Nobuyuki Sudo

Mood and gut feelings

Evidence is accumulating to suggest that gut microbes (microbiota) may be involved in neural development and function, both peripherally in the enteric nervous system and centrally in the brain. There is an increasing and intense current interest in the role that gut bacteria play in maintaining the health of the host. Altogether the mass of intestinal bacteria represents a virtual inner organ with 100 times the total genetic material contained in all the cells in the human body. Surprisingly, the characterization of this extraordinarily diverse population is only just beginning, since some 60% of these microbes have never been cultured. Commensal organisms live in a state of harmonious symbiosis with each other and their host, however, a disordered balance amongst gut microbes is now thought to be an associated or even causal factor for chronic medical conditions as varied as obesity and inflammatory bowel diseases. While evidence is still limited in psychiatric illnesses, there are rapidly coalescing clusters of evidence which point to the possibility that variations in the composition of gut microbes may be associated with changes in the normal functioning of the nervous system. This review focuses on these data and suggests that the concept should be explored further to increase our understanding of mood disorders, and possibly even uncover missing links to a number of co-morbid medical diseases.

Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice

There is increasing interest in the bidirectional communication between the mammalian host and prokaryotic cells. Catecholamines (CA), candidate molecules for such communication, are presumed to play an important role in the gut lumen; however, available evidence is limited because of the lack of actual data about luminal CA. This study evaluated luminal CA levels in the gastrointestinal tract and elucidated the involvement of gut microbiota in the generation of luminal CA by comparing the findings among specific pathogen-free mice (SPF-M), germ-free mice (GF-M), and gnotobiotic mice. Substantial levels of free dopamine and norepinephrine were identified in the gut lumen of SPF-M. The free CA levels in the gut lumen were lower in GF-M than in SPF-M. The majority of CA was a biologically active, free form in SPF-M, whereas it was a biologically inactive, conjugated form in GF-M. The association of GF-M with either Clostridium species or SPF fecal flora, both of which have abundant β-glucuronidase activity, resulted in the drastic elevation of free CA. The inoculation of E. coli strain into GF-M induced a substantial amount of free CA, but the inoculation of its mutant strain deficient in the β-glucuronidase gene did not. The intraluminal administration of DA increased colonic water absorption in an in vivo ligated loop model of SPF-M, thus suggesting that luminal DA plays a role as a proabsorptive modulator of water transport in the colon. These results indicate that gut microbiota play a critical role in the generation of free CA in the gut lumen.

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.

Commensal microbiota modulate murine behaviors in a strictly contamination-free environment confirmed by culture-based methods

There is increasing evidence suggesting the existence of an interaction between commensal microbiota, the gut and the brain. The aim of this study was to examine the influence of commensal microbiota on the host behaviors in a contamination‐free environment, which was verified by culture‐based methods.

The effects of psychological intervention on atopic dermatitis. A systematic review and meta-analysis.

Background: Psychological interventions may be valuable in atopic dermatitis. We systematically reviewed and carried out a meta-analysis of randomized controlled trials of psychological interventions. Methods: Electronic searches and manual journal searches were carried out. Two coders independently coded study designs, participants, treatments and outcome characteristics of the studies meeting the selection criteria. Results: Eight journal articles published between 1986 and 2006 were included. Eight types of intervention were tested: aromatherapy, autogenic training, brief dynamic psychotherapy, cognitive-behavioral therapy, dermatological education and cognitive-behavioral therapy, habit reversal behavioral therapy, a stress management program, and structured educational programs. Effect sizes were computed as correlation coefficient (r), and random effects models were used in the analysis. For eczema severity, the average effect size for the 8 trials including 8 interventions was –0.367 [χ2(1) = 7.452, p = 0.006; 95% CI –0.579 to –0.108]. The average effect sizes on itching intensity (5 trials with 5 interventions) and scratching (5 trials with 4 interventions) were –0.805 [χ2(1) = 4.719, p = 0.030; 95% CI –0.971 to –0.108] and –0.620 [χ2(1) = 24.24, p < 0.0001; 95% CI –0.767 to –0.410], respectively. Conclusions: Although the present meta-analysis revealed that psychological interventions had a significant ameliorating effect on eczema severity, itching intensity and scratching in atopic dermatitis patients, a definite conclusion about their effectiveness seems premature. Accordingly, future studies should involve more sophisticated methodologies, use established measures of outcome variables, adjust for possible confounders between the intervention and control groups, and provide sufficient data to calculate the effect sizes for future meta-analyses.

Restraint stress elevates the plasma interleukin-6 levels in germ-free mice.

Several recent reports demonstrated that restraint stress elevates plasma IL-6 levels; however, the precise mechanism whereby stress stimuli trigger the production of IL-6 remains to be clarified. In this study, in order to elucidate whether or not the intestinal microflora contribute to the stress-induced IL-6 elevation, the plasma IL-6 response of germ-free (GF) mice, which are indeed devoid of indigenous microflora, was compared to that of specific pathogen-free (SPF) mice. The plasma IL-6 level increased after 1 h of restraint stress and thereafter gradually decreased in GF mice as well as in SPF mice. In addition, such a stress-induced IL-6 elevation was also found in the mice reconstituted with SPF feces. The expression levels of IL-6 mRNA in the liver increased after 1 h of stress in both GF and SPF mice based on the findings of a semiquantitative RT-PCR method, although no such increase was observed in the spleen and kidney of both groups of mice. These results thus indicate that restraint stress is capable of elevating the plasma IL-6 levels independently of the intestinal microflora and the liver is one of the main sources responsible for the increased plasma IL-6 during stress.

The restraint stress-induced reduction in lymphocyte cell number in lymphoid organs correlates with the suppression of in vivo antibody production

In this study, we examined the effects of restraint stress on some immune parameters such as the in vivo antibody levels, cytokine production, and lymphocyte cell number in the spleen or mesenteric lymph node (MLN). BALB/c mice were thus injected intraperitoneally 2-times with OVA absorbed into alum on days 0 and 21. Before the first injection, the animals were either restrained for 12 h (stress group) or returned to their home cage (control group). Exposure to stress resulted in a reduction in the serum levels of anti-OVA IgE, IgG1, and IgG2a. In addition, stress also caused a decrease in the IL-4 and IFN-gamma levels in the spleen or mesenteric lymph node cell culture supernatants. Furthermore, exposure to stress resulted in a decrease in the splenic and mesenteric lymphocyte cell number when examined immediately after the cessation of stress. This decrease persisted for at least 12 h after the termination of stress and thereafter disappeared 24 h after stress. The stress-induced reductions in antibody and cytokine production occurred only when antigen was given either immediately or 6 h after stress, but not when antigen was given 24 h post stress. These results thus suggest that the restraint stress-induced change in lymphocyte cell number in the spleen or MLN closely correlates with the altered antibody and cytokine levels.

Social defeat stress induces hyperthermia through activation of thermoregulatory sympathetic premotor neurons in the medullary raphe region

Psychological stress‐induced hyperthermia is a fundamental autonomic response in mammals. However, the central circuitry underlying this stress response is poorly understood. Here, we sought to identify sympathetic premotor neurons that mediate a hyperthermic response to social defeat stress, a psychological stress model. Intruder rats that were defeated by a dominant resident conspecific exhibited a rapid increase in abdominal temperature by up to 2.0 °C. In these defeated rats, we found that expression of Fos, a marker of neuronal activation, was increased in the rostral medullary raphe region centered in the rostral raphe pallidus and adjacent raphe magnus nuclei. In this region, Fos expression was observed in a large population of neurons expressing vesicular glutamate transporter 3 (VGLUT3), which are known as sympathetic premotor neurons controlling non‐shivering thermogenesis in brown adipose tissue (BAT) and thermoregulatory constriction of skin blood vessels, and also in a small population of tryptophan hydroxylase‐positive serotonergic neurons. Intraperitoneal injection of diazepam, an anxiolytic agent, but not indomethacin, an antipyretic, significantly reduced both the stress‐induced hyperthermia and Fos expression in these medullary raphe neuronal populations. Systemic blockade of β3‐adrenoreceptors, which are abundantly expressed in BAT, also attenuated the stress‐induced hyperthermia. These results suggest that psychological stress signals activate VGLUT3‐expressing medullary raphe sympathetic premotor neurons, which then drive hyperthermic effector responses including BAT thermogenesis through β3‐adrenoreceptors.

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.

Profile of mood states and stress-related biochemical indices in long-term yoga practitioners

BackgroundPrevious studies have shown the short-term or intermediate-term practice of yoga to be useful for ameliorating several mental disorders and psychosomatic disorders. However, little is known about the long-term influences of yoga on the mental state or stress-related biochemical indices. If yoga training has a stress-reduction effect and also improves an individuals mental states for a long time, long-term yoga practitioners may have a better mental state and lower stress-related biochemical indices in comparison to non-experienced participants. This study simultaneously examined the differences in mental states and urinary stress-related biochemical indices between long-term yoga practitioners and non-experienced participants.MethodsThe participants were 38 healthy females with more than 2 years of experience with yoga (long-term yoga group) and 37 age-matched healthy females who had not participated in yoga (control group). Their mental states were assessed using the Profile of Mood States (POMS) questionnaire. The level of cortisol, 8-hydroxydeoxyguanosine (8-OHdG) and biopyrrin in urine were used as stress-related biochemical indices.ResultsThe average self-rated mental disturbance, tension-anxiety, anger-hostility, and fatigue scores of the long-term yoga group were lower than those of the control group. There was a trend toward a higher vigor score in the long-term yoga group than that in the control group. There were no significant differences in the scores for depression and confusion in the POMS between the two groups. The urine 8-OHdG concentration showed a trend toward to being lower in the long-term yoga group in comparison to the control group. There were no significant differences in the levels of urine biopyrrin or cortisol.ConclusionsThe present findings suggest that long-term yoga training can reduce the scores related to mental health indicators such as self-rated anxiety, anger, and fatigue.