Symposium
Brain-gut axis: the cutting edge
シンポジウム
脳腸相関研究の最前線 |
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| 7月27日（土）16:40～17:05 第1会場（朱鷺メッセ 4F 国際会議室）
3S01e-1
Host-microbe interactions regulating synaptic plasticity and behavior
Shelly A Buffington（Buffington Shelly A）1,2,3
1Department of Neuroscience, Cell Biology, & Anatomy, University of Texas Medical Branch, Galveston, TX, USA
2Recent Affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA
3Recent Affiliation: Memory and Brain Research Center, Baylor College of Medicine, Houston, TX, USA
It is becoming increasingly evident that behavioral phenotypes are determined not only by the host genome, but by the metagenome, the combination of host and microbial genes. Gut microbiota, in particular, are emerging as key regulators of both normal central nervous system physiology and disease states. Our lab is focused on establishing a molecular-to-systems level understanding of how gut microbiota contribute to host brain development, function, and behavior and how gut microbiota dysbiosis (a pathological imbalance of microbial ecology) contributes to neurodysfunction. To this end, we combine metagenomics with biochemistry, electrophysiology, and behavioral analysis to determine the mechanisms by which gut microbiota, down to the level of single species, impact host neurophysiology and behavior. In this talk, I will review our work in the maternal high-fat diet (MHFD) model of autism spectrum disorder (ASD) in which we identified a single bacterial species, Lactobacillus (L.) reuteri, which rescues social dysfunction and related deficits in social reward circuit plasticity. Here, we found that MHFD exposure induces long-term, functional changes in the offspring gut microbiome associated with dysregulation of the oxytocinergic system, deficits in social interaction-induced long-term plasticity in ventral tegmental area dopaminergic neurons, and resulting social impairments. Precision reconstitution with L. reuteri, which is negatively selected for by MHFD, restored oxytocin levels, interaction-induced VTA plasticity, and normal social behavior in the offspring. In addition, I will discuss our recent follow-up study in which we showed that L. reuteri rescues social dysfunction in multiple models of ASD of diverse pathoetiology (i.e., environmental, idiopathic, and genetic ASD models) and that this rescue depends on vagus nerve integrity and oxytocin receptor signaling in dopaminergic neurons. Taken together, our findings identify the gut microbiome as a potential therapeutic target for neurodevelopmental disorders characterized by social dysfunction, including ASD. | | 7月27日（土）17:05～17:30 第1会場（朱鷺メッセ 4F 国際会議室）
3S01e-2
PSYCHONEUROIMMUNOLOGY AND GUT MICROBES
Paul Forsythe（Forsythe Paul）
McMaster University
accentIntroduction:accent Psychoneuroimmunology is the study of the interaction between the brain, neural functions and immune processes. It is now clear that the gut microbiota is an important modulator of these relationships.
accentMethods:accent We have conducted preclinical studies to investigate the role of the nervous and immune systems in mediating the relationship between gut microbes and the brain. These studies have focused on how disruption of the existing microbiota with antibiotics, or exposure to specific bacteria, in the form of probiotics, modulate anxiety and depression-like behaviours.
accentResults:accent Psychological stress induces changes in the gut microbiota with accompanying pro-inflammatory changes in the immune system. Conversely, modulation of the gut microbiota or exposure to specific microbes results in changes in behaviour with associated alterations in neural and immune function. With regard to causal relationships, while the enteric nervous system and vagus nerve play a critical role in transmitting antidepressant signals from the gut to the brain, the balance between pro-inflammatory and anti-inflammatory immune responses also contributes significantly to the behavioral effects of gut microbes.
accentConclusions: accentBoth the nervous and immune systems contribute to the effect of gut microbes on the brain and behavior. A better understanding of how these systems interact with micro-organisms and in turn communicate with the CNS will aid in determining the therapeutic potential of gut microbes in mood disorders. | | 7月27日（土）17:30～17:55 第1会場（朱鷺メッセ 4F 国際会議室）
3S01e-3
腸内細菌叢と多発性硬化症の病態
Takashi Yamamura（山村 隆）
国立精神神経医療研究センター神経研究所免疫
Multiple sclerosis (MS) is a demyelinating disease affecting the central nervous system (CNS). This disorder is thought to be an autoimmune disease, which is influenced by both genetic and environmental factors. Of note, we have seen a remarkable increase in the incidence of MS in the developed countries, in particular Japan, which could be correlated with the change of life style, so-called westernization. The major component of westernization can be a reduced intake of diet fiber and alterations of intestinal contents. We previously reported that dysbiosis in the gut microbiome is significantly present in Japanese patients with MS (Miyake et al. 2015). More recently, analysis by using 16S rRNA gene and metagenomic sequence data has further revealed a reduction of butyrate-producing bacteria species, such as Eubacterium rectale, in relapsing-remitting type of MS (submitted for publication). As butyrate is able to serve as an anti-inflammatory molecule against the activation of microglia and would induce Foxp3+ regulatory T cells as well, the reduction of the butyrate producers should have significant implications. Moreover, since Eubacterium rectale in the fecus depends on diet fiber intake, the increase of MS in Japan associated with westernization can be reasonably explained based on the results. Our analysis of fecal samples from over 100 patients with MS and its variant also indicates a significant correlation between disease subtype SPMS (secondary progressive MS) and changes of certain bacterial species or functional pathways. Clinical and therapeutic implications of these observations will be discussed in the symposium. | | 7月27日（土）17:55～18:20 第1会場（朱鷺メッセ 4F 国際会議室）
3S01e-4
過敏性腸症候群における腸内細菌と脳腸相関
Shin Fukudo（福土 審）
東北大学大学院医学系研究科行動医学
The scientific importance of irritable bowel syndrome (IBS) is increasing and many clinicians and basic scientists are recently interested in this syndrome. IBS and allied conditions are known to be risk factors for depressive disorders, anxiety disorders, and dementia. The genetic predisposition and influence of environment especially gut micribiota may underlie in the pathogenesis and/or pathophysiology of IBS. This phenomenon, gene x environment interaction together with brain-gut interactions is emerging area to be clarified in IBS research. Research focused on candidate genes of neurotransmitters, cytokines, and growth factors. Among them, some studies but not all studies revealed association between phenotypes of IBS and 5-hydroxytryptamine (5-HT) transporter gene-linked polymorphic region (5-HTTLPR), 5-HT receptor genes, interleukin (IL)-10 gene, IL-6 gene, toll-like receptor-9 gene, cadherin-1 gene, genes relating corticotropin-releasing hormone (CRH), or other genes. Therefore, not only genes coding neurotransmitters but also genes that encode proteins involved in epithelial cell barrier function and the innate immune response to enteric bacteria are associated with development of IBS.
Growing evidence indicated that altered microbiota are present in IBS patients. Earlier studies suggest that microbiota composition is altered by psychosocial stress, psychosocial stress changes host mucosal immune response and mucosal permeability, and that visceral hypersensitivity is induced by this entire process. Gut microbiota and products of gut microbiota especially short chain fatty acid relate to quantified symptoms of healthy controls and IBS patients.
How microbiota play a role in pathophysiology of IBS via dysregulated brain-gut interactions is still unknown. However, brain imaging using positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and electroencephalography (EEG) with or without combination of barostat stimulation or electrical stimulation of the colorectum enables us to depict the detailed information of brain-gut interactions. In IBS patients, thalamus, insula, anterior cingulate cortex, amygdala, and brainstem are more activated in response to visceral stimulation than controls. IBS patients also have more desynchronized patterns of EEG and shorter latency of viscerosensory evoked potential. Dysfunction of the prefrontal cortex is also present in IBS patients. Therefore, now it is possible to predict system physiological mechanism of IBS via gut microbiota and brain function.
Further research in gut microbiota and human brain function for the symptom generation in IBS patients is warranted. IBS research will provide an important key to solve how brain and visceral organs communicate at normal and pathological condition in humans. | |
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