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

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.

AhR may be involved in Th17 cell differentiation in chronic hepatitis B

“…In Alzheimer's disease (AD), the dysregulated gut microbes produced large amounts of tryptophan metabolites that activate AhR signalling in the brain, disrupting the blood-brain barrier and promoting inflammation and AD pathology. 57 Human umbilical mesenchymal stem cells (HUMSCs) cured collagen-induced arthritis (CIA) in mice by modulating the interplay between host immunity and gut microbiota via the AhR. 58 It suggested that AhR is essential for the control of immune responses and gut microbiota.…”

The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

“…The aryl hydrocarbon receptor (AhR) is an evolutionarily conserved, ligand-regulated transcription factor which is not only a major sensor of environmental toxins but it is also activated by a number of metabolites ranging from heme, arachidonic acid, and kynurenine pathways as well as indoles from microbiota [ 155 , 156 ]. AhR signaling cooperates closely with indoleamine 2,3-dioxygenase 1 (IDO1), a common immune checkpoint, in the regulation of the aging process [ 157 , 158 ].…”

“…Moreover, Wang et al [ 161 ] reported that the inhibition of AhR signaling potentiated the therapeutic response induced with anti-PD-L1 antibody treatment in mouse lung cancer model. Tryptophan metabolites, e.g., compounds produced via the kynurenine, indole, serotoinin, or tryptamine pathways, are activators of AhR signaling as well as immune modulators [ 156 , 164 ]. Currently, there is clear evidence that the gut microbiota can modulate the efficacy of anti-PD-1/PD-L1 therapy both in humans and mice [ 165 ].…”

“…Currently, there is clear evidence that the gut microbiota can modulate the efficacy of anti-PD-1/PD-L1 therapy both in humans and mice [ 165 ]. The gut microbiota generates several indole derivatives which are potent agonists of the AhR protein in many tissues via the circulation [ 156 ]. For example, oxidative stress triggered the formation of 2-oxindole which stimulated the expression of PD-L1 in human keratinocytes [ 162 ].…”

Roles of gut microbes in metabolic-associated fatty liver disease

“…Tryptophan is an essential amino acid for humans commonly found in everyday diets. Recently the roles of tryptophan metabolites in disease development have been reported in various diseases, including MAFLD [ 71 ], dermatological diseases [ 72 ], neurodegenerative diseases [ 73 ] and kidney diseases [ 74 ]. Tryptophan can be metabolized through the following pathways in the human gut: the kynurenine pathway (90%–95% of tryptophan metabolism), the serotonin/melatonin pathway (1%–2%), and indole pathway (5%) [ 71 ].…”