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Review
. 2023 Mar;101(3):201-222.
doi: 10.1007/s00109-023-02289-5. Epub 2023 Feb 9.

Activation of aryl hydrocarbon receptor (AhR) in Alzheimer's disease: role of tryptophan metabolites generated by gut host-microbiota

Affiliations
Review

Activation of aryl hydrocarbon receptor (AhR) in Alzheimer's disease: role of tryptophan metabolites generated by gut host-microbiota

Antero Salminen. J Mol Med (Berl). 2023 Mar.

Abstract

Gut microbiota in interaction with intestinal host tissues influences many brain functions and microbial dysbiosis has been linked with brain disorders, such as neuropsychiatric conditions and Alzheimer's disease (AD). L-tryptophan metabolites and short-chained fatty acids (SCFA) are major messengers in the microbiota-brain axis. Aryl hydrocarbon receptors (AhR) are main targets of tryptophan metabolites in brain microvessels which possess an enriched expression of AhR protein. The Ah receptor is an evolutionarily conserved, ligand-activated transcription factor which is not only a sensor of xenobiotic toxins but also a pleiotropic regulator of both developmental processes and age-related tissue degeneration. Major microbiota-produced tryptophan metabolites involve indole derivatives, e.g., indole 3-pyruvic acid, indole 3-acetaldehyde, and indoxyl sulfate, whereas indoleamine and tryptophan 2,3-dioxygenases (IDO/TDO) of intestine host cells activate the kynurenine (KYN) pathway generating KYN metabolites, many of which are activators of AhR signaling. Chronic kidney disease (CKD) increases the serum level of indoxyl sulfate which promotes AD pathogenesis, e.g., it disrupts integrity of blood-brain barrier (BBB) and impairs cognitive functions. Activation of AhR signaling disturbs vascular homeostasis in brain; (i) it controls blood flow via the renin-angiotensin system, (ii) it inactivates endothelial nitric oxide synthase (eNOS), thus impairing NO production and vasodilatation, and (iii) it induces oxidative stress, stimulates inflammation, promotes cellular senescence, and enhances calcification of vascular walls. All these alterations are evident in cerebral amyloid angiopathy (CAA) in AD pathology. Moreover, AhR signaling can disturb circadian regulation and probably affect glymphatic flow. It seems plausible that dysbiosis of gut microbiota impairs the integrity of BBB via the activation of AhR signaling and thus aggravates AD pathology. KEY MESSAGES: Dysbiosis of gut microbiota is associated with dementia and Alzheimer's disease. Tryptophan metabolites are major messengers from the gut host-microbiota to brain. Tryptophan metabolites activate aryl hydrocarbon receptor (AhR) signaling in brain. The expression of AhR protein is enriched in brain microvessels and blood-brain barrier. Tryptophan metabolites disturb brain vascular integrity via AhR signaling. Dysbiosis of gut microbiota promotes inflammation and AD pathology via AhR signaling.

Keywords: Aging; Hypoperfusion; Immunosuppression; Microbiome; Microflora; Uremic toxin.

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Conflict of interest statement

The author declares no competing interests.

Figures

Fig. 1
Fig. 1
Gut host-microbiota-derived tryptophan metabolites activate AhR signaling in the brain via different pathways and induce pathological changes observed in AD pathology. Microbial bacteria secrete indole molecules which via circulation can activate AhR signaling in the brain. Liver and kidney process the secreted indole molecules into uremic toxins, e.g., indole sulfate. Uremic toxins accumulate in the blood during chronic kidney disease. There is a close interplay between the microbiota and the host cells of the gastrointestinal tract, stimulating the generation of serotonin by enterochromaffin cells. Some microbes can convert tryptophan into tryptamine which activates AhR signaling. Gut host-microbiota interplay, e.g., in inflammation, activates the IDO1/TDO-induced KYN pathway which generates novel agonists for the Ah receptor. Subsequently, AhR signaling stimulates the expression of IDO1 enzyme inducing a positive feedback loop. Below, the pathological effects induced by AhR signaling are listed, many of which are also observed in AD pathology (see the text). Abbreviations: AD, Alzheimer’s disease; AhR, aryl hydrocarbon receptor; BBB, blood–brain barrier; IDO1, indoleamine 2,3-dioxygenase, KYN, kynurenine; TDO, tryptophan 2,3-dioxygenase
Fig. 2
Fig. 2
AhR agonists generated via different tryptophan metabolic pathways. The AhR-activating metabolites produced by the kynurenine, indole, serotonin, and tryptamine pathways have been compiled. The pathological responses which also exist in AD pathology are displayed underneath. The detailed reactions have been explained in the text

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