Neurobiology of Disease 156 (2021) 105403

Contents lists available at ScienceDirect

Neurobiology of Disease
journal homepage: www.elsevier.com/locate/ynbdi

Review

Indoles as essential mediators in the gut-brain axis. Their role in

Alzheimer’s disease
Miguel A. Pappolla a, *, George Perry b, Xiang Fang a, Michael Zagorski c, Kumar Sambamurti d,
Burkhard Poeggeler e
a
University of Texas Medical Branch, Department of Neurology, Galveston, TX, United States of America
b
University of Texas at San Antonio, Department of Biology, San Antonio, TX, United States of America
c
Case Western Reserve University, Department of Chemistry, Cleveland, United States of America
d
Medical University of South Carolina, Department of Neurobiology, Charleston, SC, United States of America
e
Quiris Health, Gütersloh, Germany

A B S T R A C T

Sporadic late-onset Alzheimer’s disease (AD) is the most frequent cause of dementia associated with aging. Due to the progressive aging of the population, AD is
becoming a healthcare burden of unprecedented proportions. Twenty years ago, it was reported that some indole molecules produced by the gut microbiota possess
essential biological activities, including neuroprotection and antioxidant properties. Since then, research has cemented additional characteristics of these substances,
including anti-inflammatory, immunoregulatory, and amyloid anti-aggregation features. Herein, we summarize the evidence supporting an integrated hypothesis
that some of these substances can influence the age of onset and progression of AD and are central to the symbiotic relationship between intestinal microbes and the
brain. Studies have shown that some of these substances’ activities result from interactions with biologically conserved pathways and with genetic risk factors for AD.
By targeting multiple pathologic mechanisms simultaneously, certain indoles may be excellent candidates to ameliorate neurodegeneration. We propose that
management of the microbiota to induce a higher production of neuroprotective indoles (e.g., indole propionic acid) will promote brain health during aging. This
area of research represents a new therapeutic paradigm that could add functional years of life to individuals who would otherwise develop dementia.

1. Introduction alternative interventions that could explain the ruthless progression of

AD independent of amyloid formation. These approaches included
Due to the progressive aging of the population, AD is becoming a revitalized propositions involving oxidative stress,(Pappolla et al., 1992;
healthcare burden of unparalleled proportions. The strongest risk factors Martins et al., 2018; Nunomura et al., 1999) inflammation,(Bettcher
for AD are advanced age and being a carrier of the apolipoprotein E4 et al., 2018) immune dysfunction,(Bettcher et al., 2018) hormonal
allele.(Strittmatter and Roses, 1996) Pathologically, AD is characterized senescence,(Imtiaz et al., 2017; Kantarci et al., 2016) reactivation of
by brain deposits of mostly 40 to 42 amino acid peptides, the amyloid β latent infections,(Itzhaki et al., 2016; Readhead et al., 2018) and other
protein (Aβ)(Glenner and Wong, 1984; Selkoe and Hardy, 2016; Zolo­ abnormalities in the brain microenvironment leading to the misfolding
chevska and Taglialatela, 2016) and by abnormal intracellular aggre­ of an old foe, the tau protein.(Wu et al., 2016; Leuzy et al., 2019) One
gates of the microtubule-associated protein tau.(Bancher et al., 1989) interesting strategy is ramping up neuroresilience. If one could increase
The “amyloid hypothesis” of AD proposes that elevated levels of Aβ brain resistance to injury, it may be possible to maintain cognition and
oligomers trigger a downstream cascade that leads to widespread death add functional years to individuals that would otherwise become
of neurons and dementia.(Selkoe and Hardy, 2016; Karran and De demented at an earlier age.
Strooper, 2016) Research related to Aβ peptides or the amyloid pre­ Clinically, dementia due to AD is preceded by an intermediate stage
cursor protein (APP) has captured most of the last three decades’ of cognitive decline that falls between normal aging and dementia. This
research attention. These efforts, however, resulted in a vast amount of stage, called mild cognitive impairment or MCI,(Reisberg et al., 1988;
data but disappointing therapeutic results.(Knopman et al., 2019) While Petersen et al., 2014) affects 3–5% of adults over 60 and 15% of adults
the failure of these therapies did not disprove the amyloid hypothesis, over 75.(Panza et al., 2005) MCI is commonly classified into two sub­
(Selkoe and Hardy, 2016) the negative results reinvigorated interest in types: amnestic MCI and non-amnestic MCI, which may affect single or

* Corresponding author.
E-mail address: [email protected] (M.A. Pappolla).

https://doi.org/10.1016/j.nbd.2021.105403
Received 7 January 2021; Received in revised form 5 May 2021; Accepted 21 May 2021
Available online 1 June 2021
0969-9961/© 2021 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
M.A. Pappolla et al. Neurobiology of Disease 156 (2021) 105403

multiple cognitive domains,(Bennett et al., 2002; Petersen et al., 2009) 2015; Mancuso and Santangelo, 2018) The identities of the bacterial
depending on the performance on neuropsychological tests of episodic molecules mediating multiple effects of the microbiota in the brain
memory or in tests covering cognitive domains other than memory. began to be defined in the last two decades. The first of these studies
Clinical studies showed that not all patients diagnosed with MCI showed that naturally occurring indoles produced by commensal
necessarily progress to AD, and some even revert to normal.(Bennett microbiota can reach the brain and exert potent neuroprotective prop­
et al., 2002; Ganguli et al., 2011; Brodaty et al., 2013) Therefore, it is erties.(Chyan et al., 1999; Poeggeler et al., 2010) Multiple mechanisms
reasonable to focus some efforts on modifying the factors that may slow drive these effects. One of them is protection against oxidative stress, a
down the progression of MCI to AD. well-established form of injury in AD.(Pappolla et al., 1992; Martins
In this paper, we would like to review some of the data to provide a et al., 2018; Nunomura et al., 1999; Bozner et al., 1997; Pappolla et al.,
novel integrated hypothesis, linking the previously established neuro­ 1998a; Pappolla et al., 2002; Smith et al., 2002) Indoles cross the blood-
protective effects of indoles with indoles known to be produced by the brain barrier, and some of them, like indole-3-propionic acid (IPA) and
microbiota. We hypothesize that a healthy production of indoles by the indole-3-propionamide (IPAM), prevent neurodegeneration through
microbiota may influence the age of onset and rate of progression of AD. mechanisms that include reduction of electron leakage from mitochon­
(Chyan et al., 1999; Poeggeler et al., 2010) Although neuroprotective dria and neutralization of hydroxyl radicals.(Chyan et al., 1999;
indoles are the primary focus of our hypotheses, several other substances Poeggeler et al., 2010; Bendheim et al., 2002; Cheng and Van Breemen,
produced by the gut microbiota may also contribute to the risk for 2005; Kato et al., 2007) Serum indoles are mostly produced from tryp­
developing AD and other age-related disorders.(Wikoff et al., 2009) tophan by commensal bacteria that express tryptophanase.(Wikoff et al.,
These include short-chain fatty acids (SCFAs), trimethylamine N-oxide 2009; Zhang and Davies, 2016) Tryptophanase is expressed by the
and oxidized fatty acids.(Zhang and Davies, 2016) A detailed discussion gastrointestinal bacteria and depending on the particular species, indole
of the latter interactions and mechanisms is outside the scope of this is further metabolized into specific indole molecules.(Zhang and Davies,
review. However, it is worth mentioning that recent research has shown 2016) For example, the genus Bacteroides (B.) including B. ovatus, B.
correlations between diet, the microbiota and host metabolism and eggerthii, B. thetaiotaomicron, and B. fragilis, are the main bacteria
suggested that microbiota-derived SCFAs are associated with important responsible for synthesizing indole-3-acetic acid (IAA).(Lee and Lee,
systemic consequences for the host(Morrison and Preston, 2016) 2010; Cervantes-Barragan et al., 2017) IAA is also synthesized by several
including maintenance of intestinal integrity, immune regulation and Clostridium (C.) such as C. bartlettii, C. difficile, C. limosum and C.
glucose homeostasis.(Scher et al., 2015) Several studies have shown bifermentans. Indole-3-aldehyde (IAld) is produced by Lactobacillus (L.)
associations with reductions in the mentioned metabolites and age- acidophilus, L. murinus, and L. reuteri.(Zhang and Davies, 2016)IPA is
related cognitive frailty.(Ticinesi et al., 2018) synthesized primarily by Clostridium sporogenes, which metabolizes
tryptophan into indole and subsequently to IPA,(Wikoff et al., 2009;
2. The emerging roles of the human microbiota in chronic Zhang and Davies, 2016) a potent neuroprotective substance.(Poeggeler
diseases associated with aging et al., 2010) Following absorption from the intestine, IPA can be found
in the brain(Lian et al., 2016) (Fig. 1).
The mammalian gastrointestinal tract harbors a complex ecosystem Other protective indoles include indole-3-propionamide (IPAM),
consisting of countless bacteria, which for the most part, remains in (Poeggeler et al., 2010) discovered in 2010, and indole-3-aldehyde
homeostasis with the host. Shaped by evolution, this biologically (I3A).(Zhang and Davies, 2016) The latter is produced by intestinal
conserved partnership between humans and bacteria has substantive Lactobacillus species. I3A acts on the aryl hydrocarbon receptor (AhR)
symbiotic benefits. In the last two decades, several investigators have in intestinal immune cells, leading to an increase in interleukin-22 (IL-
generated data indicating that the commensal microbiota facilitates host 22), an anti-inflammatory cytokine.(Parks et al., 2016) Several indoles
metabolism, augment healthspan, modulate systemic inflammation, and produced by microbial metabolism of tryptophan enhance the secretion
enhance host immunity.(Mazmanian et al., 2005; Langille et al., 2014; of glucagon-like peptide-1 (GLP-1) by intestinal L cells and acts as a li­
Lee and Hase, 2014) The microbiota is known to synthesize vitamins B gands for AhR(Roager and Licht, 2018; Hubbard et al., 2015) (Fig. 2).
and vitamin K and many other substances that interact systemically with Indoles can be metabolized by hepatocytes into indoxyl sulfate (Fig. 2), a
the host, such as tryptophan derivatives and SCFAs.(Alkhalaf and Ryan, substance that is toxic in high concentrations and associated with
2015; Doifode et al., 2021) Dietary tryptophan is the principal substrate vascular and kidney injury.(Roager and Licht, 2018)
for production of indoles like indole-3-propionic acid,(De Mello et al., A number of cell-protective indoles can be derived from cruciferous
2017) indole-3-aldehyde (I3A),(Zhang and Davies, 2016; Gao et al., vegetables (Verhoeven et al., 1996; Fuentes et al., 2015) and may also
2018) indole acetic acid (IAA)(Gao et al., 2018) and several others.(Gao have neuroprotective activity,(El-Naga et al., 2014) which overlaps with
et al., 2018) Tryptophan also undergoes complex enzymatic modifica­ microbiota-derived indoles (see below). In terms of neutralizing free
tions by the microbiota including halogenation, oxidation methylation radicals, IPA and IPAM are at least twice as potent as melatonin.(Chyan
and decarboxylation, and is a biological precursor of a large number of et al., 1999; Poeggeler et al., 2010).
substances.(Alkhalaf and Ryan, 2015) Many tryptophan-derived natural
products contain heterocycles in addition to the indole.(Alkhalaf and 2.1. Indoles as antioxidant and neuroprotective agents
Ryan, 2015) The function of many of these substances is still unknown.
Certain starches and dietary fibers, are considered the principal Two decades ago, a biochemical pathway underlying one of the
substrates for the production of SCFAs; the main ones being butyrate, mechanisms of action of indoles was identified. IPA and IPAM neutralize
propionate and acetate.(Wong et al., 2006) The low pH of the proximal highly reactive hydroxyl radicals by electron donation (Figs. 3 and 4)
gastrointestinal system results in a relatively small number of bacterial (Chyan et al., 1999; Poeggeler et al., 2010; Bendheim et al., 2002).
types compared with the colon, where the bulk of the microbiota’s Recognition of this pathway is essential due to the following reasons.
species reside. More than 99% of the bacteria are anaerobes throughout Most antioxidants, such as ascorbic acid (vitamin C), tocopherol
the large bowel although the cecum contains a slight preponderance of (vitamin E), and other chain-breaking free-radical scavengers, produce
aerobe species.(Palmer et al., 2007) In the adult intestine, the main harmful quantities of pro-oxidant intermediates as they scavenge free
species are Actinobacteria, Firmicutes, Bacteroidetes, Fusobacteria, radicals Table 1. Such toxic intermediates counteract the potential
Verrucomicrobia and Proteobacteria (Khanna and Tosh, 2014). beneficial effects of the parent molecules and can underlie the failure of
Shifts in the microbiota are proposed to contribute to age-related antioxidant therapies for aging or disease prevention. (Bjelakovic et al.,
infirmity,(Langille et al., 2014) including the development of neurode­ 2007) In fact, in an analysis of 47 low-bias trials that included 180,938
generative disease.(Chyan et al., 1999; Naseer et al., 2014; Mayer et al., participants, the antioxidant supplements significantly increased

2
M.A. Pappolla et al. Neurobiology of Disease 156 (2021) 105403

Fig. 1. Indoles are synthesized from tryptophan by bacteria in the microbiota that express tryptophanase.(Zhang and Davies, 2016) Indolepropionic acid (IPA) is
synthesized by Clostridium sporogenes. IPA is a neuroprotective substance that neutralizes hydroxyl radicals and binds to several receptors, including the pregnane X
receptor (PXR) in intestinal cells, to facilitate mucosal homeostasis. Following absorption from the intestine, IPA is found in the brain, where neutralizes hydroxyl
radicals, reduces DNA damage, and prevents β-amyloid fibril formation. Lactobacillus species metabolize tryptophan into indole-3-aldehyde (I3A), which acts on the
aryl hydrocarbon receptor (AhR) in intestinal immune cells.(Parks et al., 2016) Several other functions resulting from the AhR -indole interactions are described in
the paper. Image credit: Wikipedia (en.wikipedia.org/wiki/3-Indolepropionic_acid).

mortality. (Bjelakovic et al., 2007) In contrast to free radical scavengers, metabolic stress(De Mello et al., 2017) and its increased concentration
IPA and IPAM do not generate pro-oxidant intermediates while has also been associated with reduced levels of C-reactive protein
neutralizing free radicals. (Chyan et al., 1999) See below, Fig. 3 and (hsCRP), a marker of inflammation. Increased levels of hsCRP are
Table 1 (Pappolla et al., 2002). correlated with higher T2D risk and several other clinical conditions. It
Another important mechanism of action of neuroprotective indoles is has therefore been postulated that IPA may lower the risk of T2D risk by
the reduction of reactive oxygen species produced by electron leakage in several mechanisms including decreased inflammation, direct effects on
mitochondria. Experiments showed that IPA and IPAM penetrate mito­ β-cell function or by cell protection from oxidative stress.(De Mello
chondria, bind to the rate-limiting component of oxidative phosphory­ et al., 2017; Tuomainen et al., 2018)
lation in complex I of the respiratory chain, and act as a stabilizer of Intermittent fasting (IF) treatment of diabetic mice also resulted in a
energy metabolism, thereby reducing the production of reactive oxygen higher concentration of metabolites of the gut microbiota, including
species. (Chyan et al., 1999; Poeggeler et al., 2010) IPA, and correlated strongly with improvements in cognitive function.
(Liu et al., 2020) IF was found to enhance mitochondrial biogenesis and
3. Neuroprotective indoles like IPA increase in the brain by energy metabolism gene expression in the hippocampus via microbial
dietary modification metabolites. This was demonstrated bidirectionally; that is, eradicating
the microbiota with antibiotics partly eliminated the neuroprotective
The bacterium Clostridium sporogenes was found to produce higher effects of IF and, conversely, IPA supplementation, or short-chain fatty
levels of IPA from deamination of the amino acid tryptophan. Fluoro­ acids or tauroursodeoxycholic acid administration restored the benefi­
metric HPLC detection showed that IPA and other indoles can be cial effects seen with IF on cognitive function.(Liu et al., 2020)
increased in the brain after administration of L-tryptophan (Fig. 5).
(Poeggeler et al., 2010) There is a high degree of interindividual vari­ 4. Aryl hydrocarbon receptor. Neuroprotection and aging
ation. (Menni et al., 2019).
Interestingly, IPA was found to modulate the secretion of incretin The aryl hydrocarbon receptor (AhR) was initially identified as a
(GLP-1), which can influence the T2D progression by improving the conserved sensor of small xenobiotic molecules.(Poland et al., 1976)
secretion of insulin and through other mechanisms.(De Mello et al., However, it was later discovered that it is a transcription factor activated
2017)IPA was reported to protect the β-cells from oxidative and by several endogenous and exogenous ligands, including indole-related

3
M.A. Pappolla et al. Neurobiology of Disease 156 (2021) 105403

Fig. 2. Tryptophan is an essential amino acid derived from dietary proteins, used a source of nitrogen by some of the resident microbiota, such as E. coli. Bacteria use
three permeases for its transport into the bacterium (Mtr, AroP and TnaB).(Yanofsky et al., 1991) Once inside the bacterium, tryptophan is then converted to various
indole compounds, some of which are AhR ligands (small red circle in the AhR-ARNT complex). Metabolism of L-tryptophan by the enzyme tryptophanase produces
pyruvate and indole that is further metabolized by the liver. Abbreviations: Iaa: indole acetic acid. AcrF: multidrug efflux system complex, SULT: sulfotrasferase
enzyme, TnaA: tryptophanase, AhR: aryl hydrocarbon receptor, ARNT: aryl hydrocarbon receptor nuclear translocator. Diagram adapted from Hubbard et al., with
permission.(Hubbard et al., 2015) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3. Electron donation is a central pathway in the anti-oxidant activity of indoles.

Oxidation Products of IPA. By pulse radiolysis with spectrophotometric detection using a 4-MeV van de Graaf accelerator as described, the chemical nature of the 1
electron oxidation product of IPA was determined. The end product is the formation of kynurenic acid. Methodologic details have been published.(Poeggeler et al.,
2010). Figure credit: Journal Biol Chem (Chyan et al., 1999).

molecules produced by the microbiota. The extensive number of genes Some of the effects of indoles on healthspan are due to interactions
modulated by the AhR suggested multiple physiologic functions, far with the AhR.(Sonowal et al., 2017) After binding to AhR, indoles
beyond xenobiotic metabolism.(Hubbard et al., 2015) These genes are induce a gene expression profile in aged animals reminiscent of that seen
involved in diverse biological pathways such as enzyme regulation, in the young organisms.(Sonowal et al., 2017) The healthspan benefits
neurogenesis, intestinal homeostasis, immune modulation, stem cell of indoles have been demonstrated in varied organisms, including Cae­
survival, cellular proliferation and differentiation.(Gutiérrez-Vázquez norhabditis elegans, Drosophila melanogaster, and mice. In older animals,
and Quintana, 2018; Kawajiri and Fujii-Kuriyama, 2017; Carreira et al., indole induces genes that expand fecundity and reproductive lifespan.
2015; Dever et al., 2016; Thatcher et al., 2016; Yamada et al., 2016; Yin (Poeggeler et al., 2010).
et al., 2016). The AhR is a cytosolic regulatory protein of the Per-ARNT-Sim (PAS)

4
M.A. Pappolla et al. Neurobiology of Disease 156 (2021) 105403

Fig. 4. Potent hydroxyl radical-neutralizing activity of IPA.

Shown are the results obtained with the 5,5-dimethyl-1-pyrroline N-oxide method (A) and the ABTS method (B). Inhibition of 5,5-dimethyl-1-pyrrolineN-oxide-hy­
droxyl radical adduct formation by IPA and melatonin is shown in A as the means ± SE of three independent triplicate experiments. Inhibition of ABTS cation radical
formation by IPA and melatonin is shown in B (triplicate experiments). Melatonin; ▪, indole-3-propionic acid. Methodologic details have been published.(Poeggeler
et al., 2010). Figure credit: Journal Biol Chem (Chyan et al., 1999).

5. AhR and the inflammatory response

Table 1
Pro-oxidant activities of several agents as evaluated by the formation
Several pathways have been implicated in pro-inflammatory or anti-
of 2,3- and 2,5-DHBA, an indicator of OH- radical formation.
inflammatory cascade responses mediated by AhR activation which can
Agent 2,3- and 2,5-DHBA potentially impact the neuropathology of AD. In fact, Cattaneo et al.
% of control showed an association between brain amyloidosis and pro-inflammatory
Indole-3-propionic acid 4±1 gut bacteria, which also correlated with the levels of pro-inflammatory
Indole-3-acetic acid 173 ± 14 cytokines and cognitive impairment.(Cattaneo et al., 2017).
Indole-3-pyruvic acid 152 ± 11 The mechanisms involved in modulating the inflammatory response
Melatonin 25 ± 6 by the microbiota are not fully understood. They are typified by complex
Ascorbate 225 ± 18
Trolox 197 ± 16
interactions that comprise a multitude of interacting factors, favoring
Glutathione 165 ± 12 either a pro-inflammatory or an anti-inflammatory tissue microenvi­
ronment, depending on the type of ligands involved and the degree of
Pro-oxidant activities of several agents as evaluated by the formation
activation or deactivation of the AhR. Our knowledge of the pathways
of 2,3- and 2,5-DHBA, an indicator of OH- radical formation. In
contrast with free-radical scavengers, IPA is virtually devoid of pro-
which can have a significant impact on neurological disease is also
oxidant activity. The measured pro-oxidant properties reported by limited, and some relevant studies are reviewed by Doifode et al.(Doi­
us(Poeggeler et al., 2010) agree with published results.(Candeias fode et al., 2021) and listed in Table 2. Several studies have shown that
et al., 1995; Nappi and Vass, 1997) Our studies showed that 12 μs after activation of the AhR regulates genes involved in inflammation and
pulse radiolysis of N2O-saturated potassium bromide solutions con­ immunity, including IL-6, IL-22, PTGS2, VEGFA, and CYP1A1.(Hubbard
taining IPA generated the respective indolyl cation radical, charac­ et al., 2015; Schiering et al., 2017) The activation of AhR by indoxyl
terized by an absorption band centered at 570 nm (ε = 2400 sulfate has been reported to modulate IL-6, various CYP enzymes
dm3mol− 1 cm− 1) and another band at 360 nm (ε = 4800 dm3 mol− 1 (CYP1A1, CYP1A2, CYP1B1), uridine diphosphate glucuronosyl­
cm− 1). Table credit: Journal Biol Chem (Chyan et al., 1999). transferase (UGT) and serum amyloid A1 (SAA1), which contribute to
the overall inflammatory burden.(Schroeder et al., 2010; Shimizu et al.,
protein family and can be stimulated by several endogenous and exog­ 2012; Yisireyili et al., 2017) On the other hand, indole-3-pyruvic acid
enous ligands; many are microbiota-derived metabolites of tryptophane promotes the differentiation of Tr1 cells and increase IL-10 production, a
(Roager and Licht, 2018) (Fig. 2). In the soluble form, the receptor is cytokine with potent anti-inflammatory properties.(Quintana et al.,
bound to a chaperone complex, which includes the dimer of Hsp90, p23, 2008; Aoki et al., 2018).
XAP2 and AIP(Perdew, 1988; Meyer et al., 1998; Kazlauskas et al., In a colitis model, studies have shown that 6-formylindolo (3,2-b)
1999) (Fig. 6). The ligand binding to the complex induces structural carbazole (FICZ), a photoproduct of tryptophan, can induce the AhR
changes, which dissociates the chaperone complex and exposes the activation and mediate the inhibition of inflammation by antagonizing
nuclear localization sequence and enables its translocation to the nu­ the IL-6 effects in lipopolysaccharide-treated dendritic cells.(Furumatsu
cleus along with ligand.(Petrulis and Perdew, 2002; Denison and Nagy, et al., 2011; Wang et al., 2014; Wang et al., 2018) The FICZ-AhR
2003) The ARNT association promotes the formation of the high-affinity interaction was reported to regulate cell growth and differentiation
DNA binding complex, a complex of heterodimeric transcription factors. and could conceivably enhance neurogenesis (Table 2),(Rannug and
(Reyes et al., 1992) The formed AhR/ARNT heterodimer enables its Rannug, 2018) although this pathway has not been studied in the brain.
binding to nuclear DNA and remodeling of chromatin, leading to the Another indole metabolite of tryptophan, 3,3′ -diindolylmethane (DIM),
transcription of downstream genes.(Lusska et al., 1993; Denison et al., appears to be a selective AhR modulator, reported to inhibit AhR/ARNT-
2011; Soshilov and Denison, 2011). dependent apoptosis and autophagy and protect the hippocampal cells

5
M.A. Pappolla et al. Neurobiology of Disease 156 (2021) 105403

Fig. 6. . In the absence of a ligand, AhR is inside the cytoplasm bound to two
molecules of heat shock protein 90 and other co-chaperones.(Perdew, 1988;
Meyer et al., 1998; Kazlauskas et al., 1999) Upon ligand binding, the AhR is
shuttled to the nucleus where the AhR dissociates from its cytoplasmic proteins
in the presence of the aryl hydrocarbon receptor nuclear translocator (ARNT),
forming a transcription factor complex,(Reyes et al., 1992) ready for binding to
a consensus DNA sequence (5′ -TNGCGTG-3′ ), the dioxin response element
(DRE). Upon binding to DNA, there is chromatin remodeling and subsequent
target gene transcription. Diagram adapted from Hubberd et al., with permis­
sion (Hubbard et al., 2015)

Fig. 5. Detection that IPA after dietary administration of tryptophan. shown to significantly suppress IS-induced mRNA and protein expres­
Fluorometric HPLC detection showed that IPA and IPAM cross the blood-brain sion of AhR, and other pro-inflammatory factors such as CYP1A1, TGF-
barrier and can be found in the brain of one-month-old male Sprague-Dawley β1, and MCP-1. Although not all these pathways have yet been
rats: Peaks with identical elution times as synthetic IPAM, melatonin and IPA demonstrated to be operational in the brain, one cannot ignore their
were consistently observed in rat brain. One hour after administration of 300 potential relevance of the AhR to neurological disease, considering that
mg/kg L-tryptophan, IPAM (1), melatonin (2), and indole-3-propionic acid (3) this receptor is extensively expressed in the brain cortex, medulla
concentrations reached levels of 346 ± 9 (IPAM), 713 ± 32 (MEL) and 281 ± 14 oblongata, cerebellum, and hippocampus. In fact, inhibition of AhR has
(IPA) pg indole/mg protein, respectively, in rat brain (n = 6). b) Co-elution of proved to reduce the excitotoxicity mediated through NMDA receptor
the endogenous indoles IPAM, melatonin and IPA along with the standards of
on cortical neurons.(Hays et al., 2002; Williamson et al., 2005; Gohlke
these indole compounds results in larger single elution peaks representing
et al., 2009; Lin et al., 2009) In a model of stroke, the AhR was shown to
endogenous plus exogenous indoles. c) Synthetic IPAM standard (1 ng) eluted
play a substantive role in determining the extent of brain damage.
at 30 min. Methodological details have been published(Poeggeler et al., 2010)
Dietary interventions can lead to profound changes in the microbiota. Smith (Cuartero et al., 2014) This is mediated by L-kynurenine, a tryptophan
and Macfarlane showed that environmental factors such as the type of carbo­ metabolite with AhR agonistic properties and an endogenous ligand
hydrate available in the diet and the pH level could affect the production of mediating AhR activation.(Cuartero et al., 2014) It has been shown that
metabolites including indole compounds by the microbiota.(Jack et al., 1999) brain ischemia increases total and nuclear AhR levels and AhR tran­
In a study by De Mello et al., higher levels of IPA were associated with higher scriptional activity in neurons in vivo and in vitro and conversely,
levels of dietary fiber intake, mainly from whole grains, which in their study pharmacological, or genetic loss-of-function of AhR results in neuro­
was correlated with a decreased risk for development of type 2 diabetes (T2D). protection and modulation of neurogenesis.(Chen et al., 2019).
(De Mello et al., 2017) In another investigation, the long-term consumption of In summary, available data shows that the interaction between
the Mediterranean diet (35% fat, 22% monounsaturated fatty acids) or of a
microbiota-derived indoles and other substances with the AhR results in
specific low-fat, high carbohydrate diet (28% fat, 12% monounsaturated) was
complex downstream immunoregulatory phenomena and in pro-
associated with a protective effect on the development of T2D presumably by
inducing specific changes in the composition of the microbiota(Jack et al.,
inflammatory or anti-inflammatory responses. The latter may be either
1999; Haro et al., 2016). Figure credit: PLOS One (Poeggeler et al., 2010). beneficial or deleterious to the host depending on the degree of acti­
vation of the AhR by different ligands and various other factors. Several
microbiota-derived indoles, like IPA, have shown to exert a marked
against hypoxia (Table 2).(Rzemieniec et al., 2019) The substituted
degree of neuroprotection through interactions with the AhR, but to our
analogs of DIM at para position with phenyl groups were shown to have
knowledge, the understanding of these interactions is incomplete and in
neuroprotective and anti-inflammatory activities by inhibiting the NF-
need of further research. There are other factors that can potentially
kB mediated articulation of nitric oxide synthase (NOS2) and modu­
impact the AD neuropathology, including effects of enteric dysbiosis on
lating the NR4A nuclear receptors in astrocytes.(Carbone et al., 2009; De
blood-brain barrier permeability.(Doifode et al., 2021) The increase in
Miranda et al., 2013) Indoxyl sulfate (IS) induces fibrosis and inflam­
certain bacterial metabolites not only can affect microglial function and
mation in kidneys via oxidative stress through the induction of trans­
enhance inflammation but also, as proposed by other authors, patho­
forming growth factor-β1 (TGF-β1) and monocyte chemotactic protein-1
genic microorganisms may take over resident microbiota, translocate
(MCP-1). IS is a potent endogenous AhR agonist, which regulates the
and ultimately reach the central nervous system,(Dando et al., 2014)
transcription of genes such as cytochrome P450 (CYP) 1A1. IPA was

6
M.A. Pappolla et al. Neurobiology of Disease 156 (2021) 105403

Table 2
Indoles derived from the microbiota are indicated by an asterisk, indolyl acrylic acid is a liver metabolite of indole-3-propionic acid.
S. Compound Pharmacodynamic effect Endogenous Target Reference
No.

1 3,3′ -Diindolylmethane Neuroprotective AhR/CYP1A1 signaling & HDAC (Rzemieniec et al., 2019; Rzemieniec et al.,
2015)
2 p-Phenyl Substituted Neuroprotective NR4A, NF-kB (De Miranda et al., 2013)
Diindolylmethanes
3 Indole-3-carbinol Anticancer agent ERα, ERβ, GATA3, & AhR (Marconett et al., 2010)
Anticarcinogenic AhR (Hubbard et al., 2015)
4 Brominated indoles Anticancer agent Nonclassical AhR ligands (Degroot et al., 2016)
5 Indole-3-aldehyde * Anti-inflammatory AhR/IL-22/IL-18 axis (Zelante et al., 2013; Bruno, 2019)
Anti-inflammatory IL-17A, IL-23p19, IL-23p40, INF- (Yu et al., 2019)
γ
6 ITE Anti-proliferative AhR (Bian et al., 2019)
7 6-Formylindolo(3,2-b) carbazole Protective- epithelial AhR/IL-6/claudin-2 (Ma et al., 2018)
Anti-proliferative AhR/N.K. cells (Rannug and Rannug, 2018)
8 Indole-3-propionic acid * Anti-inflammatory AHR, CYP1A1, TGF-β1, & MCP-1 (Yisireyili et al., 2017)
Inhibition of Aβ Fibrillogenesis ApoE4 (Bendheim et al., 2002)
Antioxidant 8-Hydroxydeoxyguanisine (Bendheim et al., 2002)
Neuroprotective & Cytoprotective (Chyan et al., 1999; Bendheim et al., 2002)
9 Indole-3-acetate Anti-inflammatory AhR, CYP1A1 & CYP1B1 (Jin et al., 2014)
Anti-inflammatory AhR-cytokine (Krishnan et al., 2019)
10 Indole-3-Pyruvic Acid Anti-inflammatory AhR, Type 1 regulatory T cells (Aoki et al., 2018)
11 indolyl acrylic acid * Anti-inflammatory AhR, IL-10 & mucin gene (Gao et al., 2018)
12 Indomethacin Anti-inflammatory, Aβ- aggregation Aβ40 & Aβ42 inhibitor (Kaur and Goyal, 2018)
inhibitor
13 Halogenated indoles Neuroprotective Aβ inhibitor (Gurer-Orhan et al., 2016)

directly impacting on mechanisms involved in AD pathogenesis. administered as a preventative agent (i.e., before the onset or at a very
Conversely, certain metabolites from resident bacteria can also tilt the early stage of AD pathogenesis).(Pappolla et al., 2018) To the best of our
scales toward an anti-inflammatory state.(Westfall et al., 2019) The knowledge, AD prevention trials (or MCI trials) of melatonin or of other
topic of bacteria dysbiosis is a developing exciting area outside the scope neuroprotective indoles like IPA, have never been conducted.
of this paper.(Doifode et al., 2021). Several indole derivatives also share anti-inflammatory, neuro­
protective features in addition to the Aβ anti-aggregation properties of
6. Inhibition of beta-fibrillogenesis by indoles melatonin, IPA and IPAM. Indoles with nitrile, piperidine and N-methyl
piperidine substitution on the 3rd position of indole ring have shown
Other properties of indoles that can impact the neuropathology of AD inhibition of Aβ aggregation.(Sreenivasachary et al., 2017) Hydrazide
is the inhibition of aggregation of the amyloid beta-protein into neuro­ derivatives of indole were also shown to have protective effects against
toxic oligomers and amyloid fibrils.(Sreenivasachary et al., 2017) This Aβ-induced neuronal damage and powerful antioxidant properties.
phenomenon can potentially contribute to a delay in the onset of amy­ (Gurer-Orhan et al., 2016) Together, the data suggest that a spectrum of
loid accumulation early in the disease. Inhibition of beta-fibrillogenesis structurally related molecules, primarily derived from the microbiota
by indoles was initially identified with the indoleamine melatonin, but also synthesized in the lab, may directly or indirectly modify the
(Pappolla et al., 1998a) a neurohormone structurally related to the neuropathology of AD. These properties of indoles, as seen with mela­
intestinally produced indoles [for review on melatonin and AD see the tonin, have been confirmed in many independent laboratories(Sreeni­
papers by Cardinali(Cardinali and Melatonin, 2019) and Rosales-Corral vasachary et al., 2017) and further substantiated by the results of
et al.(Rosales-Corral et al., 2012)]. This substance can also impact AD experiments performed in animal models of AD.(Lahiri et al., 2004a;
neuropathology through mechanisms which to various extents overlap Pappolla et al., 2018; O’Neal-Moffitt et al., 2015) It is highly likely that
with some of the indoles discussed in this paper.(Poeggeler et al., 2010; some of the mentioned effects of indoles are markedly enhanced through
Bendheim et al., 2002; Lahiri et al., 2004a; Lahiri et al., 2004b; Mat­ specific interactions with apolipoprotein E4 (apoE4),(Poeggeler et al.,
subara et al., 2003; Pappolla et al., 2018; Pappolla et al., 1997; Poegg­ 2001) one of the major risk factors for AD. It has been observed that in
eler et al., 2001; Bondy et al., 2002; Song and Lahiri, 1997) Melatonin, the presence of melatonin and apoE4, there is a remarkable switch in the
like IPA and IPAM, also protects neurons against the neurotoxic effects properties of apoE4 from pro-aggregatory to pro-inhibitory of amyloid
of amyloid peptides.(Pappolla et al., 1997) Melatonin interacts with fibril formation (apoE4 > apoE3). This interaction can be of great
Abeta1–40 and Abeta1–42 and inhibits the progressive formation of consequence to AD risk, which is greater for carriers of the apoE4 iso­
beta-sheets and amyloid fibrils.(Pappolla et al., 1998a) The interactions form. The inhibition of amyloid fibril formation is substantively greater
between melatonin and the amyloid peptides were consistently in the presence of melatonin plus apoE4 than that observed with the
demonstrated by many techniques, including circular dichroism, elec­ indoleamine alone.(Poeggeler et al., 2001) This inhibitory effect is un­
tron microscopy and nuclear magnetic resonance spectroscopy and related to the antioxidant properties of melatonin since it is not seen
reproduced in many independent laboratories. The inhibition of beta- with other non-indole antioxidants like ascorbate, alpha-tocopherol, or
sheets and fibrils formation by melatonin was also reproduced with PBN.(Poeggeler et al., 2001).
other indoles,(Sreenivasachary et al., 2017) including IPA and IPAM
(Poeggeler, unpublished data). 7. Indoles in cruciferous vegetables
One important property of melatonin and IPA is that they inhibit
aggregation of amyloid fibers, but do not reverse preformed aggregates It is important to briefly consider the presence of indoles in edible
(Pappolla and Poeggeler, unpublished data). Such characteristic may vegetables because of their overlapping functional impact with those
explain the failed improvement of cognitive outcomes of melatonin produced by the microbiota and the bidirectional relationship of diet on
therapeutic trials in advanced AD(Wang et al., 2017). as melatonin may the microbiome. Historically, numerous essential therapeutic drugs
be only effective, as previously proposed,(Pappolla et al., 2018) if were extracted or derived from plants. It, therefore, comes as no surprise

7
M.A. Pappolla et al. Neurobiology of Disease 156 (2021) 105403

that various indole derivatives are also present in many plants as sec­ therapeutic strategies for these conditions. The multitude of potential
ondary metabolites, such as glucosinolates and phytohormones, that mechanisms and the variety of molecular species involved offers ad­
were initially recognized for their chemoprotective and anti- vantages but also, potential limitations and challenges for the design of
proliferative properties.(Revelou et al., 2018) Indole glucosinolates, clinical trials. It is possible, however, that by targeting multiples
which have side chains derived from tryptophan, are among the most mechanisms simultaneously, indole-based therapies may be advanta­
widely distributed glucosinolates in nature.(Agerbirk et al., 2008) The geously developed as disease-modifying strategies for AD and Parkin­
main glucosinolate in plants is glucobrassicin (GBR), and it is present in son’s disease, which share features like inflammation(Sampson et al.,
large quantities in cruciferous vegetables such as Brussels sprouts, 2016) and oxidative stress.(Cenini et al., 2019; Nunomura et al., 2000;
cauliflower, broccoli, and cabbage. Glucosinolates, particularly GBR, Omar, 1996; Zhang et al., 1999) Both pathological processes are known
are biosynthesized from various amino acids such as aliphatic and aro­ to exacerbate neurodegeneration and neuronal loss in these disorders.
matic amino acids, including alanine, methionine, and tryptophan. In (Smith et al., 2002; Zhang et al., 1999; Pappolla et al., 1998b) If we
GBR, tryptophan serves as a precursor molecule, and methionine pro­ could delay the progression of these diseases, even by a few years, we
vides the sulfur group for glucoside formation after a series of would realize vast benefits for patients, caregivers, and healthcare.
biochemical conversions, including the N-hydroxylation, oxidation,
decarboxylation and glucosylation for resulting the thioglucoside. References
(Popolo et al., 2017) However, GBR is an S-glucoside that contains 1-
thio-β-D-glucopyranose that requires the hydrolysis of the thioglucoside Agerbirk, N., De Vos, M., Kim, J.H., Jander, G., 2008. Indole glucosinolate breakdown
and its biological effects. Phytochem. Rev. 8, 101. https://doi.org/10.1007/s11101-
bond to indole-3-carbinol (I3C) by Myrosinase enzyme via the inter­ 008-9098-0.
mediate indole-3-methyl isothiocyanate (IMITC). Basically, the I3C is Alkhalaf, L.M., Ryan, K.S., 2015. Biosynthetic manipulation of tryptophan in bacteria:
part of the aglycan portion of glucoside, which has diverse pharmaco­ pathways and mechanisms. Chem. Biol. 22, 317–328. https://doi.org/10.1016/j.
chembiol.2015.02.005.
dynamic properties. Further, I3C at a low pH environment is converted Aoki, R., Aoki-Yoshida, A., Suzuki, C., Takayama, Y., 2018. Indole-3-pyruvic acid, an aryl
to different metabolites such as di-indolyl methane (DIM), indole-3- hydrocarbon receptor activator suppresses experimental colitis in mice. J. Immunol.
tryptophan, indole-3-cysteine, indole-3-carboxaldehyde, indole-3-yl- 201, 3683–3693. https://doi.org/10.4049/jimmunol.1701734.
Auborn, K.J., et al., 2003. Nutritional genomics in Cancer processes Indole-3-Carbinol is
methyl-glutathione, indolyl[3,2-b]-carbazole (ICZ) and indol-3-yl a negative regulator of estrogen. J. Nutr. 133, 2470–2475.
methyl ascorbate.(Song et al., 2002; Reed et al., 2006; Bradlow and Bancher, C., et al., 1989. Accumulation of abnormally phosphorylated tau precedes the
Zeligs, 2010; Chamovitz et al., 2018) Some of these indoles possess formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res. 477, 90–99.
https://doi.org/10.1016/0006-8993(89)91396-6.
neuroprotective, antioxidant, or anti-inflammatory properties as refer­
Bendheim, P.E., et al., 2002. Development of indole-3-propionic acid (OXIGONTM) for
enced in Table 2. Alzheimer’s disease. J. Mol. Neurosci. 19, 213–217. https://doi.org/10.1007/
Indole derivatives from GBR have shown chemoprotective and s12031-002-0036-0.
cancer-preventive properties by several mechanisms and became po­ Bennett, D.A., et al., 2002. Natural history of mild cognitive impairment in older persons.
Neurology 59, 198–205. https://doi.org/10.1212/WNL.59.2.198.
tential drug candidates for certain malignancies. Among the indole Bettcher, B.M., et al., 2018. Cerebrospinal fluid and plasma levels of inflammation
metabolites derived from GBR, I3C got much attention due to its inter­ differentially relate to CNS markers of Alzheimer’s disease pathology and neuronal
action with a wide range of targets in the human body. Importantly, I3C damage. J. Alzheimers Dis. 62, 385–397. https://doi.org/10.3233/JAD-170602.
Bian, Y., et al., 2019. ITE, an endogenous aryl hydrocarbon receptor ligand, suppresses
was described to inhibit the PI3K/Akt/mTOR signaling pathway, which endometrial cancer cell proliferation and migration. Toxicology 421, 1–8. https://
is not only a component in cancer pathology(Royston and Tollefsbol, doi.org/10.1016/j.tox.2019.03.017.
2015) but also important in the aging process.(Papadopoli et al., 2019) Bjelakovic, G., Nikolova, D., Gluud, L.L., Simonetti, R.G., Gluud, C., 2007. Mortality in
randomized trials of antioxidant supplements for primary and secondary prevention:
I3C and other indole compounds also exhibit anti-oxidant properties and systematic review and meta-analysis. JAMA 297, 842–857. https://doi.org/
influence gene expression of CYP1A, p21, p27, Bax/BCI2, BRCA, 10.1001/jama.297.8.842.
GADD153 & PhIP.(Auborn et al., 2003; Kim and Milner, 2005) Some of Bondy, S.C., Yang, Y.E., Walsh, T.J., Gie, Y.W., Lahiri, D.K., 2002. Dietary modulation of
age-related changes in cerebral pro-oxidant status. Neurochem. Int. 40, 123–130.
the inhibitory effects on tumor growth and survival are thought to be https://doi.org/10.1016/s0197-0186(01)00084-5.
mediated by the amelioration of estrogenic effects. Indole derivatives in Bozner, P., et al., 1997. The amyloid 13 protein induces oxidative damage of
plants have overlapping properties with those produced by the micro­ mitochondrial DNA. J. Neuropathol. Exp. Neurol. 56, 1356–1362. https://doi.org/
10.1097/00005072-199712000-00010.
biota, including anti-inflammatory, neuroprotective and Aβ aggregation
Bradlow, H.L., Zeligs, M.A., 2010. Diindolylmethane (DIM) spontaneously forms from
inhibition in neuronal studies (Table 2). indole-3-carbinol (I3C) during cell culture experiments. In Vivo 24, 387–391.
Brodaty, H., et al., 2013. Mild cognitive impairment in a community sample: The Sydney
Memory and Ageing Study. Alzheimers Dement. 9, 310–317 e311. https://doi.
8. Conclusion
org/10.1016/j.jalz.2011.11.010.
Bruno, V., 2019. Targeting the aryl hydrocarbon receptor with Indole-3-aldehyde
We would like to emphasize that there are many mechanisms beyond protects from Vulvovaginal candidiasis via the IL-22-IL-18. Front. Immunol. 10,
indoles linking the gut and the brain with potential neuropathological 1–10. https://doi.org/10.3389/fimmu.2019.02364.
Candeias, L.P., Folkes, L.K., Porssa, M., Parrick, J., Wardman, P., 1995. Enhancement of
ramifications.(Doifode et al., 2021; Westfall et al., 2019) These include lipid peroxidation by indole-3-acetic acid and derivatives: substituent effects. Free
modulation of innate and adaptive immunity by the microbiome, inde­ Radic. Res. 23, 403–418. https://doi.org/10.3109/10715769509065262.
pendent of indoles, with substantive functional consequences for the Carbone, D.L., Popichak, K.A., Moreno, J.A., Safe, S., Tjalkens, R.B., 2009. Suppression of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nitric-oxide synthase 2
host.(Fung, 2020; Fung et al., 2017) Similarly, high-throughput ampli­ expression in astrocytes by a novel diindolylmethane analog protects striatal neurons
con sequencing studies conducted during the last decade have provided against apoptosis. Mol. Pharmacol. 75, 35–43. https://doi.org/10.1124/
new taxonomic insights into the enormous diversity of the microbiome mol.108.050781.
Cardinali, D., Melatonin, P., 2019. Clinical perspectives in Neurodegeneration. Front.
(Eckburg et al., 2005)(Salazar et al., 2020)(The Integrative Human Endocrinol. (Lausanne) 10, 480. https://doi.org/10.3389/fendo.2019.00480.
Microbiome Project, 2019),(Li et al., 2014) unveiling novel microbiota- Carreira, V.S., et al., 2015. Disruption of Ah receptor signaling during mouse
based disease mechanisms and their regulation through dietary modi­ development leads to abnormal cardiac structure and function in the adult. PLoS
ONE 10. https://doi.org/10.1371/journal.pone.0142440.
fications.(Westfall et al., 2019; Turnbaugh et al., 2009; Claesson et al., Cattaneo, A., et al., 2017. Association of brain amyloidosis with pro-inflammatory gut
2012) A discussion of these factors and potential dietary interventions is bacterial taxa and peripheral inflammation markers in cognitively impaired elderly.
outside the scope of this paper. Neurobiol. Aging 49, 60–68. https://doi.org/10.1016/j.
neurobiolaging.2016.08.019.
All things considered, the central message of this paper is that several
Cenini, G., Lloret, A., Cascella, R., 2019. Oxidative stress in neurodegenerative diseases:
indoles produced by intestinal bacteria possess properties relevant to AD from a mitochondrial point of view. Oxidative Med. Cell. Longev. 2019, 2105607.
and other neurodegenerative diseases, including neuroprotective, anti- https://doi.org/10.1155/2019/2105607.
inflammatory, immunoregulatory, antioxidant and amyloid-β anti-
aggregation properties, and their research opens a window into novel

8
M.A. Pappolla et al. Neurobiology of Disease 156 (2021) 105403

Cervantes-Barragan, L., et al., 2017. <em>lactobacillus reuteri</em> induces gut Haro, C., et al., 2016. Two healthy diets modulate gut microbial community improving
intraepithelial CD4⁺CD8αα⁺ T cells. Science 357, insulin sensitivity in a human obese population. J. Clin. Endocrinol. Metab. 101,
806–810. https://doi.org/10.1126/science.aah5825. 233–242. https://doi.org/10.1210/jc.2015-3351.
Chamovitz, D.A., Katz, E., Nisani, S., 2018. Indole-3-carbinol: A plant hormone Hays, L.E., Carpenter, C.D., Petersen, S.L., 2002. Evidence that GABAergic neurons in the
combatting cancer. F1000Research 7. https://doi.org/10.12688/ preoptic area of the rat brain are targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin
f1000research.14127.1. during development. Environ. Health Perspect. 110, 369–376. https://doi.org/
Chen, W.C., et al., 2019. Aryl hydrocarbon receptor modulates stroke-induced 10.1289/ehp.02110s3369.
astrogliosis and neurogenesis in the adult mouse brain. J. Neuroinflammation 16, Hubbard, T.D., Murray, I.A., Perdew, G.H., 2015. Indole and tryptophan metabolism:
187. https://doi.org/10.1186/s12974-019-1572-7. endogenous and dietary routes to Ah receptor activation. Drug Metab. Dispos. 43,
Cheng, X., Van Breemen, R.B., 2005. Mass spectrometry-based screening for inhibitors of 1522–1535. https://doi.org/10.1124/dmd.115.064246.
β-amyloid protein aggregation. Anal. Chem. 77, 7012–7015. https://doi.org/ Imtiaz, B., et al., 2017. Postmenopausal hormone therapy and Alzheimer disease: a
10.1021/ac050556a. prospective cohort study. Neurology 88, 1062–1068. https://doi.org/10.1212/
Chyan, Y.J., et al., 1999. Potent neuroprotective properties against the Alzheimer wnl.0000000000003696.
β-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic Itzhaki, R.F., et al., 2016. Microbes and Alzheimer’s disease. J. Alzheimers Dis. 51,
acid. J. Biol. Chem. 274, 21937–21942. https://doi.org/10.1074/jbc.274.31.21937. 979–984. https://doi.org/10.3233/jad-160152.
Claesson, M.J., et al., 2012. Gut microbiota composition correlates with diet and health Jack, C.R., et al., 1999. Prediction of AD with MRI-based hippocampal volume in mild
in the elderly. Nature 488, 178–184. https://doi.org/10.1038/nature11319. cognitive impairment. Neurology 52, 1397–1403. https://doi.org/10.1212/
Cuartero, M.I., et al., 2014. L-kynurenine/aryl hydrocarbon receptor pathway mediates wnl.52.7.1397.
brain damage after experimental stroke. Circulation 130, 2040–2051. https://doi. Jin, U.H., et al., 2014. Microbiome-derived tryptophan metabolites and their aryl
org/10.1161/CIRCULATIONAHA.114.011394. hydrocarbon receptor-dependent agonist and antagonist activities. Mol. Pharmacol.
Dando, S.J., et al., 2014. Pathogens penetrating the central nervous system: infection 85, 777–788. https://doi.org/10.1124/mol.113.091165.
pathways and the cellular and molecular mechanisms of invasion. Clin. Microbiol. Kantarci, K., et al., 2016. Early postmenopausal transdermal 17β-estradiol therapy and
Rev. 27, 691–726. https://doi.org/10.1128/cmr.00118-13. amyloid-β deposition. J. Alzheimers Dis. 53, 547–556. https://doi.org/10.3233/jad-
De Mello, V.D., et al., 2017. Indolepropionic acid and novel lipid metabolites are 160258.
associated with a lower risk of type 2 diabetes in the Finnish diabetes prevention Karran, E., De Strooper, B., 2016. The amyloid cascade hypothesis: are we poised for
study. Sci. Rep. 7, 1–12. https://doi.org/10.1038/srep46337. success or failure? J. Neurochem. 139 (Suppl. 2), 237–252. https://doi.org/
De Miranda, B.R., et al., 2013. Neuroprotective efficacy and pharmacokinetic behavior of 10.1111/jnc.13632.
novel anti-inflammatory Para-phenyl substituted diindolylmethanes in a mouse Kato, M., et al., 2007. Analytical method for β-amyloid fibrils using CE-laser induced
model of Parkinson’s disease. J. Pharmacol. Exp. Ther. 345, 125–138. https://doi. fluorescence and its application to screening for inhibitors of β-amyloid protein
org/10.1124/jpet.112.201558. aggregation. Anal. Chem. 79, 4887–4891. https://doi.org/10.1021/ac0701482.
Degroot, D.E., Franks, D.G., Higa, T., Tanaka, J., Hahn, M.E., 2016. Naturally-occurring Kaur, A., Goyal, B., 2018. Benzofuran and indole: a promising scaffold for drug
marine brominated Indoles are aryl hydrocarbon receptor ligands/agonists. Chem. development in Alzheimer’s disease. ChemMedChem 13, 1275–1299. https://doi.
Res. Toxicol. 28, 1176–1185. https://doi.org/10.1021/acs.chemrestox.5b00003. org/10.1002/cmdc.201800156.
Naturally-Occurring. Kawajiri, K., Fujii-Kuriyama, Y., 2017. The aryl hydrocarbon receptor: a multifunctional
Denison, M.S., Nagy, S.R., 2003. Activation of the aryl hydrocarbon receptor by chemical sensor for host defense and homeostatic maintenance. Exp. Anim. 66,
structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. 75–89. https://doi.org/10.1538/expanim.16-0092.
Toxicol. 43, 309–334. https://doi.org/10.1146/annurev. Kazlauskas, A., Poellinger, L., Pongratz, I., 1999. Evidence that the co-chaperone p23
pharmtox.43.100901.135828. regulates ligand responsiveness of the dioxin (aryl hydrocarbon) receptor. J. Biol.
Denison, M.S., Soshilov, A.A., He, G., Degroot, D.E., Zhao, B., 2011. Exactly the same but Chem. 274, 13519–13524. https://doi.org/10.1074/jbc.274.19.13519.
different: promiscuity and diversity in the molecular mechanisms of action of the Khanna, S., Tosh, P.K., 2014. A clinician’s primer on the role of the microbiome in
aryl hydrocarbon (dioxin) receptor. Toxicol. Sci. 124, 1–22. https://doi.org/ human health and disease. Mayo Clin. Proc. 89, 107–114. https://doi.org/10.1016/
10.1093/toxsci/kfr218. j.mayocp.2013.10.011.
Dever, D.P., et al., 2016. Aryl hydrocarbon receptor deletion in cerebellar granule neuron Kim, Y.S., Milner, J.A., 2005. Targets for indole-3-carbinol in cancer prevention. J. Nutr.
precursors impairs neurogenesis. Dev. Neurobiol. 76, 533–550. https://doi.org/ Biochem. 16, 65–73. https://doi.org/10.1016/j.jnutbio.2004.10.007.
10.1002/dneu.22330. Knopman, D.S., Jones, D.T., Greicius, M.D., 2019. Failure to demonstrate efficacy of
Doifode, T., et al., 2021. The impact of the microbiota-gut-brain axis on Alzheimer’s aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen.
disease pathophysiology. Pharmacol. Res. 164, 105314. https://doi.org/10.1016/j. December Alzheimers Dement.. https://doi.org/10.1002/alz.12213.
phrs.2020.105314. Krishnan, S., et al., 2019. Gut microbiota-derived tryptophan metabolites modulate
Eckburg, P.B., et al., 2005. Diversity of the human intestinal microbial flora. Science 308, inflammatory response in hepatocytes and macrophages. Cell Rep. 23, 1099–1111.
1635–1638. https://doi.org/10.1126/science.1110591. https://doi.org/10.1016/j.celrep.2018.03.109.Gut.
El-Naga, R.N., Ahmed, H.I., Abd Al Haleem, E.N., 2014. Effects of indole-3-carbinol on Lahiri, D.K., Chen, D., Ge, Y.W., Bondy, S.C., Sharman, E.H., 2004a. Dietary
clonidine-induced neurotoxicity in rats: impact on oxidative stress, inflammation, supplementation with melatonin reduces levels of amyloid beta-peptides in the
apoptosis and monoamine levels. Neurotoxicology 44, 48–57. https://doi.org/ murine cerebral cortex. J. Pineal Res. 36, 224–231. https://doi.org/10.1111/j.1600-
10.1016/j.neuro.2014.05.004. 079X.2004.00121.x.
Fuentes, F., Paredes-Gonzalez, X., Kong, A.-N.T., 2015. Dietary Glucosinolates Lahiri, D.K., Ge, Y.W., Sharman, E.H., Bondy, S.C., 2004b. Age-related changes in serum
Sulforaphane, Phenethyl Isothiocyanate, Indole-3-Carbinol/3,3′ -Diindolylmethane: melatonin in mice: higher levels of combined melatonin and 6-hydroxymelatonin
Antioxidative stress/inflammation, Nrf2. Epigenetics/Epigenomics and In Vivo sulfate in the cerebral cortex than serum, heart, liver and kidney tissues. J. Pineal
Cancer Chemopreventive Efficacy. Curr. Pharmacol. Rep. 1, 179–196. https://doi. Res. 36, 217–223. https://doi.org/10.1111/j.1600-079X.2004.00120.x.
org/10.1007/s40495-015-0017-y. Langille, M.G.I., et al., 2014. Microbial shifts in the aging mouse gut. Microbiome 2,
Fung, T.C., 2020. The microbiota-immune axis as a central mediator of gut-brain 1–12. https://doi.org/10.1186/s40168-014-0050-9.
communication. Neurobiol. Dis. 136, 104714. https://doi.org/10.1016/j. Lee, W.J., Hase, K., 2014. Gut microbiota-generated metabolites in animal health and
nbd.2019.104714. disease. Nat. Chem. Biol. 10, 416–424. https://doi.org/10.1038/nchembio.1535.
Fung, T.C., Olson, C.A., Hsiao, E.Y., 2017. Interactions between the microbiota, immune Lee, J.H., Lee, J., 2010. Indole as an intercellular signal in microbial communities. FEMS
and nervous systems in health and disease. Nat. Neurosci. 20, 145–155. https://doi. Microbiol. Rev. 34, 426–444. https://doi.org/10.1111/j.1574-6976.2009.00204.x.
org/10.1038/nn.4476. Leuzy, A., et al., 2019. Tau PET imaging in neurodegenerative tauopathies-still a
Furumatsu, K., et al., 2011. A role of the aryl hydrocarbon receptor in attenuation of challenge. Mol. Psychiatry 24, 1112–1134. https://doi.org/10.1038/s41380-018-
colitis. Dig. Dis. Sci. 56, 2532–2544. https://doi.org/10.1007/s10620-011-1643-9. 0342-8.
Ganguli, M., et al., 2011. Outcomes of mild cognitive impairment by definition: a Li, J., et al., 2014. An integrated catalog of reference genes in the human gut
population study. Arch. Neurol. 68, 761–767. https://doi.org/10.1001/ microbiome. Nat. Biotechnol. 32, 834–841. https://doi.org/10.1038/nbt.2942.
archneurol.2011.101. Lian, B., Hanley, R., Schoenfeld, S., 2016. A phase 1 randomized, double-blind, placebo-
Gao, J., et al., 2018. Impact of the gut microbiota on intestinal immunity mediated by controlled, multiple ascending dose study to evaluate safety, tolerability and
tryptophan metabolism. Front. Cell. Infect. Microbiol. 8, 1–22. https://doi.org/ pharmacokinetics of the liver-selective TR-BETA agonist VK2809 (MB07811) in
10.3389/fcimb.2018.00013. hypercholesterolemic subjects. J. Am. Coll. Cardiol. 67, 1932. https://doi.org/
Glenner, G.G., Wong, C.W., 1984. Alzheimer’s disease and Down’s syndrome: sharing of 10.1016/s0735-1097(16)31933-7.
a unique cerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun. Lin, C.-H., et al., 2009. Knockdown of the aryl hydrocarbon receptor attenuates
122, 1131–1135. https://doi.org/10.1016/0006-291X(84)91209-9. excitotoxicity and enhances NMDA-induced BDNF expression in cortical neurons.
Gohlke, J.M., Stockton, P.S., Sieber, S., Foley, J., Portier, C.J., 2009. AhR-mediated gene J. Neurochem. 111, 777–789. https://doi.org/10.1111/j.1471-4159.2009.06364.x.
expression in the developing mouse telencephalon. Reprod. Toxicol. 28, 321–328. Liu, Z., et al., 2020. Gut microbiota mediates intermittent-fasting alleviation of diabetes-
https://doi.org/10.1016/j.reprotox.2009.05.067. induced cognitive impairment. Nat. Commun. 11 https://doi.org/10.1038/s41467-
Gurer-Orhan, H., et al., 2016. Novel indole-based melatonin analogues: evaluation of 020-14676-4.
antioxidant activity and protective effect against amyloid β-induced damage. Bioorg. Lusska, A., Shen, E., Whitlock, J.P., 1993. Protein-DNA interactions at a dioxin-
Med. Chem. 24, 1658–1664. https://doi.org/10.1016/j.bmc.2016.02.039. responsive enhancer Analysis of six bona fide DNA-binding sites for the liganded Ah
Gutiérrez-Vázquez, C., Quintana, F.J., 2018. Regulation of the immune response by the receptor. J. Biol. Chem. 268, 6575–6580.
aryl hydrocarbon receptor. Immunity 48, 19–33. https://doi.org/10.1016/j. Ma, Y., et al., 2018. 6-Formylindolo(3,2-b)carbazole induced aryl hydrocarbon receptor
immuni.2017.12.012. activation prevents intestinal barrier dysfunction through regulation of claudin-2

9
M.A. Pappolla et al. Neurobiology of Disease 156 (2021) 105403

expression. Chem. Biol. Interact. 288, 83–90. https://doi.org/10.1016/j. Petrulis, J.R., Perdew, G.H., 2002. The role of chaperone proteins in the aryl
cbi.2018.04.020. hydrocarbon receptor core complex. Chem. Biol. Interact. 141, 25–40. https://doi.
Mancuso, C., Santangelo, R., 2018. Alzheimer’s disease and gut microbiota org/10.1016/S0009-2797(02)00064-9.
modifications: the long way between preclinical studies and clinical evidence. Poeggeler, B., et al., 2001. Melatonin reverses the profibrillogenic activity of
Pharmacol. Res. 129, 329–336. https://doi.org/10.1016/j.phrs.2017.12.009. apolipoprotein E4 on the Alzheimer amyloid Abeta peptide. Biochemistry 40,
Marconett, C.N., et al., 2010. Indole-3-carbinol triggers aryl hydrocarbon receptor- 14995–15001. https://doi.org/10.1021/bi0114269.
dependent estrogen receptor (ER)α protein degradation in breast cancer cells Poeggeler, B., et al., 2010. A novel endogenous indole protects rodent mitochondria and
disrupting an ERαGATA3 transcriptional cross-regulatory loop. Mol. Biol. Cell 21, extends rotifer lifespan. PLoS ONE 5. https://doi.org/10.1371/journal.
1166–1177. https://doi.org/10.1091/mbc.E09-08-0689. pone.0010206.
Martins, R.N., et al., 2018. Alzheimer’s disease: a journey from amyloid peptides and Poland, A., Glover, E., Kende, A.S., 1976. Stereospecific, high affinity binding of 2,3,7,8-
oxidative stress, to biomarker technologies and disease prevention strategies-gains tetrachlorodibenzo-p-dioxin by hepatic cytosol evidence that the binding species is
from AIBL and DIAN cohort studies. J. Alzheimers Dis. 62, 965–992. https://doi.org/ receptor for induction of aryl hydrocarbon hydroxylase. J. Biol. Chem. 251,
10.3233/JAD-171145. 4936–4946.
Matsubara, E., et al., 2003. Melatonin increases survival and inhibits oxidative and Popolo, A., et al., 2017. Two likely targets for the anti-cancer effect of indole derivatives
amyloid pathology in a transgenic model of Alzheimer’s disease. J. Neurochem. 85, from cruciferous vegetables: PI3K/Akt/mTOR signalling pathway and the aryl
1101–1108. https://doi.org/10.1046/j.1471-4159.2003.01654.x. hydrocarbon receptor. Semin. Cancer Biol. 46, 132–137. https://doi.org/10.1016/j.
Mayer, E.A., Tillisch, K., Gupta, A., 2015. Gut/brain axis and the microbiota. Review semcancer.2017.06.002.
Series: Enteric Nervous System 125, 926–938. https://doi.org/10.1172/JCI76304. Quintana, F.J., et al., 2008. Control of Treg and TH17 cell differentiation by the aryl
Mazmanian, S.K., Cui, H.L., Tzianabos, A.O., Kasper, D.L., 2005. An immunomodulatory hydrocarbon receptor. Nature 453, 65–71. https://doi.org/10.1038/nature06880.
molecule of symbiotic bacteria directs maturation of the host immune system. Cell Rannug, A., Rannug, U., 2018. The tryptophan derivative 6-formylindolo[3,2- <i>b</i>
122, 107–118. https://doi.org/10.1016/j.cell.2005.05.007. ]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor
Menni, C., et al., 2019. Circulating levels of the anti-oxidant indoleproprionic acid are signaling, balances cell growth and differentiation. Crit. Rev. Toxicol. 48, 555–574.
associated with higher gut microbiome diversity. Gut Microbes 10, 688–695. https://doi.org/10.1080/10408444.2018.1493086.
https://doi.org/10.1080/19490976.2019.1586038. Readhead, B., et al., 2018. Multiscale analysis of independent Alzheimer’s cohorts finds
Meyer, B.K., Pray-Grant, M.G., Vanden Heuvel, J.P., Perdew, G.H., 1998. Hepatitis B disruption of molecular, genetic, and clinical networks by Human Herpesvirus.
virus X-associated protein 2 is a subunit of the Unliganded aryl hydrocarbon receptor Neuron 99, 64–82 e67. https://doi.org/10.1016/j.neuron.2018.05.023.
Core complex and exhibits transcriptional enhancer activity. Mol. Cell. Biol. 18, Reed, G.A., et al., 2006. Single-dose and multiple-dose administration of indole-3-
978–988. https://doi.org/10.1128/mcb.18.2.978. carbinol to women: Pharmacokinetics based on 3,3′ -diindolylmethane. Cancer
Morrison, D.J., Preston, T., 2016. Formation of short chain fatty acids by the gut Epidemiol. Biomark. Prev. 15, 2477–2481. https://doi.org/10.1158/1055-9965.EPI-
microbiota and their impact on human metabolism. Gut Microbes 7, 189–200. 06-0396.
https://doi.org/10.1080/19490976.2015.1134082. Reisberg, B., et al., 1988. Stage-specific behavioral, cognitive, and in vivo changes in
Nappi, A.J., Vass, E., 1997. Comparative studies of enhanced iron-mediated production community residing subjects with age-associated memory impairment and primary
of hydroxyl radical by glutathione, cysteine, ascorbic acid, and selected catechols. degenerative dementia of the Alzheimer type. Drug Dev. Res. 15, 101–114. https://
Biochim. Biophys. Acta Gen. Subj. 1336, 295–302. https://doi.org/10.1016/S0304- doi.org/10.1002/ddr.430150203.
4165(97)00039-1. Revelou, P.K., Kokotou, M.G., Constantinou-Kokotou, V., 2018. Determination of indole-
Naseer, M., et al., 2014. Role of gut microbiota in obesity, type 2 diabetes and type phytonutrients in cruciferous vegetables. Nat. Prod. Res. https://doi.org/
Alzheimer’s disease. CNS Neurol. Disord. Drug Targets 13, 305–311. https://doi. 10.1080/14786419.2018.1543680.
org/10.2174/18715273113126660147. Reyes, H., Reisz-Porszasz, S., Hankinson, O., 1992. Identification of the Ah receptor
Nunomura, A., et al., 1999. RNA oxidation is a prominent feature of vulnerable neurons nuclear translocator protein (Arnt) as a component of the DNA binding form of the
in Alzheimer’s disease. J. Neurosci. 19, 1959–1964. https://doi.org/10.1523/ Ah receptor. Science 256, 1193–1195. https://doi.org/10.1126/
jneurosci.19-06-01959.1999. science.256.5060.1193.
Nunomura, A., et al., 2000. Neuronal oxidative stress precedes amyloid-β deposition in Roager, H.M., Licht, T.R., 2018. Microbial tryptophan catabolites in health and disease.
down syndrome. J. Neuropathol. Exp. Neurol. 59, 1011–1017. https://doi.org/ Nat. Commun. 9, 3294. https://doi.org/10.1038/s41467-018-05470-4.
10.1093/jnen/59.11.1011. Rosales-Corral, S.A., et al., 2012. Alzheimer’s disease: pathological mechanisms and the
Omar, R.A., 1996. Imunohistochemical evidence of oxidative stress in Parkinson’s beneficial role of melatonin. J. Pineal Res. 52, 167–202. https://doi.org/10.1111/
disease. J. Neuropathol. Exp. Neurol. 55, 634. j.1600-079X.2011.00937.x.
O’Neal-Moffitt, G., Delic, V., Bradshaw, P.C., Olcese, J., 2015. Prophylactic melatonin Royston, K.J., Tollefsbol, T.O., 2015. The epigenetic impact of cruciferous vegetables on
significantly reduces Alzheimer’s neuropathology and associated cognitive deficits Cancer prevention. Curr. Pharmacol. Rep. 1, 46–51. https://doi.org/10.1007/
independent of antioxidant pathways in AβPP(swe)/PS1 mice. Mol. Neurodegener. s40495-014-0003-9.
10, 27. https://doi.org/10.1186/s13024-015-0027-6. Rzemieniec, J., et al., 2015. Selective Aryl Hydrocarbon receptor modulator 3, 3 ′
Palmer, C., Bik, E.M., DiGiulio, D.B., Relman, D.A., Brown, P.O., 2007. Development of -Diindolylmethane impairs AhR and ARNT signaling and protects mouse neuronal
the human infant intestinal microbiota. PLoS Biol. 5, e177 https://doi.org/10.1371/ cells against Hypoxia. Mol. Neurobiol. 53, 5591–5606. https://doi.org/10.1007/
journal.pbio.0050177. s12035-015-9471-0.
Panza, F., et al., 2005. Current epidemiology of mild cognitive impairment and other Rzemieniec, J., Wnuk, A., Lasoń, W., Bilecki, W., Kajta, M., 2019. The neuroprotective
predementia syndromes. Am. J. Geriatr. Psychiatr. 13, 633–644. https://doi.org/ action of 3,3′ -diindolylmethane against ischemia involves an inhibition of apoptosis
10.1097/00019442-200508000-00002. and autophagy that depends on HDAC and AhR/CYP1A1 but not ERα/CYP19A1
Papadopoli, D., et al., 2019. mTOR as a central regulator of lifespan and aging. signaling. Apoptosis 24, 435–452. https://doi.org/10.1007/s10495-019-01522-2.
F1000Research 8. F1000 Faculty Rev. 1998. https://doi.org/10.12688/ Salazar, N., et al., 2020. Microbiome: Effects of ageing and diet. Curr. Issues Mol. Biol.
f1000research.17196.1. 36, 33–62. https://doi.org/10.21775/cimb.036.033.
Pappolla, M.A., Omar, R.A., Kim, K.S., Robakis, N.K., 1992. Immunohistochemical Sampson, T.R., et al., 2016. Gut microbiota regulate motor deficits and
evidence of oxidative [corrected] stress in Alzheimer’s disease. Am. J. Pathol. 140, neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480 e1412.
621–628. https://doi.org/10.1016/j.cell.2016.11.018.
Pappolla, M.A., et al., 1997. Melatonin prevents death of neuroblastoma cells exposed to Scher, J.U., et al., 2015. Decreased bacterial diversity characterizes the altered gut
the Alzheimer amyloid peptide. J. Neurosci. 17, 1683–1690. https://doi.org/ microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory
10.1523/jneurosci.17-05-01683.1997. bowel disease. Arthritis Rheum. 67, 128–139. https://doi.org/10.1002/art.38892.
Pappolla, M., et al., 1998a. Inhibition of Alzheimer β-fibrillogenesis by melatonin. J. Biol. Schiering, C., et al., 2017. Feedback control of AHR signalling regulates intestinal
Chem. 273, 7185–7188. https://doi.org/10.1074/jbc.273.13.7185. immunity. Nature 542, 242–245. https://doi.org/10.1038/nature21080.
Pappolla, M.A., et al., 1998b. Evidence of oxidative stress and in vivo neurotoxicity of Schroeder, J.C., et al., 2010. The uremic toxin 3-indoxyl sulfate is a potent endogenous
beta-amyloid in a transgenic mouse model of Alzheimer’s disease: a chronic agonist for the human aryl hydrocarbon receptor. Biochemistry 49, 393–400.
oxidative paradigm for testing antioxidant therapies in vivo. Am. J. Pathol. 152, https://doi.org/10.1021/bi901786x.
871–877. Selkoe, D.J., Hardy, J., 2016. The amyloid hypothesis of Alzheimer’s disease at 25 years.
Pappolla, M.A., et al., 2002. Cholesterol, oxidative stress, and Alzheimer’s disease: EMBO Mol. Med. 8, 595–608. https://doi.org/10.15252/emmm.201606210.
expanding the horizons of pathogenesis. Free Radic. Biol. Med. 33, 173–181. https:// Shimizu, H., et al., 2012. Indoxyl sulfate upregulates renal expression of MCP-1 via
doi.org/10.1016/S0891-5849(02)00841-9. production of ROS and activation of NF-κB, p53, ERK, and JNK in proximal tubular
Pappolla, M.A., et al., 2018. Melatonin treatment enhances Aβ lymphatic clearance in a cells. Life Sci. 90, 525–530. https://doi.org/10.1016/j.lfs.2012.01.013.
transgenic mouse model of amyloidosis. Curr. Alzheimer Res. 15, 637–642. https:// Smith, M.A., et al., 2002. Amyloid-β deposition in Alzheimer transgenic mice is
doi.org/10.2174/1567205015666180411092551. associated with oxidative stress. J. Neurochem. 70, 2212–2215. https://doi.org/
Parks, O.B., Pociask, D.A., Hodzic, Z., Kolls, J.K., Good, M., 2016. Interleukin-22 10.1046/j.1471-4159.1998.70052212.x.
signaling in the regulation of intestinal health and disease. Front. Cell Song, W., Lahiri, D.K., 1997. Melatonin alters the metabolism of the beta-amyloid
Developmental Biol. 3 https://doi.org/10.3389/fcell.2015.00085. precursor protein in the neuroendocrine cell line PC12. J. Mol. Neurosci. 9, 75–92.
Perdew, G.H., 1988. Association of the Ah receptor with the 90-kDa heat shock protein. https://doi.org/10.1007/bf02736852.
J. Biol. Chem. 263, 13802–13805. Song, J., et al., 2002. A ligand for the aryl hydrocarbon receptor isolated from lung. Proc.
Petersen, R.C., et al., 2009. Mild cognitive impairment: ten years later. Arch. Neurol. 66, Natl. Acad. Sci. U. S. A. 99, 14694–14699. https://doi.org/10.1073/
1447–1455. https://doi.org/10.1001/archneurol.2009.266. pnas.232562899.
Petersen, R.C., et al., 2014. Mild cognitive impairment: a concept in evolution. J. Intern.
Med. 275, 214–228. https://doi.org/10.1111/joim.12190.

10
M.A. Pappolla et al. Neurobiology of Disease 156 (2021) 105403

Sonowal, R., et al., 2017. Indoles from commensal bacteria extend healthspan. Proc. disease. Prog. Mol. Biol. Transl. Sci. 168, 147–181. https://doi.org/10.1016/bs.
Natl. Acad. Sci. U. S. A. 114, E7506–E7515. https://doi.org/10.1073/ pmbts.2019.06.013.
pnas.1706464114. Wikoff, W.R., et al., 2009. Metabolomics analysis reveals large effects of gut microflora
Soshilov, A., Denison, M.S., 2011. Ligand displaces heat shock protein 90 from on mammalian blood metabolites. Proc. Natl. Acad. Sci. U. S. A. 106, 3698–3703.
overlapping binding sites within the aryl hydrocarbon receptor ligandbinding https://doi.org/10.1073/pnas.0812874106.
domain. J. Biol. Chem. 286, 35275–35282. https://doi.org/10.1074/jbc. Williamson, M.A., Gasiewicz, T.A., Opanashuk, L.A., 2005. Aryl hydrocarbon receptor
M111.246439. expression and activity in cerebellar granule neuroblasts: implications for
Sreenivasachary, N., et al., 2017. Discovery and characterization of novel indole and 7- development and dioxin neurotoxicity. Toxicol. Sci. 83, 340–348. https://doi.org/
azaindole derivatives as inhibitors of β-amyloid-42 aggregation for the treatment of 10.1093/toxsci/kfi031.
Alzheimer’s disease. Bioorg. Med. Chem. Lett. 27, 1405–1411. https://doi.org/ Wong, J.M., de Souza, R., Kendall, C.W., Emam, A., Jenkins, D.J., 2006. Colonic health:
10.1016/j.bmcl.2017.02.001. fermentation and short chain fatty acids. J. Clin. Gastroenterol. 40, 235–243.
Strittmatter, W.J., Roses, A.D., 1996. Apolipoprotein E and Alzheimer’s disease. Annu. https://doi.org/10.1097/00004836-200603000-00015.
Rev. Neurosci. 19, 53–77. https://doi.org/10.1146/annurev.ne.19.030196.000413. Wu, J.W., et al., 2016. Neuronal activity enhances tau propagation and tau pathology in
Thatcher, T.H., et al., 2016. Endogenous ligands of the aryl hydrocarbon receptor vivo. Nat. Neurosci. 19, 1085–1092. https://doi.org/10.1038/nn.4328.
regulate lung dendritic cell function. Immunology 147, 41–54. https://doi.org/ Yamada, T., et al., 2016. Constitutive aryl hydrocarbon receptor signaling constrains
10.1111/imm.12540. type I interferon-mediated antiviral innate defense. Nat. Immunol. 17, 687–694.
The Integrative Human Microbiome Project, 2019. Nature, 569, pp. 641–648. https:// https://doi.org/10.1038/ni.3422.
doi.org/10.1038/s41586-019-1238-8. Yanofsky, C., Horn, V., Gollnick, P., 1991. Physiological studies of tryptophan transport
Ticinesi, A., et al., 2018. Gut microbiota, cognitive frailty and dementia in older and tryptophanase operon induction in Escherichia coli. J. Bacteriol. 173,
individuals: a systematic review. Clin. Interv. Aging 13, 1497–1511. https://doi.org/ 6009–6017. https://doi.org/10.1128/jb.173.19.6009-6017.1991.
10.2147/cia.S139163. Yin, J., et al., 2016. Role of AhR in positive regulation of cell proliferation and survival.
Tuomainen, M., et al., 2018. Associations of serum indolepropionic acid, a gut Cell Prolif. 49, 554–560. https://doi.org/10.1111/cpr.12282.
microbiota metabolite, with type 2 diabetes and low-grade inflammation in high-risk Yisireyili, M., Takeshita, K., Saito, S., Murohara, T., Niwa, T., 2017. Indole-3-propionic
individuals. Nutrition Diabetes 8, 4–8. https://doi.org/10.1038/s41387-018-0046-9. acid suppresses indoxyl sulfate-induced expression of fibrotic and inflammatory
Turnbaugh, P.J., et al., 2009. The effect of diet on the human gut microbiome: a genes in proximal tubular cells. Nagoya J. Med. Sci. 79, 477–486. https://doi.org/
metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 1, 6ra14. 10.18999/nagjms.79.4.477.
https://doi.org/10.1126/scitranslmed.3000322. Yu, J., et al., 2019. A tryptophan metabolite of the skin microbiota attenuates
Verhoeven, D.T.H., Goldbohm, R.A., Van Poppel, G., Verhagen, H., Van Den Brandt, P.A., inflammation in patients with atopic dermatitis through the aryl hydrocarbon
1996. Epidemiological studies on Brassica vegetables and cancer risk. Cancer receptor. J. Allergy Clin. Immunol. 143, 2108–2119 e2112. https://doi.org/10.1016
Epidemiol. Biomark. Prev. 5, 733–748. /j.jaci.2018.11.036.
Wang, C., Ye, Z., Kijlstra, A., Zhou, Y., Yang, P., 2014. Activation of the aryl hydrocarbon Zelante, T., et al., 2013. Tryptophan catabolites from microbiota engage aryl
receptor affects activation and function of human monocyte-derived dendritic cells. hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity
Clin. Exp. Immunol. 177, 521–530. https://doi.org/10.1111/cei.12352. 39, 372–385. https://doi.org/10.1016/j.immuni.2013.08.003.
Wang, Y.Y., et al., 2017. Meta-analysis of randomized, double-blind, placebo-controlled Zhang, L.S., Davies, S.S., 2016. Microbial metabolism of dietary components to bioactive
trials of melatonin in Alzheimer’s disease. Int J. Geriatr. Psychiatry 32, 50–57. metabolites: opportunities for new therapeutic interventions. Genome Med. 8, 1–18.
https://doi.org/10.1002/gps.4571. https://doi.org/10.1186/s13073-016-0296-x.
Wang, J., et al., 2018. Aryl hydrocarbon receptor/IL-22/Stat3 signaling pathway is Zhang, J., et al., 1999. Parkinson’s disease is associated with oxidative damage to
involved in the modulation of intestinal mucosa antimicrobial molecules by cytoplasmic DNA and RNA in substantia nigra neurons. Am. J. Pathol. 154,
commensal microbiota in mice. Innate Immun 24, 297–306. https://doi.org/ 1423–1429. https://doi.org/10.1016/S0002-9440(10)65396-5.
10.1177/1753425918785016. Zolochevska, O., Taglialatela, G., 2016. Non-demented individuals with Alzheimer’s
Westfall, S., Iqbal, U., Sebastian, M., Pasinetti, G.M., 2019. Gut microbiota mediated disease neuropathology: resistance to cognitive decline may reveal new treatment
allostasis prevents stress-induced neuroinflammatory risk factors of Alzheimer’s strategies. Curr. Pharm. Des. 22, 4063–4068. https://doi.org/10.2174/
1381612822666160518142110.

11