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The Kynurenine Pathway as a Convergent Hub Linking Toll-Like Receptor Signaling, Environmental Exposures, and Gut–Brain Axis Dysfunction in Neurodegenerative Diseases
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This review pulls together research showing how your gut bacteria, immune system, and environment (including pollutants like pesticides, heavy metals, and microplastics) can all influence how your body processes tryptophan, an amino acid from food. When this process gets thrown off balance, often due to inflammation or toxin exposure, it produces harmful byproducts instead of protective ones, potentially fueling brain inflammation linked to diseases like Alzheimer's and Parkinson's. The findings point to promising future treatments, like targeting specific gut bacteria or blocking harmful enzymes, though these approaches still need to be tested in hum
Tryptophan (Trp) metabolism plays a central role in neuroimmune communication, integrating immune, metabolic, endocrine, and neural responses. In addition to serving as a precursor for serotonin and melatonin biosynthesis, Trp is metabolized by both host cells and the gut microbiota, generating bioactive metabolites that influence gut homeostasis, immune regulation, and brain function. Approximately 95% of free Trp is metabolized via the kynurenine pathway through indoleamine 2,3-dioxygenase-1 (IDO-1) and tryptophan 2,3-dioxygenase (TDO), a pathway considered inflammatory, producing neuroactive metabolites such as kynurenine (KYN), quinolinic acid (QUIN), kynurenic acid (KYNA), and 3-hydroxykynurenine (3-HK). In parallel, a portion of intestinal tryptophan is converted by the gut microbiota into indole and indole-derived metabolites, including indole-3-acetic acid (IAA), indole-3-propionic acid (IPA), and indole-3-aldehyde (IAld). These microbial metabolites contribute to intestinal barrier integrity, immune homeostasis, and gut-brain axis signaling, primarily through activation of the aryl hydrocarbon receptor (AhR). Growing evidence indicates that inflammatory signals mediated by Toll-like receptors (TLRs), interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) induce IDO-1 activity, redirecting tryptophan metabolism to the kynurenine pathway and promoting the accumulation of neurotoxic metabolites at the expense of neuroprotective indole-derived compounds. Furthermore, environmental factors such as heavy metals, pesticides, air pollutants, and microplastics can trigger gut dysbiosis and neuroinflammation, thus disrupting tryptophan metabolism and gut-brain communication. This review discusses the mechanisms by which TLR activation, environmental toxins, gut dysbiosis, and dysregulation of the kynurenine and indole pathways contribute to neuroinflammation and neurodegeneration. Additionally, we highlight emerging therapeutic targets, including IDO-1 inhibitors and modulation of kynurenine monooxygenase (KMO), sensitization of AhR, GPR35, and microbiota-derived metabolites, as promising strategies for the prevention and treatment of neurodegenerative disorders.
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This review examines how environmental pollutants, including microplastics and nanoplastics, can disrupt the metabolism of tryptophan, an essential amino acid involved in producing neurotransmitters and regulating the immune system. Researchers found that exposure to these contaminants can alter tryptophan pathways in ways that affect the nervous system, digestive health, and even pregnancy outcomes. The study highlights an important but underexplored mechanism by which plastic pollution may affect human health at the molecular level.
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This review summarizes existing research on how pollutants, including air pollution, heavy metals, pesticides, and micro- and nanoplastics, may enter the brain and contribute to processes linked to Alzheimer's disease, such as protein buildup and inflammation. The authors note that most evidence comes from lab and animal studies, with limited research so far in humans.
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