Probiotics normalize the gut-brain-microbiota axis in immunodeficient mice.

The gut-brain-microbiota axis is increasingly recognized as an important regulator of intestinal physiology. Exposure to psychological stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis and causes altered intestinal barrier function, intestinal dysbiosis, and behavioral changes. The primary aim of this study was to determine whether the effects of psychological stress on intestinal physiology and behavior, including anxiety and memory, are mediated by the adaptive immune system. Furthermore, we wanted to determine whether treatment with probiotics would normalize these effects. Here we demonstrate that B and T cell-deficient Rag1(-/-) mice displayed altered baseline behaviors, including memory and anxiety, accompanied by an overactive HPA axis, increased intestinal secretory state, dysbiosis, and decreased hippocampal c-Fos expression. Both local (intestinal physiology and microbiota) and central (behavioral and hippocampal c-Fos) changes were normalized by pretreatment with probiotics, indicating an overall benefit on health conferred by changes in the microbiota, independent of lymphocytes. Taken together, these findings indicate a role for adaptive immune cells in maintaining normal intestinal and brain health in mice and show that probiotics can overcome this immune-mediated deficit in the gut-brain-microbiota axis.

Relationship between the induction of inflammatory processes and infectious diseases in patients with ischemic stroke.

Pro-inflammatory cytokines participate in the induction of ischemic stroke. So far, their participation in the cerebral ischemia was proven for the tumor necrosis factor TNF-α, interleukin-1 (IL-1), and interleukin-6 (IL-6). The release of the pro-inflammatory cytokines into the extracellular space causes the enlargement of the brain damage region, and consequently increases the neurological deficit and negatively affects the survival rate prognoses. That is confirmed by the increased concentration of pro-inflammatory cytokines in blood and the cerebrospinal fluid of patients with brain stroke, as well as by the research on the induced/experimental cerebral ischemia in animals. The pro-inflammatory cytokines participate in the migration of the reactive T lymphocytes to the regions of brain ischemia where they enhance the nerve tissue damage by down-regulation of microcirculation, induce the pro-thrombotic processes and release other neurotoxic cytokines. Also, in the early stage of cerebral ischemia, cytokines activate the axis hypothalamus-pituitary gland-adrenal cortex and increase the cortisol concentration in blood, what results in the decreased resistance to infectious diseases. Administration of the inhibitor of the interleukin-1 receptor (IL-1Ra) inhibits the inflammatory processes in the region of brain ischemia, and subsequently improves the prognosis for the size of the neurological deficit and the survival rate, as well as resistance to infectious diseases.

[Endocytosymbiosis of microorganisms in mammal eukaryotic cells and factors of its regulation].

Morphofunctional equivalents of the process of long-term intracellular prokaryotes--eukaryotes interaction were studied by light and electron microscopy. The mechanisms for adaptation, elaborated in the course of evolution of bacteria-host interaction, were analysed on the ultrastructural level. A concept on the role of hypothalamic nonapeptides, as factors of regulation of intracellular persistence and symbiosis of prokaryotes, is discussed.

Hypothalamus-pituitary-adrenal axis during Trypanosoma cruzi acute infection in mice.

Functional interactions between neuroendocrine and immune systems are mediated by similar ligands and receptors, which establish a bi-directional communication that is relevant for homeostasis. We investigated herein the hypothalamus-pituitary-adrenal (HPA) axis in mice acutely infected by Trypanosoma cruzi, the causative agent of Chagas' disease. Parasites were seen in the adrenal gland, whereas T. cruzi specific PCR gene amplification product was found in both adrenal and pituitary glands of infected mice. Histological and immunohistochemical analyses of pituitary and adrenal glands of infected animals revealed several alterations including vascular stasis, upregulation of the extracellular matrix proteins fibronectin and laminin, as well as T cell and macrophage infiltration. Functionally, we detected a decrease in CRH and an increase in corticosterone contents, in hypothalamus and serum respectively. In contrast, we did not find significant changes in the amounts of ACTH in sera of infected animals, whereas the serum levels of the glucocorticoid-stimulating cytokine, IL-6 (interleukin-6), were increased as compared to controls. When we analyzed the effects of T. cruzi in ACTH-producing AtT-20 cell line, infected cultures presented lower levels of ACTH and pro-opiomelanocortin production when compared to controls. In these cells we observed a strong phosphorylation of STAT-3, together with an increased synthesis of IL-6, suppressor of cytokine signaling 3 (SOCS-3) and inhibitor of activated STAT-3 (PIAS-3), which could explain the partial blockage of ACTH production. In conclusion, our data reveal that the HPA axis is altered during acute T. cruzi infection, suggesting direct and indirect influences of the parasite in the endocrine homeostasis.

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.

Suppression of host resistance to Listeria monocytogenes by acute cold/restraint stress: lack of direct IL-6 involvement.

We conducted kinetic studies to evaluate the effects of acute cold/restraint stress (ACRS) on both primary and secondary host resistance to Listeria monocytogenes (LM). The involvement of IL-6 also was investigated using IL-6 knockout (KO) mice on the BALB/c background. ACRS dramatically increased the serum corticosterone levels, indicating that ACRS activated the hypothalamic-pituitary-adrenal (HPA) axis. ACRS significantly inhibited host resistance to LM during a primary but not a secondary LM infection. During the primary infection, ACRS caused a significant delay in clearance of LM, loss of body weight, reduced food/water intake, and elevated levels of pro-inflammatory cytokines (IL-6, IL-1beta, and TNFalpha) and IFNgamma. ACRS IL-6 KO mice showed higher LM burdens than did IL-6 KO controls, suggesting that IL-6 is not required for the ACRS-impairment of host resistance. Elevated levels of IL-1beta and TNFalpha may compensate for the absence of IL-6 and maintain the ACRS-induced impairment, in that the serum and splenic IL-1beta and TNFalpha levels were significantly higher in infected ACRS IL-6 KO mice, but not in control IL-6 KO mice, as compared to respective wild type controls. ACRS appears to inhibit IL-6 independent mechanisms associated with innate immunity and/or the development of adaptive immunity, but these reactions are unable to modulate the more efficient secondary immune responses.

Differential immune responses in mice with left- and right-turning preference.

Humoral and cell-mediated immune responses of inbred BALB/c male mice were assayed for differential reactivities associated with behavioral sidedness, which was evaluated by spontaneous rotational behavior in a circular cage model system. Mice with left-turning preference had lower in vivo primary IgM and IgG anti-Keyhole Limpet Hemocyanin (KLH) antibody responses, delayed-type hypersensitivity (DTH) responses, and host-resistance against the intracellular bacteria, Listeria monocytogenes, than mice with right-turning preference. The only immune parameter not shown to be associated with turning preference was the secondary humoral immune response to KLH. The weak innate immune response of left-turners for clearance of Listeria showed close intercorrelation with elevated serum IL-6 levels. Serum corticosterone and splenic norepinephrine levels were differentially increased and decreased by infection, respectively. We suggest that the observed differential immune reactivities of individual animals with same age, gender, and genetic background are associated with functional asymmetries within the brain, that the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic innervation are involved in the regulatory brain: immune interconnection after infection, and that the HPA axis and sympathetic nervous system are involved in the brain laterality effects on immune responses.

Failure to thrive, wasting syndrome, and immunodeficiency in rabies: a hypophyseal/hypothalamic/thymic axis effect of rabies virus.

Studies of rabies virus in several animal models consistently showed hypothalamic infection, hypophyseal infection, dramatic growth impairment (in the form of failure to thrive), wasting syndrome, and immune depletion. Rabies virus infection was studied through routine monoclonal antinucleocapsid antibody immunofluorescence and through a peroxidase-antiperoxidase immunoperoxidase method. The latter was modified to detect the in situ production of growth hormone by uninfected and rabies virus-infected adeno-a-pituicytes (with confirmation of the results both in vivo and in vitro). Infection with rabies virus made the specialized pituicytes produce less growth hormone. Growth before rabies virus infection and its reduction due to infection were investigated in a linear regression model. The fit was statistically significant (P less than .05) in all species studied: mouse, rat, rabbit, cow, and cat. Immune depression was studied in terms of alterations in the immunotopography of the thymus and also the specific T- and B-cell homing areas of the spleen (although spleen data are not presented here). On the basis of these results and a thorough review of wasting syndromes encountered in other diseases, a primary failure to thrive and an ensuing wasting syndrome were described and characterized for rabies, and their origin was assigned to a dysfunction of the hypophyseal/hypothalamic/thymic axis associated with at least (but not necessarily only) one of the centrally controlled growth hormones.