Xiao-Nian Yu

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.

Dehydroepiandrosterone attenuates the spontaneous elevation of serum IgE level in NC/Nga mice

Dehydroepiandrosterone (DHEA) and its sulfate derivatives are known to affect host immune function; however if such hormones influence the development of atopic dermatitis has not yet been clarified. In this study, we examined the effects of DHEA on the allergic process using NC/Nga mouse, a model animal of human atopic dermatitis. The administration of DHEA profoundly suppressed the spontaneous elevation of both serum IgE and interleukin-6 levels in NC/Nga mice during the observation period. These results indicate that DHEA promotes a shift in Thl/Th2 balance toward Th1-dominant immunity, and thus may be one of the effective alternatives in treating atopic dermatitis.

The Restraint Stress-Induced Elevation in Plasma Interleukin-6 Negatively Regulates the Plasma TNF-α Level

Although a considerable amount of evidence has shown that physical and psychological stress elevates the plasma interleukin 6 (IL-6) levels, the physiological significance of such an elevation remains to be elucidated. In this study, in order to determine whether the restraint stress-induced elevation of plasma IL-6 contributes to the activation of the hypothalamic-pituitary-adrenal axis, and whether or not such elevation can affect the inflammatory processes, the plasma levels of ACTH, corticosterone, interleukin-1 (IL-1), and tumor necrosis factor-α (TNF-α) in mice pretreated with anti-IL-6 antibody (MP5-20F3 monoclonal antibody) were compared with those in mice pretreated with rat IgG (control antibody) both during and after stress. Both the anti-IL-6-antibody- and control-antibody-pretreated mice showed the same extent of plasma ACTH and corticosterone increases during stress, and no significant difference was found between the two groups of animals. On the other hand, the level of plasma TNF-α in the anti-IL-6-treated animals was also significantly higher than that in the control animals both immediately after cessation of stress and 60 min after the cessation of the 120-min period of restraint. Plasma IL-1 activity, however, did not reach a detectable level in either group of animals at any time point examined. These results thus indicate that the restraint-stress-induced elevation of plasma IL-6 negatively regulates the plasma TNF-α levels and may thus contribute to the maintenance of homeostasis.

Dietary nucleic acids promote a shift in Th1/Th2 balance toward Th1-dominant immunity

Dietary sources of nucleic acids and their relative components are known to affect host immune function; however, it has not yet been clarified whether such dietary nucleic acids influence the pathogenesis of allergic reaction.

Dietary Nucleic Acid and Intestinal Microbiota Synergistically Promote a Shift in the Th1/Th2 Balance toward Th1-Skewed Immunity

Background: Intestinal microbiota are known to play an important role in the establishment of oral tolerance, thereby protecting the organism from food allergies. Dietary intake of nucleic acid (NA) is also reported to have such an anti-allergic effect; however, one unsolved question is whether or not dietary NA would act through a process of toll-like receptor 9 signaling activated by DNA containing a CpG motif, a well-known sequence leading to immunostimulatory activity. In this study, we focused on the question of whether the addition of dietary NA lacking CpG motifs would allow continued modulation of the Th1/Th2 balance. Methods: Germ free (GF) and Bifidobacterium-infantis-monoassociated BALB/c mice were maintained on either an NA-free casein diet or on an NA-supplemented casein diet for 4 weeks. Thereafter, both the in vivo anti-casein antibody levels and in vitro splenocyte cytokine secretion pattern were evaluated. Results: Feeding with a casein diet elicited a substantial increase in the serum anti-casein-specific IgG1, IgG2a, and IgE levels of GF mice fed the NA free-diet. The in vitro cytokine production profile showed that enhanced IL-4 production in the GF mice fed the NA free-diet was markedly reduced by the supplementation with dietary NA in both the GF and B.-infantis-monoassociated mice. In addition, IFN-γ secretion increased in the B.-infantis-reconstituted mice fed the diet containing NA. Conclusions: These results suggest that dietary intake of NA devoid of CpG motifs may prevent the development of allergies via acceleration of Th1-dominant immunity.

Restraint Stress-Induced Elevation of Endogenous Glucocorticoids Decreases Peyer’s Patch Cell Numbers via Mechanisms That Are either Dependent or Independent on Apoptotic Cell Death

In this study, we investigated whether restraint stress induces either apoptotic cell death or lymphocyte migration in Peyer’s patches. Exposure to stress induced a striking decrease in the number of CD3+CD4+, CD3+CD8+ and B220+ cells. Such decreases were accompanied by the enhanced induction of apoptosis in Peyer’s patches. The apoptosis of Peyer’s patch cells was completely reversed by pretreatment with either high or low doses of RU-486, a glucocorticoid receptor antagonist. In contrast, the stress-induced lymphopenia was little affected by administration of low doses of RU-486, although such lymphopenia was perfectly inhibited by treatment with high doses of RU-486. Taken together, these results suggest that the stress-induced lymphopenia in Peyer’s patches is partly due to apoptotic cell death, although other systems such as lymphocyte migration, may contribute to such a reduction in the number of Peyer’s patch cells.

Central and peripheral catecholamines regulate the exercise-induced elevation of plasma interleukin 6 in rats

Several recent reports indicate that exercise elevates the plasma interleukin 6 levels; however, the precise regulation of such an elevation still remains to be clarified. In this study, in order to clarify the requirements of central and peripheral catecholaminergic system for this exercise-induced interleukin 6 elevation, rats were either intraperitoneally or intracerebroventricularly injected with 6-hydroxydopamine which depletes the catecholamine in the central or peripheral tissues. As a result, our exercise protocol elevated the plasma interleukin 6, ACTH, and corticosterone levels in response to exercise. All such exercise-induced increases in the interleukin 6, ACTH, and corticosterone levels were significantly inhibited by pretreatment with an intracerebroventricular injection of 6-hydroxydopamine. In the intraperitoneal 6-hydroxydopamine-treated animals, the exercise-induced interleukin 6 elevation was significantly suppressed compared with the vehicle-treated animals, although no significant difference was found in either the ACTH level or the corticosterone level between both groups of animals. These results thus suggest that central and peripheral catecholamines are involved in the regulation of the exercise-induced interleukin 6 elevation.