Host-microbiome interactions: the aryl hydrocarbon receptor and the central nervous system

Journal of Molecular Medicine, Nov 2016

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 microbiome-gut-brain axis in regard to the aryl hydrocarbon receptor signaling pathway and its impact on underlying mechanisms in neurodegeneration.

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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 - 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)


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Hae Ung Lee, Zachary E McPherson, Bryan Tan, Agata Korecka, Sven Pettersson. Host-microbiome interactions: the aryl hydrocarbon receptor and the central nervous system, Journal of Molecular Medicine, 2017, pp. 29-39, Volume 95, Issue 1, DOI: 10.1007/s00109-016-1486-0