Host-microbiome interactions: the aryl hydrocarbon receptor and the central nervous system
Host-microbiome interactions: the aryl hydrocarbon receptor and the central nervous system
Hae Ung Lee 0 1 2 3
Zachary E McPherson 0 1 2 3
Bryan Tan 0 1 2 3
Agata Korecka 0 1 2 3
Sven Pettersson 0 1 2 3
0 The School of Medicine, Imperial College , London , UK
1 The School of Medicine and Public Health, University of Newcastle , Newcastle , Australia
2 The LKC School of Medicine, Nanyang Technological University , Singapore, Singapore
3 Department of Microbiology, Cell and Tumor Biology, Karolinska Institutet , Solna , Sweden
The microbiome located within a given host and its organs forms a holobiont, an intimate functional entity with evolutionarily designed interactions to support nutritional intake and reproduction. Thus, all organs in a holobiont respond to changes within the microbiome. The development and function of the central nervous system and its homeostatic mechanisms are no exception and are also subject to regulation by the gut microbiome. In order for the holobiont to function effectively, the microbiome and host must communicate. The aryl hydrocarbon receptor is an evolutionarily conserved receptor recognizing environmental compounds, including a number of ligands produced directly and indirectly by the microbiome. This review focuses on the microbiomegut-brain axis in regard to the aryl hydrocarbon receptor signaling pathway and its impact on underlying mechanisms in neurodegeneration.
Host-microbiome interactions; Neurodevelopment; Neurodegeneration; Aryl hydrocarbon receptor
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The alimentary tract contains trillions of microbes with
overlapping biological and biochemical needs due to
coevolutionary mechanisms, collectively termed the gut microbiome.
Though researchers have shown that the gut microbiome
impacts virtually all aspects of host function, the mechanisms
and signaling pathways by which the gut microbiota
communicates with its host are still unknown.
Bacteria and archaea, two of the predominant kingdoms
within the microbiome, were the dominant forms of life on
Earth for approximately three billion years prior to the
evolution of the animal kingdom [1, 2]. Current understanding
increasingly considers the host and its microbiome as a working
functional unit known as the holobiont. Environmental
changes affect both the host and its microbiome. The last decade of
genome-wide association studies has ignored the microbiome
and, consequently, missed the response elicited within it. In
the last 20 years, germ-free (GF) mice, mice that are raised
without exposure to any microbes, have been used to address
the holobiont concept using a systems biology approach [3]. A
prerequisite for a holobiont to function is the ability of the host
and microbiome to communicate, to maintain homeostasis,
and to act correspondingly when exposed to assaults. We
postulate that many of the ligands and receptors identified and
used for host-microbiome interactions are evolutionary. This
review focuses on the well-described xenobiotic aryl
hydrocarbon receptor (AHR) as one possible evolutionarily
conserved signaling pathway that contributes to
hostmicrobiome homeostasis within the holobiont.
The aryl hydrocarbon receptor
The AHR is a cytoplasmic ligand-induced receptor originally
discovered as a xenobiotic sensor mediating the toxicity of
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), also known as
dioxin [4–7]. The metabolism of xenobiotic compounds is
initiated by activation of the AHR, which then translocates
to the nucleus, where it acts as a transcription factor for
specific target genes, such as cytochrome P450 1A1 and
cytochrome P450 1B1 [4, 5, 8–12]. However, invertebrates do not
have a toxic response to dioxin, and none of the currently
known invertebrate AHR orthologues, including spineless in
Drosophila, have dioxin binding capacity, which suggests that
the ancestral role of the AHR is not specifically toxin response
[13, 14]. Furthermore, physiological roles of the AHR in
responses to endogenous ligands have been reported in cell
cycle regulation, cell differentiation, and immune responses
[11, 15–18]. A number of endogenous AHR ligands have
been suggested through in silico research and biological
testing, including tryptophan metabolites [5, 11, 19]. Recently,
our group discovered that AHR expression is attenuated in
GF mice [20]. This finding suggests that the AHR acts as a
mediator in communication between the host and gut
microbiota.
Function of the aryl hydrocarbon receptor
in host-environment interactions
Dioxin-activated AHR attenuates lipid metabolism via
negative regulation of peroxisome proliferator-activated receptor
(PPAR) [21]. Dysregulation of lipid metabolism leading to
hepatic steatosis and insulin resistance suggests that the
AHR plays an important role in integrating exogenous and
endogenous influences in lipid and energy metabolism [22,
23]. Findings from AHR-deficient mice show that, like GF
mice [24, 25], they are protected from high fat diet-induced
obesity, hepatic steatos (...truncated)