Symposia

Symposia Gut-brain link grabs neurochemists／脳腸相関からみた神経化学

2S3-1 The functions of maternal gut microbiota linking mother with offspring during perinatal periods Shiro Tochitani^1,2 ¹Faculty of Health Science, Suzuka University of Medical Science，²Research Center for Child Mental Development, University of Fukui Many lines of evidences have shown that environmental factors play important roles in brain development. Although the healthy status of maternal gut microbiota appears to be an important environmental factor for brain development of offspring because maternal gut microbiota is a potent source for the gut microbiota of offspring, it has been unknown whether and how the status of maternal gut microbiota contributes to brain development of offspring. To address this question, we examined whether perturbing the maternal gut microbiota by administering the non-absorbable antibiotics (AB) to pregnant dams by voluntary drinking on embryonic day 9-16 influences the behaviors of their offspring both at postnatal week four (PW4) and at the postnatal week eight (PW8). The mice born from AB-treated dams (AB offspring) exhibited reduced voluntary activity in the dark phase compared to the mice from the control dams (Control offspring) in the 24 hr-home cage activity test at PW4. The reduced voluntary activity in AB offspring compared with that in Control offspring was also observed at PW4 in the open field test. AB offspring spent a shorter amount of time exploring the center of the novel environment than Control offspring at PW4 in the open field test. This spatial preference in a novel environment was still observed at PW8. Notably, the behavioral phenotypes of AB offspring were partially rescued by fostering of these mice by normal dams from P1, whereas the offspring born from control dams and fostered by AB-treated dams exhibited the phenotypes similar to those of AB offspring. These results suggest that perturbation of maternal gut microbiota during pregnancy affect the postnatal brain development, resulting in the long-lasting alterations in the behaviors of the offspring.		2S3-2 Nutritional and metabolic studies on chronic social defeat models Atsushi Toyoda^1,2 ¹Department of Food and Life Sciences, College of Agriculture, Ibaraki University，²United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology Recently, World Health Organization reported that about 300 million patients are suffering from depression in the world (2015). Although pathophysiological mechanisms of depression have been investigated, it is hard to develop novel antidepressants because of lack of appropriate animal models and biomarkers. Compared to other models, chronic social defeat stress (CSDS) models are widely used for understanding depression. We tried to understand nutritional and metabolic characteristics in CSDS models and conducted several approaches. Metabolomics revealed that taurine metabolism in the liver was affected by CSDS. Therefore, we investigated the effects of chronic feeding of taurine on depressive behaviors and signal transduction in rat hippocampus. Chronic taurine increased phosphorylation of hippocampal key proteins for depression such as MAP kinase and CaM kinase II, and decreased immobility in the forced swimming test (Iio, 2012). Collectively, taurine may have a potential for fighting depression. Moreover, the level of cholic acid was increased by CSDS in cecum (Aoki-Yoshida, 2016), so taurine metabolism may be crucial for depression.CSDS produces resilient and vulnerable individuals in C57BL/6J mice (Krishnan, 2007). Vulnerable individuals have similar characteristics with depressive patients (Hodes, 2014). We discovered that diet purity impacts stress tolerance (Goto, 2016), namely non-purified diet increased resilience compared with purified diet (AIN-93G). Non-purified diet contains various natural ingredients derived from plants, fishes, and microbes, so possibly these ingredients have several factors which impact stress tolerance. Now, we are screening various natural resources using CSDS models for discovering nutrients preventing depression.

2S3-3 The role of the gut microbiota in the production of monoamines in the gut lumen Tomokazu Hata，Nobuyuki Sudo Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University Recently, accumulating evidence has shown that bacterial chemical molecules signal to eukaryotic cells. Conversely, host hormones can signal to microbial cells through converging pathways to bacterial signaling molecules. This type of bidirectional communication is called “interkingdom signaling”, which thus mediates the relationships between the bacteria and mammalian hosts. In this regard, there is increasing interest in monoamines as the candidate molecules for such communication. Monoamines, such as catecholamine (CA) and serotonin (5-HT), are utilized in the central and peripheral nervous systems, which are presumed to play an important role in the gut lumen. In the 1990s, it was first demonstrated that some species of pathogens could recognize exogenous CA in vitro, and such recognition increased bacterial proliferative capacity. In the 2000s, the bacterial adrenergic receptor QseC was discovered to activate virulence genes in response to interkingdom cross-signaling. The interkingdom signaling through CA is presumed to be performed continually in the gut lumen and to play an important role in the regulation of various pathophysiological functions. However, available evidence was still extremely limited because of the paucity of actual data about luminal CA. Therefore, we evaluated luminal CA levels through gastrointestinal tract using a reliable and reproducible HPLC method. As a result, gut microbiota was found to play a crucial role in generating the biologically active, free form of CA in the lumen of the gut.In this symposium, I’d like to talk about the involvement of gut microbiota in the regulation of monoamines, such as 5-HT and CA, based on our series of animal experiments.		2S3-4 Investigation of the molecule related to the intestinal microbiota-gut-brain axis using metabolomics Mitsuharu Matsumoto Dairy Science and Technology Institute, Kyodo Milk Industry Co. Ltd. Recent studies have investigated the effect of gut microbiota on the emotional aspect of behavior, using motor activity, and anxiety as parameters for measurement. The results of these studies suggest that intestinal microbiota have a great impact on gut-brain communication. However, to the best of our knowledge, no study has clarified the mechanism connecting the level of certain molecules in the brain, and an implicated behavioral phenotype. For this purpose, we have been investigating low-molecular-weight metabolites produced by the intestinal microbiota, and their presence in the brain, to clarify the relationship between the intestinal environment and brain activity, using metabolomics. The metabolome in the prefrontal cortex of germ-free (GF) mice and Ex-GF mice, who were inoculated with suspensions of feces obtained from speciﬁc pathogen-free mice, was analyzed using CE-TOFMS. As a result, 196 metabolites were identified from the prefrontal cortex metabolome in both GF and Ex-GF mice. The concentrations of 38 metabolites differed signiﬁcantly between those of GF, and Ex-GF mice. Approximately 10 of these metabolites, including Trp, Tyr, N-acetylaspartic acid, and pipecolic acid, are known to be involved in brain activity or function. Furthermore, the concentrations of metabolites involved in glycolysis/gluconeogenesis pathways were characteristically higher in GF mice than in Ex-GF mice. Moreover, six cerebral metabolites, such as aspartic acid, serine, and pipecolic acid, had similar Ex-GF/GF ratios between colonic luminal content, cardiac plasma, and the prefrontal cortex. This may suggest that these metabolites may be transported from the colonic lumen to the prefrontal cortex in the bloodstream without ﬁltration by the blood brain barrier.

2S3-5 Oral intake of umami in early life effects on emotional behavior mediated by gut-brain interaction Hideki Hida Department of Neurophysiology & Brain Science, Nagoya City University Graduate School of Medical Sciences To investigate if a taste substance of umami, monosodium L- glutamate (MSG), during the period of development could modify emotional behavior, 60 mM MSG solution was orally given to an ADHD model rat (spontaneously hypertensive rat: SHR) from P25 for 5 weeks in isolated condition, followed by open-field test and social-interaction test. It revealed that oral MSG intake caused in reduced aggression in SHR. No significant change of the blood pressure was shown in MSG oral intake for 5 weeks. To know the mechanism of reduced aggression, we first investigate the effect of MSG intake on brain damage. It found that neuronal death was minor in oral intake of MSG: no Argyophill III-positive cells were shown in vivo and no apparent cell death (LDH assay) was induced by MSG treatment in blood-brain barrier in vitro model. To investigate the effect of gut-brain communication via vagus nerve, the vagotomy was performed at the stomach level in P25 followed by MSG intake for 5 weeks. The vagotomy with MSG administration failed to decrease aggressiveness: the number of attack became to the same level as H2O-treated control group. Data indicates that less aggression was induced by MSG intake during the period of development, which is medicated by vagus nerve from the gastrointestinal tract (gut-brain communication).