Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior

Gacias, Mar; Gaspari, Sevasti; Santos, Patricia-Mae G; Tamburini, Sabrina; Andrade, Mônica de; Zhang, Fan; Shen, Nan; Tolstikov, Vladimir; Kiebish, Michael A.; Dupree, Jeffrey L.; Zachariou, Venetia; Clemente, José C.; Casaccia, Patrizia

doi:10.7554/elife.13442

Cited by 251 publications

(221 citation statements)

References 77 publications

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“…However, it is not yet apparent whether this has any consequences for discrete populations of neurons that provide the interface between endogenous kynurenine pathway neuroactives and glutamatergic, and cholinergic neurotransmission. In addition, recent preclinical evidence using different approaches demonstrating that the gut microbiota regulate myelination in the prefrontal cortex (Gacias et al, 2016;Hoban et al, 2016) further expands the repertoire of CNS functions influenced by gut microbial composition.…”

Section: Microbial Regulation Of Cns Receptors Neurogenesis and Myelmentioning

confidence: 99%

Kynurenine pathway metabolism and the microbiota-gut-brain axis

et al. 2017

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Section: Microbial Regulation Of Cns Receptors Neurogenesis and Myelmentioning

confidence: 99%

Kynurenine pathway metabolism and the microbiota-gut-brain axis

et al. 2017

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“…Third, these data point to a new gut-brain signaling axis in controlling the development of inflammatory and degenerative pathology in humans. These findings also add to recent advancements made in studies of neuropsychiatric disease where the gut microbiota modulate transcriptional programs that control social behavior (92), modulate synaptic dysfunction (93), and can modulate phenotypes associated with autism (94). It should also be kept in mind that, besides acting as a CNS sensor for immunomodulatory metabolites produced in the gut, based on its effects on gut immunity AhR may also shape the gut flora, impacting the gut-brain axis at multiple levels.…”

Section: Role Of Ahr In Astrocyte-mediated Inflammatory Processesmentioning

confidence: 99%

Control of immune-mediated pathology via the aryl hydrocarbon receptor

Wheeler

Rothhammer

Quintana

2017

Journal of Biological Chemistry

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Edited by George M. Carman Genetic and environmental factors contribute to the development of immune-mediated diseases. Although numerous genetic factors contributing to autoimmunity have been identified in recent years, our knowledge on environmental factors contributing to the pathogenesis of autoimmune diseases and the mechanisms involved is still limited. In this context, the diet, microbiome, geographical location, as well as environmental pollutants have been shown to modulate autoimmune disease development. These environmental factors interact with cellular components of the immune system in distinct and defined ways and can influence immune responses at the transcriptional and protein level. Moreover, endogenous metabolites generated from basic cellular processes such as glycolysis and oxidative phosphorylation also contribute to the shaping of the immune response. In this minireview, we highlight recent progress in our understanding of the modulation of the immune response by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor whose activity is regulated by small molecules provided by diet, commensal flora, environmental pollutants, and metabolism. We focus on the role of AhR in integrating signals from the diet and the intestinal flora to modulate ongoing inflammation in the central nervous system, and we also discuss the potential therapeutic value of AhR agonists for multiple sclerosis and other autoimmune diseases. Multiple sclerosis (MS)4 is an autoimmune disease of the central nervous system (CNS). In 85% of the affected individuals, MS initially presents with a relapsing-remitting course characterized by temporally defined relapses, which are followed by a varying degree of remission. Most patients eventually enter the secondary progressive phase of MS, which is characterized by the progressive and irreversible accumulation of neurological deficits (1). Several biological pathways are involved in the regulation of the immune response in MS both in the peripheral and central immune compartment and are thought to play dominant roles in the different stages of the disease. Although the role of several molecules such as cytokines and toll-like receptor agonists in MS pathology has been studied at length, particularly in relation to the relapsing-remitting phase of the disease, only recently has the role of metabolites generated in basic biological processes such as glycolysis and oxidative phosphorylation become appreciated with regard to their relevance for the development, propagation, and resolution of autoimmune inflammation. Prominent examples of endogenous metabolites with central roles in MS pathology include bioactive lipids, reactive oxygen species, and adenosine triphosphate (ATP) (2-13). The effects of these endogenous metabolites are modulated by a multitude of exogenous factors such as pollutants, dietary factors, and products from the commensal flora to trigger transcriptional programs that control the immune response during MS. Ultimately, the understanding of ...

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“…For example, recent work suggests that metabolites released from the gut microbiota early in the life of the host influence the development of the brain and the blood-brain barrier (Braniste et al, 2014;Goyal et al, 2015), and there is increasing evidence for bacterial metabolites modulating the gut-brain axis (Perry et al, 2016). The microbiota have been implicated in a variety of animal behaviors, including stress responses, sociality, fear and even mate choice (Arentsen et al, 2015;Buffington et al, 2016;Gacias et al, 2016;Mika and Fleshner, 2016;Sharon et al, 2010).…”

Section: Resident (Or Indigenous) Microbesmentioning

confidence: 99%

A place for host–microbe symbiosis in the comparative physiologist's toolbox

Kohl

Carey

2016

Journal of Experimental Biology

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Although scientists have long appreciated that metazoans evolved in a microbial world, we are just beginning to appreciate the profound impact that host-associated microbes have on diverse aspects of animal biology. The enormous growth in our understanding of hostmicrobe symbioses is rapidly expanding the study of animal physiology, both technically and conceptually. Microbes associate functionally with various body surfaces of their hosts, although most reside in the gastrointestinal tract. Gut microbes convert dietary and host-derived substrates to metabolites such as short-chain fatty acids, thereby providing energy and nutrients to the host. Bacterial metabolites incorporated into the host metabolome can activate receptors on a variety of cell types and, in doing so, alter host physiology (including metabolism, organ function, biological rhythms, neural activity and behavior). Given that host-microbe interactions affect diverse aspects of host physiology, it is likely that they influence animal ecology and, if they confer fitness benefits, the evolutionary trajectory of a species. Multiple variables -including sampling regime, environmental parameters, host metadata and analytical methods -can influence experimental outcomes in host-microbiome studies, making careful experimental design and execution crucial to ensure reproducible and informative studies in the laboratory and field. Integration of microbiomes into comparative physiology and ecophysiological investigations can reveal the potential impacts of the microbiota on physiological responses to changing environments, and is likely to bring valuable insights to the study of host-microbiome interactions among a broad range of metazoans, including humans.

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Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior

Cited by 251 publications

References 77 publications

Kynurenine pathway metabolism and the microbiota-gut-brain axis

Kynurenine pathway metabolism and the microbiota-gut-brain axis

Control of immune-mediated pathology via the aryl hydrocarbon receptor

A place for host–microbe symbiosis in the comparative physiologist's toolbox

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