Amino Acid Trp: The Far Out Impacts of Host and Commensal Tryptophan Metabolism

Grifka-Walk, Heather M.; Jenkins, Brittany R.; Kominsky, Douglas J.

doi:10.3389/fimmu.2021.653208

Cited by 66 publications

(42 citation statements)

References 182 publications

(232 reference statements)

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“…Indole derivatives, which are produced exclusively by the gut microbiota, impact the functional differentiation of naive CD4 + T cells into Tregs and T-helper 17 (Th17) cells [ 21 ]. Indoles are also involved in the control of mucosal Tregs/Th17 ratio and thus anti-/pro-inflammatory balance in different compartments of the gastrointestinal tract [ 22 ]. Of note, gut-activated Th17 cells trigger T cell-dependent high-affinity Immunoglobulin A (IgA) secretion [ 23 ].…”

Section: Immunomodulatory Actions Of Microbiotamentioning

confidence: 99%

Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease

Bairamian

Sha

Rolhion

et al. 2022

Mol Neurodegeneration

130

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Background The implication of gut microbiota in the control of brain functions in health and disease is a novel, currently emerging concept. Accumulating data suggest that the gut microbiota exert its action at least in part by modulating neuroinflammation. Given the link between neuroinflammatory changes and neuronal activity, it is plausible that gut microbiota may affect neuronal functions indirectly by impacting microglia, a key player in neuroinflammation. Indeed, increasing evidence suggests that interplay between microglia and synaptic dysfunction may involve microbiota, among other factors. In addition to these indirect microglia-dependent actions of microbiota on neuronal activity, it has been recently recognized that microbiota could also affect neuronal activity directly by stimulation of the vagus nerve. Main messages The putative mechanisms of the indirect and direct impact of microbiota on neuronal activity are discussed by focusing on Alzheimer’s disease, one of the most studied neurodegenerative disorders and the prime cause of dementia worldwide. More specifically, the mechanisms of microbiota-mediated microglial alterations are discussed in the context of the peripheral and central inflammation cross-talk. Next, we highlight the role of microbiota in the regulation of humoral mediators of peripheral immunity and their impact on vagus nerve stimulation. Finally, we address whether and how microbiota perturbations could affect synaptic neurotransmission and downstream cognitive dysfunction. Conclusions There is strong increasing evidence supporting a role for the gut microbiome in the pathogenesis of Alzheimer’s disease, including effects on synaptic dysfunction and neuroinflammation, which contribute to cognitive decline. Putative early intervention strategies based on microbiota modulation appear therapeutically promising for Alzheimer’s disease but still require further investigation.

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Section: Immunomodulatory Actions Of Microbiotamentioning

confidence: 99%

Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease

Bairamian

Sha

Rolhion

et al. 2022

Mol Neurodegeneration

130

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“…The concentration of KYN is generally only one-tenth that of L-TRP [ 75 , 76 ]. Only 2% of L-TRP is converted to 5-HT and MT that are critical for regulation of sleep, mood, appetite, and metabolism [ 71 , 77 ]. Oxidative cleavage of the indole ring of L-TRP is followed by formation of N-formyl-L-kynurenine (NFKYN) by indoleamine-2,3-dioxygenase (IDO1 and IDO2) and tryptophan 2,3-dioxygenase (TDO) [ 78 – 80 ].…”

Section: The Kynurenine Pathwaymentioning

confidence: 99%

Kynurenine Pathway Metabolites as Biomarkers in Alzheimer’s Disease

Liang

Xie

et al. 2022

Disease Markers

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that deteriorates cognitive function. Patients with AD generally exhibit neuroinflammation, elevated beta-amyloid (Aβ), tau phosphorylation (p-tau), and other pathological changes in the brain. The kynurenine pathway (KP) and several of its metabolites, especially quinolinic acid (QA), are considered to be involved in the neuropathogenesis of AD. The important metabolites and key enzymes show significant importance in neuroinflammation and AD. Meanwhile, the discovery of changed levels of KP metabolites in patients with AD suggests that KP metabolites may have a prominent role in the pathogenesis of AD. Further, some KP metabolites exhibit other effects on the brain, such as oxidative stress regulation and neurotoxicity. Both analogs of the neuroprotective and antineuroinflammation metabolites and small molecule enzyme inhibitors preventing the formation of neurotoxic and neuroinflammation compounds may have potential therapeutic significance. This review focused on the KP metabolites through the relationship of neuroinflammation in AD, significant KP metabolites, and associated molecular mechanisms as well as the utility of these metabolites as biomarkers and therapeutic targets for AD. The objective is to provide references to find biomarkers and therapeutic targets for patients with AD.

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“…Although some commensal bacterial species can generate Trp de novo, Trp is an essential amino acid, and most Trp found in the human gut is diet-derived. Dietary Trp enters the intestinal tract and reaches its highest relative concentration in the distal colon, where most proteolytic metabolism occurs [ 28 ]. Despite the fact that adults’ ingestion of Trp is far above the recommended amount (3.5–6 mg/kg/day), circulating and stored Trp concentrations are the lowest among all amino acids, indicating intense metabolic pathways.…”

Section: Microbial Indolesmentioning

confidence: 99%

Pharmaceutically Active Microbial AhR Agonists as Innovative Biodrugs in Inflammation

et al. 2022

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Alterations of the microbiome occur in inflammatory and autoimmune diseases, a finding consistent with the role of the microbiome in the maintenance of the immune system homeostasis. In this regard, L-tryptophan (Trp) metabolites, of both host and microbial origin, act as important regulators of host–microbial symbiosis by acting as aryl hydrocarbon receptor (AhR) ligands. The intestinal and respiratory barriers are very sensitive to AhR activity, suggesting that AhR modulation could be a therapeutic option to maintain the integrity of the epithelial barrier, which has substantial implications for health even beyond the mucosal site. A number of studies have highlighted the capacity of AhR to respond to indoles and indolyl metabolites, thus positioning AhR as a candidate indole receptor. However, the context-and ligand-dependent activity of AhR requires one to resort to suitable biopharmaceutical formulations to enable site-specific drug delivery in order to achieve therapeutic effectiveness, decrease unwanted toxicities and prevent off-target effects. In this review, we highlight the dual activity of the microbial metabolite indole-3-aldehyde at the host–microbe interface and its ability to orchestrate host pathophysiology and microbial symbiosis and discuss how its proper clinical development may turn into a valuable therapeutic strategy in local and distant inflammatory diseases.

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Amino Acid Trp: The Far Out Impacts of Host and Commensal Tryptophan Metabolism

Cited by 66 publications

References 182 publications

Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease

Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease

Kynurenine Pathway Metabolites as Biomarkers in Alzheimer’s Disease

Pharmaceutically Active Microbial AhR Agonists as Innovative Biodrugs in Inflammation

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