanal, tetradecanal; #Methyl isobutyl ketone, 2-hexanone, acetone; acetic, propanoic, 3-methyl-butanoic and 2-methyl-propanoic acids; indole and #Skatole; and o-cymene.
• [#Autism] - Indole and #Skatole concentrations were increased in children with ASD. - indole was more represented in ASD subgroups characterized by low severity symptoms and without GI symptoms
• [#Autism] - #Tryptophan derivatives such as indole and #Skatole were significantly increased (p ≤ 0.05) in #Children with ASD, particularly #Skatole, and thus were also identified as biomarkers by the ML predictive model.
• - indole is an inter-kingdom signal in gut epithelial cells, reinforcing the host cell-barrier assets - It is derived from #Tryptophan, produced by several microbes (i.e., #Bacteroides, #Clostridium, #Desulfovibrio) colonizing the human GI tract - It is a critical precursor of physiologically important molecules, such as #Serotonin and #Melatonin
• [#Blood Brain Barrier Integrity] [#Alcohol Consumption] - Alcohols promote dysbiosis and gut permeability and may alter the mucosal tight junctions and the immune activity in the GI tract, leading to a modification of gut barrier integrity, which allows microbial products such as indoles and FA to cross into the circulatory system
• - indole and its derivatives seem to increase the integrity of the epithelial barrier and function of tight junctions > reduce #Colitis related to #Citrobacter rodentium and #Candida albicans infection
• - high levels of #Oxindole and #Isatin, after the epithelial and hepatic enzymatic digestion of indole in blood and urine, respectively, have been detected in #Hepatic encephalopathy and #Parkinson’s Disease
• - excessive production of indole by GM > increased brain exposure to #Oxindole and #Isatin, affecting behavior and thus defining another pathway whereby indole could act as a signal to the brain and cause behavior alterations
• - GM indole derivatives may influence the level of #Serotonin precursors that affect the amount of #Serotonin in the brain.
• [1.25] [#Collagen-induced arthritis , #Rheumatoid Arthritis, #Spondyloarthritis] [#Lachnospiraceae bacterium] 
  - in CIA (such as Lachnospiraciae and Lactobacillaeae), RA (#Lachnospiraceae bacterium, #Lactobacillus spp., #Faecalibacterium), and SpA (#Ruminococcaceae, #Rikenellaceae, #Porphyromonadaceae, #Bacteroidaceae, #Lachnospiraceae) are either predicted or known to produce indole
• [#Collagen-induced arthritis ] - Indole supplementation appears to affect several aspects of CIA pathophysiology, including the induction of proinflammatory cytokines, CD4+ T cell skewing toward Th17 cells, and antibody-mediated complement activation.
• [#Reactive arthritis] - indole induces pathogenic antibody formation through class switching to IgG2b as well as decreased antibody sialyation that enhances complement fixation, and that these changes may occur through the #IL-23/Th17 axis.
• [#Rheumatoid Arthritis] - Intra-articular injection of indole, but not #kynurenine, into rabbit knees induced RA-like synovitis
• [1.26] [#Radiofrequency field] 
  - Decreased indole and its metabolites (IAM) after RF may result in insufficient #AHR activation, which may also contribute to RF induced #Depression-like behavior in mice
• [1.27] [#Multiple Sclerosis] [#Indole-3-lactic acid] 
  - MS > there is a notable decrease in circulating indole 3-#Lactate (ILA), having a more pronounced reduction in progressive forms compared with relapsing-remitting disease.
• [1.28] [#Tryptophan] 
  - Trp is converted to indole via the enzyme Trp identified in gut bacteria such as #Escherichia coli (E. coli), #Clostridium spp., and #Bacteroides spp. - Trp decarboxylase converts Trp to #Tryptamine > is expressed in #Clostridium, #Ruminococcus, #Blautia, and #Lactobacillus bacteria
• - indole promotes health by inducing the expression of tight junction proteins and anti-inflammatory cytokines along with decreasing the level of pro-inflammatory interleukin-8 (#IL-8)
• [#Inflamatory bowel disease] [#Tryptophan] - IBD exhibit decreased Trp absorption, enhanced #kynurenine pathway, altered indole pathway along, and altered indole pathway with decreased Trp plasma levels.

References Notes