Junko Sonoda

Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice

Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic–pituitary–adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain‐derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.

An oral introduction of intestinal bacteria prevents the development of a long-term Th2-skewed immunological memory induced by neonatal antibiotic treatment in mice

Background Recent epidemiological studies indicate that antibiotic use in infancy may be associated with an increased risk of developing atopy. Our previous work on animals demonstrated that kanamycin use during infancy promotes a shift in the Th1/Th2 balance towards a Th2‐dominant immunity.

The hepatic vagus nerve attenuates Fas-induced apoptosis in the mouse liver via α7 nicotinic acetylcholine receptor

BACKGROUND & AIMS Although accumulating evidence has recently shown that the efferent vagus nerve attenuates systemic inflammation, it remains unclear whether or not the vagus nerve can affect Fas-induced liver apoptosis. We investigated the effect of the vagus nerve by using a selective hepatic vagotomy. METHODS We assessed the mortality and apoptosis in Fas-induced fulminant hepatitis in sham-operated and vagotomized male C57BL/6 mice. To determine how the nerve influences hepatocyte apoptosis, hepatitis was preceded by pretreatment with nicotine; PNU-282987, an alpha7 nicotinic acetylcholine receptor (AChR) agonist; liposome-encapsulated dichloromethylene diphosphonate (lipo-Cl(2)MDP), a macrophage eliminator; and Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP), an oxidative inhibitor. RESULTS Mortality in the vagotomized mice was significantly higher than that in the sham-operated mice following intravenous administration with the anti-Fas antibody Jo-2. This result was also supported by the data from both terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling and caspase-3 assay, in which vagotomized livers showed a significant elevation in the number of apoptotic hepatocytes and increased caspase-3 activity following Jo-2 treatment compared with the sham-operated livers. Supplementation with nicotine and PNU-282987 dose dependently inhibited this detrimental effect of the vagotomy. Moreover, the vagotomy-triggered exacerbation of Fas-induced hepatitis was completely blocked by lipo-Cl(2)MDP. Similarly, pretreatment with MnTBAP also completely suppressed the vagotomy-triggered exacerbation. CONCLUSIONS The hepatic vagus nerve appears to play an important role in attenuating Fas-induced hepatocyte apoptosis through alpha7 nicotinic AChR, perhaps by causing the Kupffer cells to reduce their generation of an excessive amount of reactive oxygen species.

Electric foot shock stress‐induced exacerbation of α‐galactosylceramide–triggered apoptosis in mouse liver

Recently, liver natural killer T (NKT) cells, which are specifically stimulated by α‐galactosylceramide (α‐GalCer), were found to play a critical role in intrahepatic immunity to several infections and certain hepatic disorders. However, the role of psychophysical stress on NKT cell–dependent liver injury induced by α‐GalCer still remains to be elucidated. In this study, we employed inescapable electric foot shock as the mode of psychophysical stress and evaluated its effect on α‐GalCer–induced hepatitis. Pre‐exposure of 12 hours of foot shock stress before α‐GalCer administration significantly enhanced α‐GalCer–triggered increase in serum alanine aminotransferase levels, followed by increases in both liver caspase‐3 activity and terminal deoxynucleotidyl transferase–mediated dUTP nick‐end labeling (TUNEL)‐positive hepatocytes, thus indicating that the liver NKT cell–dependent apoptotic response was exacerbated by stress. Foot shock stress also significantly increased both the number of liver NKT cells and Fas expression levels on hepatocytes. Pretreatment with RU‐486, a glucocorticoid (GC) receptor antagonist, completely reversed such stress‐induced enhancement of the α‐GalCer–triggered serum alanine aminotransferase and hepatocyte Fas antigen responses. In contrast, such a reversal effect was not found in the mice pretreated with naloxone, a μ‐opioid receptor antagonist, which thus suggests that an elevation of endogenous GCs, but not β‐endorphin, as responsible for such stress‐induced aggravation in mouse hepatitis models. In conclusion, foot shock stress‐induced elevation of endogenous GCs exacerbates α‐GalCer–initiated hepatic apoptosis through the expansion of liver NKT cells and the up‐regulation of hepatocyte Fas antigen. (HEPATOLOGY 2004;39:1131–1140.)

Social Disruption Stress Exacerbates α-Galactosylceramide-Induced Hepatitis in Mice

Objective: Psychosocial stress has been suggested as a possible aggravating factor in liver diseases, however, the underlying mechanism has yet to be clarified. Recently, our research revealed that electric foot-shock stress aggravated NK1.1 Ag+ T cell-dependent α-galactosylceramide (α-GalCer)-induced hepatitis in mice via a mechanism mediated by endogenous glucocorticoids. In this study, we examined whether or not such aggravation could be applied to a psychosocially stressful situation, e.g. social disruption stress. Methods: Male wild-type C57BL/6 (B6) or B6 hepatitis virus type B surface antigen transgenic (HBs-tg) mice, a hepatitis B virus carrier mouse model, were exposed 3 times in 1 week to social disruption stress in which an 8-month-old aggressive male intruder was placed into their home cage (5 mice per group) for 2 h. Twelve hours after the final exposure to the stress, the wild-type and HBs-tg mice were intravenously injected with α-GalCer. Results: The stress-exposed wild-type mice exhibited significantly reduced thymus weight loss compared with the control animals. Moreover, this stress regimen led to a significant increase in serum alanine aminotransferase levels in both the wild-type and the HBs-tg mice, although the increase in the HBs-tg mice was higher than that in the wild-type mice. Conclusion: These findings demonstrated that, similar to electric foot-shock stress, social disruption stress exacerbated α-GalCer-induced hepatitis.

Additional file 1: Table S1. of Inhibition of emotional needs and emotional wellbeing predict disease progression of chronic hepatitis C patients: an 8-year prospective study

Baseline associations between the Stress Inventory scales and physical factors. (DOCX 16 kb)