Tryptophan {90000154}

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-Deficient diet] 
  - The mice on the Tryptophan-Deficient diet showed changes in their bacterial abundance of Coriobacteriia class, Acetatifactor genus, Lachnospiraceae family, Enterococcus faecalis species, Clostridium sp genus, and Oscillibacter genus. - Decreased Clostridium sp. may lead to lower levels of 5-HT, leading to depression, impaired digestions, and neuropsychiatric conditions. Similarly, the number of other gut bacterium significantly decreases in TRP-deficient groups such as Oscillibacter valericigenes, Mucispirillum, and Blautia genus. - The mice on the Tryptophan-Deficient diet showed significant increases in IL-6, IL-17A, and IL-1a and decreased IL-27 levels.
• [1.3] 
  - Tryptophan metabolism follows three major pathways in the gastrointestinal tract: (1) the direct transformation of Trp into several molecules, including ligands of the aryl hydrocarbon receptor (AhR), by the gut microbiota. (2) the kynurenine pathway (KP) in both immune and epithelial cells via indoleamine 2,3-dioxygenase (IDO). (3) the serotonin (5-hydroxytryptamine [5-HT]) production pathway in enterochromaffin cells via Trp hydroxylase 1 (TpH1).
• [1.4] 
  - 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.
• [1.5] 
  - Tryptophan > Microbiota Catabolism > derived ligands > act as AhR agonists expressed in several intestinal cells > AhR activation > protects the epithelial barrier, production of IL-22 and 10, promotes intestinal immune tolerance and protects from intestinal inflammation.
• [1.6] [#Alzheimer’s disease, #Parkinson’s Disease] 
  - Tryptophan metabolites can cross the blood-brain barrier > activate #AHR to regulate astrocytes and reduce central nervous system inflammation in AD and PD
• [#Indole-3-acetic acid (IAA), #Indole-3-propionic acid (IPA)] - TRP > utilized by the intestinal flora in the intestinal tract and metabolized into ligand molecules indole, indole propionic acid, indole acetic acid, #Skatole, and #Tryptamine > action on of aryl hydrocarbon receptor (AHR).
• [1.7] [#Pancreatic Cancer] [#Lactobacillus] [#Indole] [#Probiotic] 
• [1.8] [#kynurenine] 
  - Tryptophan > Excessive Kyn levels in the tumor microenvironment is one of the adaptive mechanism for the tumors to escape immune surveillance and metastasize. Most individuals with #Cancer, including hepatocellular carcinoma, CRC, kidney #Cancer, lung #Cancer often exhibit increased Kyn levels and decreased serum Trp levels, or increased kyn/Trp ratio.
• [#Colorectal cancer] - 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
• [#Colorectal cancer] - Tryptophan > #Serotonin > can exhibit both a protective and detrimental role. For example, activation of #Serotonin receptors, 5-HTR1B and 5-HTR2B stimulate tumor angiogenesis and cell proliferation. SCFAs can induce the production and release of #Serotonin though. In normal conditions, #Serotonin seems to have mainly a protective role but dysregulation of its production is linked to cancer promotion.
• [1.9] [#Serotonin] 
  - 5-HT in the body is synthesized from the essential amino acid tryptophan (Trp) in both the brain and gut, and the majority of it (approximately 95% of total 5-HT) resides in the digestive tract and is mostly produced and stored in enterochromaffin cells (ECs). - In the gut, 5-HT is responsible for one of the core signaling pathways, especially in modulating intestinal permeability and regulating mucosal inflammation. - 5-HT is related to colon inflammation in a DSS-induced murine colitis model, and treatment by inhibiting 5-HT production in colonic mucosa has a therapeutic outcome in ameliorating colitis-associated symptoms and inflammation
• - #AHR is expressed by keratinocytes, epidermal Langerhans cells, dermal and epidermal innate and adaptive immune cells. - The activation of #AHR is mostly anti-inflammatory through the regulation of cytokine production and other immune-related transcription factors, such as NF-κB. - In the skin epidermis, dead keratinocytes and broken keratin are used as substrates in the tryptophan metabolism of skin microbiota which leads to #AHR agonists production
• [1.11] [#Diabetes Type 2] 
  - #Dimethylglycine, #Imidazole propionate, tryptophan, #kynurenine and #Indolelactate associated with increased risk of T2D
• [1.12] 
  - Tryptophan metabolites, act in 2 different ways: propagating bottom-up signals that start at the local level, or crossing the intestinal barrier to enter the systemic circulation, even acting on the CNS after crossing the blood-brain barrier. - Tryptophan metabolites use aryl hydrocarbon receptors to act on astrocytes (neuroectodermal cells involved in a wide range of CNS functions).
• [1.13] [#Indole-3-aldehyde (I3A) (IAID), #Indole-3-propionic acid (IPA)] 
  - 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.
• [1.14] [#Chronic Obstructive Pulmonary Disease] [#Indole-3-acetic acid (IAA)] 
  - In Neutrophil-predominant COPD altered tryptophan metabolism in airway #Lactobacilli is associated with reduced indole-3-acetic acid (IAA), which was in turn linked to perturbed host interleukin-22 signalling and epithelial cell apoptosis pathways. - airway microbiome-derived IAA mitigates neutrophilic inflammation, apoptosis, emphysema and lung function decline, via macrophage–epithelial cell cross-talk mediated by interleukin-22. - Intranasal inoculation of two airway #Lactobacilli restored IAA and recapitulated its protective effects in mice.
• [1.15] [#Diabetes Type 2] [#Cow’s milk (Dietary Casein), #High-fiber diet] 
  - a higher milk intake and higher fiber intake were associated with a favorable profile of circulating Trp metabolites for T2D.
• [#Escherichia coli] - #Fucose increased the abundance of Trp-producing E. coli and normalized the blood Trp levels.
• [#Indole-3-carboxyaldehyde, #Indole-3-lactic acid (ILA), #Indole-3-propionic acid (IPA), #Niacin] [#Ginseng] - #Ginsenoside Rg1 could increase the levels of Trp metabolites in the serum, including indole-3-carboxaldehyde, indole-3-lactic acid, 3-indolepropionic acid and niacinamide. - In mice with high-fat diet-induced obesity, #Ginsenoside Rb1 significantly altered the gut microbiota composition and serum Trp
• [#Inflamatory bowel disease] [#kynurenine] - patients with inflammatory bowel diseases (IBD) have lower levels of Trp in both their serum and feces than healthy subjects. - active IBD > increased Kyn or Kyn/Trp ratios in IBD patients, indicating the promoted Trp metabolism along the Kyn pathway.
• [#kynurenine] - A high-serum Kyn/Trp ratio is also correlated with a poor prognosis after a PD-1 blockade in #Lung cancer, #Melanoma and #renal cell carcinomas
• [#Indole] - There are decreased circulating levels of AhR agonists in individuals with #Multiple Sclerosis.
• [#Pancreatic Cancer] - dietary Trp generated by the gut microbiota activate the aryl hydrocarbon receptor in myeloid cells, promoting an immune suppressive tumor microenvironment and facilitating pancreatic ductal adenocarcinoma growth.
• - Tryptophan metabolites such as indole-3-lactate (ILA), indole-3-acrylate (IAC), indole-3-propionate (IPA), indole-3-aldehyde (IAID), indoleacetic acid (IAA), indole-3-acetaldehyde and Kyn can be produced by intestinal microorganisms through direct Trp transformation and also, partly, the kynurenine (Kyn) pathway. - They can not only promote the differentiation and function of anti-inflammatory macrophages, Treg cells, CD4+CD8αα+ regulatory cells, IL-10+ and/or IL-35+B regulatory cells but also IL-22-producing innate lymphoid cells 3 (ILC3), which are involved in maintaining the gut mucosal homeostasis. - Trp metabolite receptors such as the ary hydrocarbon receptor (AhR) can be detected in T cells such as T-helper type 17 (Th17) cells and Tregs, B cells and antigen-presenting cells (APCs). - Trp metabolites from Trp transformation and the Kyn pathway by the gut microbiota suppress inflammatory responses in the macrophages. - Trp metabolite receptor AhR signaling has an important role in the function of macrophages.
• [1.16] [#Bifidobacterium infantis] 
  - treatment with B. infantis 35624 resulted in elevated circulating levels of both tryptophan and #kynurenic acid.
• [#Depression] - Depressed individuals receiving the #Probiotic had ↓ circulating CRP. - #Probiotic treatment, but not prebiotic treatment, decreased depressive symptoms. #Probiotic treatment resulted in ↓ circulating #kynurenine/tryptophan ratio, when adjusting for #Isoleucine
• [#Limosilactobacillus (Lactobacillus) reuteri] [#Condition of chronic stress] - chronic stress was connected with increased #Depression-like behavior (as measured by the forced swim test), reduced Lactobacillus spp. in the fecal microbiome, as well as increased circulating levels of #kynurenine, a direct metabolite of tryptophan via the enzyme IDO1. - supplemented the diet of the mice with L. reuteri ATCC 23272 for an additional 4 weeks, which was sufficient to reverse behavior and #kynurenine concentrations. - The reversal of #Depression-like behaviors was diminished if #kynurenine levels were artificially elevated during probiotic supplementation, suggesting a link between #kynurenine signaling and #Depression-like behavior.
• - Tryptophan is the precursor to many neuroactive molecules, including the neurotransmitter serotonin, the neuroprotective molecule kynurenic acid, the neurotoxic molecule 3-hydroxykynurenine (3-HK), and the neurotoxic breakdown product of 3-HK, quinolinic acid.
• [#Antibiotic Therapy] - following 13 weeks of antibiotic treatment, circulating levels of tryptophan had increased.
• [1.17] [#Parkinson’s Disease] 
  - Tryptophan, an essential amino acid only derived from microbiome or diet, is the rate limiting precursor to #Serotonin. Tryptophan biosynthesis pathway was reduced in PD. - spore forming bacteria modulate #Serotonin production and enhance gut motility - #Constipation, a common symptom of PD, may be related to the depletion of spore forming bacteria.
• [1.18] [#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.
• - 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.

References Notes