Understanding the Connection between Gut Homeostasis and Psychological Stress.

Long-term exposure to adverse life events that provoke acute or chronic psychological stress (hereinafter "stress") can negatively affect physical health and even increase susceptibility to psychological illnesses, such as anxiety and depression. As a part of the hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor (CRF) released from the hypothalamus is primarily responsible for the stress response. Typically, CRF disrupts the gastrointestinal system and leads to gut microbiota dysbiosis, thereby increasing risk of functional gastrointestinal diseases, such as irritable bowel syndrome. Furthermore, CRF increases oxidative damage to the colon and triggers immune responses involving mast cells, neutrophils, and monocytes. CRF even affects the differentiation of intestinal stem cells (ISCs), causing enterochromaffin cells to secrete excessive amounts of 5-hydroxytryptamine (5-HT). Therefore, stress is often accompanied by damage to the intestinal epithelial barrier function, followed by increased intestinal permeability and bacterial translocation. There are multi-network interactions between the gut microbiota and stress, and gut microbiota may relieve the effects of stress on the body. Dietary intake of probiotics can provide energy for ISCs through glycolysis, thereby alleviating the disruption to homeostasis caused by stress, and it significantly bolsters the intestinal barrier, alleviates intestinal inflammation, and maintains endocrine homeostasis. Gut microbiota also directly affect the synthesis of hormones and neurotransmitters, such as CRF, 5-HT, dopamine, and norepinephrine. Moreover, the Mediterranean diet enhances the stress resistance to some extent by regulating the intestinal flora. This article reviews recent research on how stress damages the gut and microbiota, how the gut microbiota can improve gut health by modulating injury due to stress, and how the diet relieves stress injury by interfering with intestinal microflora. This review gives insight into the potential role of the gut and its microbiota in relieving the effects of stress via the gut-brain axis.

Saccharomyces boulardii improves the behaviour and emotions of spastic cerebral palsy rats through the gut-brain axis pathway.

BACKGROUND: Cerebral palsy (CP) is a kind of disability that influences motion, and children with CP also exhibit depression-like behaviour. Inflammation has been recognized as a contributor to CP and depression, and some studies suggest that the gut-brain axis may be a contributing factor. Our team observed that Saccharomyces boulardii (S. boulardii) could reduce the inflammatory level of rats with hyperbilirubinemia and improve abnormal behaviour. Both CP and depression are related to inflammation, and probiotics can improve depression by reducing inflammation. Therefore, we hypothesize that S. boulardii may improve the behaviour and emotions of spastic CP rats through the gut-brain axis pathway. METHODS: Our new rat model was produced by resecting the cortex and subcortical white matter. Seventeen-day-old CP rats were exposed to S. boulardii or vehicle control by gastric gavage for 9 days, and different behavioural domains and general conditions were tested. Inflammation was assessed by measuring the inflammatory markers IL-6 and TNF-α. Hypothalamic-pituitary-adrenal (HPA) axis activity was assessed by measuring adrenocorticotropic hormone and corticosterone in the serum. Changes in the gut microbiome were detected by 16S rRNA. RESULTS: The hemiplegic spastic CP rats we made with typical spastic paralysis exhibited depression-like behaviour. S. boulardii treatment of hemiplegic spastic CP rats improves behaviour and general conditions and significantly reduces the level of inflammation, decreases HPA axis activity, and increases gut microbiota diversity. CONCLUSIONS: The model developed in this study mimics a hemiplegic spastic cerebral palsy. Damage to the cortex and subcortical white matter of 17-day-old Sprague-Dawley (SD) rats led to spastic CP-like behaviour, and the rats exhibited symptoms of depression-like behaviour. Our results indicate that S. boulardii might have potential in treating hemiplegic spastic CP rat models or as an add-on therapy via the gut-brain axis pathway.

Exploring the Role and Potential of Probiotics in the Field of Mental Health: Major Depressive Disorder.

The field of probiotic has been exponentially expanding over the recent decades with a more therapeutic-centered research. Probiotics mediated microbiota modulation within the microbiota-gut-brain axis (MGBA) have been proven to be beneficial in various health domains through pre-clinical and clinical studies. In the context of mental health, although probiotic research is still in its infancy stage, the promising role and potential of probiotics in various mental disorders demonstrated via in-vivo and in-vitro studies have laid a strong foundation for translating preclinical models to humans. The exploration of the therapeutic role and potential of probiotics in major depressive disorder (MDD) is an extremely noteworthy field of research. The possible etio-pathological mechanisms of depression involving inflammation, neurotransmitters, the hypothalamic-pituitary-adrenal (HPA) axis and epigenetic mechanisms potentially benefit from probiotic intervention. Probiotics, both as an adjunct to antidepressants or a stand-alone intervention, have a beneficial role and potential in mitigating anti-depressive effects, and confers some advantages compared to conventional treatments of depression using anti-depressants.

Psychobiotics: Mechanisms of Action, Evaluation Methods and Effectiveness in Applications with Food Products.

The gut-brain-microbiota axis consists of a bilateral communication system that enables gut microbes to interact with the brain, and the latter with the gut. Gut bacteria influence behavior, and both depression and anxiety symptoms are directly associated with alterations in the microbiota. Psychobiotics are defined as probiotics that confer mental health benefits to the host when ingested in a particular quantity through interaction with commensal gut bacteria. The action mechanisms by which bacteria exert their psychobiotic potential has not been completely elucidated. However, it has been found that these bacteria provide their benefits mostly through the hypothalamic-pituitary-adrenal (HPA) axis, the immune response and inflammation, and through the production of neurohormones and neurotransmitters. This review aims to explore the different approaches to evaluate the psychobiotic potential of several bacterial strains and fermented products. The reviewed literature suggests that the consumption of psychobiotics could be considered as a viable option to both look after and restore mental health, without undesired secondary effects, and presenting a lower risk of allergies and less dependence compared to psychotropic drugs.

Gut Microbiota: A Perspective for Psychiatrists.

There is mounting evidence that the trillions of microbes that inhabit our gut are a substantial contributing factor to mental health and, equally, to the progression of neuropsychiatric disorders. The extraordinary complexity of the gut ecosystem, and how it interacts with the intestinal epithelium to manifest physiological changes in the brain to influence mood and behaviour, has been the subject of intense scientific scrutiny over the last 2 decades. To further complicate matters, we each harbour a unique microbiota community that is subject to change by a number of factors including diet, exercise, stress, health status, genetics, medication, and age, amongst others. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the gastrointestinal (GI) microbiota, immune cells, gut tissue, glands, the autonomic nervous system (ANS), and the brain that communicate in a complex multidirectional manner through a number of anatomically and physiologically distinct systems. Long-term perturbations to this homeostatic environment may contribute to the progression of a number of disorders by altering physiological processes including hypothalamic-pituitary-adrenal axis activation, neurotransmitter systems, immune function, and the inflammatory response. While an appropriate, co-ordinated physiological response, such as an immune or stress response, is necessary for survival, a dysfunctional response can be detrimental to the host, contributing to the development of a number of central nervous system disorders.

Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus.

Gut microbiota has an important role in the immune system, metabolism, and digestion, and has a significant effect on the nervous system. Recent studies have revealed that abnormal gut microbiota induces abnormal behaviors, which may be associated with the hypothalamic-pituitary-adrenal (HPA) axis. Therefore, we investigated the behavioral changes in germ-free (GF) mice by behavioral tests, quantified the basal serum cortisol levels, and examined glucocorticoid receptor pathway genes in hippocampus using microarray analysis followed by real-time PCR validation, to explore the molecular mechanisms by which the gut microbiota influences the host's behaviors and brain function. Moreover, we quantified the basal serum cortisol levels and validated the differential genes in an Escherichia coli-derived lipopolysaccharide (LPS) treatment mouse model and fecal "depression microbiota" transplantation mouse model by real-time PCR. We found that GF mice showed antianxiety- and antidepressant-like behaviors, whereas E. coli LPS-treated mice showed antidepressant-like behavior, but did not show antianxiety-like behavior. However, "depression microbiota" recipient mice exhibited anxiety- and depressive-like behaviors. In addition, six glucocorticoid receptor pathway genes (Slc22a5, Aqp1, Stat5a, Ampd3, Plekhf1, and Cyb561) were upregulated in GF mice, and of these only two (Stat5a and Ampd3) were upregulated in LPS-treated mice, whereas the shared gene, Stat5a, was downregulated in "depression microbiota" recipient mice. Furthermore, basal serum cortisol levels were decreased in E. coli LPS-treated mice but not in GF mice and "depression microbiota" recipient mice. These results indicated that the gut microbiota may lead to behavioral abnormalities in mice through the downstream pathway of the glucocorticoid receptor. Herein, we proposed a new insight into the molecular mechanisms by which gut microbiota influence depressive-like behavior.

Microbiota affects the expression of genes involved in HPA axis regulation and local metabolism of glucocorticoids in chronic psychosocial stress.

The commensal microbiota affects brain functioning, emotional behavior and ACTH and corticosterone responses to acute stress. However, little is known about the role of the microbiota in shaping the chronic stress response in the peripheral components of the hypothalamus-pituitary-adrenocortical (HPA) axis and in the colon. Here, we studied the effects of the chronic stress-microbiota interaction on HPA axis activity and on the expression of colonic corticotropin-releasing hormone (CRH) system, cytokines and 11ß-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme that determines locally produced glucocorticoids. Using specific pathogen-free (SPF) and germ-free (GF) BALB/c mice, we showed that the microbiota modulates emotional behavior in social conflicts and the response of the HPA axis, colon and mesenteric lymph nodes (MLN) to chronic psychosocial stress. In the pituitary gland, microbiota attenuated the expression of Fkbp5, a gene regulating glucocorticoid receptor sensitivity, while in the adrenal gland, it attenuated the expression of genes encoding steroidogenesis (MC2R, StaR, Cyp11a1) and catecholamine synthesis (TH, PNMT). The pituitary expression of CRH receptor type 1 (CRHR1) and of proopiomelanocortin was not influenced by microbiota. In the colon, the microbiota attenuated the expression of 11HSD1, CRH, urocortin UCN2 and its receptor, CRHR2, but potentiated the expression of cytokines TNFα, IFNγ, IL-4, IL-5, IL-6, IL-10, IL-13 and IL-17, with the exception of IL-1ß. Compared to GF mice, chronic stress upregulated in SPF animals the expression of pituitary Fkbp5 and colonic CRH and UCN2 and downregulated the expression of colonic cytokines. Differences in the stress responses of both GF and SPF animals were also observed when immunophenotype of MLN cells and their secretion of cytokines were analyzed. The data suggest that the presence of microbiota/intestinal commensals plays an important role in shaping the response of peripheral tissues to stress and indicates possible pathways by which the environment can interact with glucocorticoid signaling.

Interactions Between Stress and Sex in Microbial Responses Within the Microbiota-Gut-Brain Axis in a Mouse Model.

OBJECTIVE: Animal models are frequently used to examine stress response, but experiments seldom include females. The connection between the microbiota-gut-brain axis and behavioral stress response is investigated here using a mixed-sex mouse cohort. METHODS: CF-1 mice underwent alternating days of restraint and forced swim for 19 days (male n = 8, female n = 8) with matching numbers of control animals at which point the 16S rRNA genes of gut microbiota were sequenced. Mixed linear models accounting for stress status and sex with individuals nested in cage to control for cage effects evaluated these data. Murine behaviors in elevated plus-maze, open-field, and light/dark box were investigated. RESULTS: Community-level associations with sex, stress, and their interaction were significant. Males had higher microbial diversity than females (p = .025). Of the 638 operational taxonomic units detected in at least 25% of samples, 94 operational taxonomic units were significant: 31 (stress), 61 (sex), and 34 (sex-stress interaction). Twenty of the 39 behavioral measures were significant for stress, 3 for sex, and 6 for sex-stress. However, no significant associations between behavioral measures and specific microbes were detected. CONCLUSIONS: These data suggest sex influences stress response and the microbiota-gut-brain axis and that studies of behavior and the microbiome therefore benefit from consideration of how sex differences drive behavior and microbial community structure. Host stress resilience and absence of associations between stress-induced behaviors with specific microbes suggests that hypothalamic-pituitary-adrenal axis activation represents a threshold for microbial influence on host behavior. Future studies are needed in examining the intersection of sex, stress response, and the microbiota-gut-brain axis.

Role of the Hypothalamic-Pituitary-Adrenal Axis in Health and Disease.

The Hypothalamic-Pituitary-adrenal (HPA) axis describes a complex set of positive and negative feedback influences between the hypothalamus, pituitary gland, and adrenal gland.[...].

Microbiota Signaling Pathways that Influence Neurologic Disease.

Though seemingly distinct and autonomous, emerging evidence suggests there is a bidirectional interaction between the intestinal microbiota and the brain. This crosstalk may play a substantial role in neurologic diseases, including anxiety, depression, autism, multiple sclerosis, Parkinson's disease, and, potentially, Alzheimer's disease. Long hypothesized by Metchnikoff and others well over 100 years ago, investigations into the mind-microbe axis is now seeing a rapid resurgence of research. If specific pathways and mechanisms of interaction are understood, it could have broad therapeutic potential, as the microbiome is environmentally acquired and can be modified to promote health. This review will discuss immune, endocrine, and neural system pathways that interconnect the gut microbiota to central nervous system and discuss how these findings might be applied to neurologic disease.

Gut Microbiota and the Neuroendocrine System.

The microbial ecosystem that inhabits the gastrointestinal tract of all mammals-the gut microbiota-has been in a symbiotic relationship with its hosts over many millennia. Thanks to modern technology, the myriad of functions that are controlled or modulated by the gut microbiota are beginning to unfold. One of the systems that is emerging to closely interact with the gut microbiota is the body's major neuroendocrine system that controls various body processes in response to stress, the hypothalamic-pituitary-adrenal (HPA) axis. This interaction is of pivotal importance; as various disorders of the microbiota-gut-brain axis are associated with dysregulation of the HPA axis. The present contribution describes the bidirectional communication between the gut microbiota and the HPA axis and delineates the potential underlying mechanisms. In this regard, it is important to note that the communication between the gut microbiota and the HPA axis is closely interrelated with other systems, such as the immune system, the intestinal barrier and blood-brain barrier, microbial metabolites, and gut hormones, as well as the sensory and autonomic nervous systems. These communication pathways will be exemplified through preclinical models of early life stress, beneficial roles of probiotics and prebiotics, evidence from germ-free mice, and antibiotic-induced modulation of the gut microbiota.

Microbiota Modulate Anxiety-Like Behavior and Endocrine Abnormalities in Hypothalamic-Pituitary-Adrenal Axis.

Intestinal microbes are an important system in the human body, with significant effects on behavior. An increasing body of research indicates that intestinal microbes affect brain function and neurogenesis, including sensitivity to stress. To investigate the effects of microbial colonization on behavior, we examined behavioral changes associated with hormones and hormone receptors in the hypothalamic-pituitary-adrenal (HPA) axis under stress. We tested germ-free (GF) mice and specific pathogen-free (SPF) mice, divided into four groups. A chronic restraint stress (CRS) protocol was utilized to induce external pressure in two stress groups by restraining mice in a conical centrifuge tube for 4 h per day for 21 days. After CRS, Initially, GF restraint-stressed mice explored more time than SPF restraint-stressed mice in the center and total distance of the OFT. Moreover, the CRH, ACTH, CORT, and ALD levels in HPA axis of GF restraint-stressed mice exhibited a significantly greater increase than those of SPF restraint-stressed mice. Finally, the Crhr1 mRNA levels of GF CRS mice were increased compared with SPF CRS mice. However, the Nr3c2 mRNA levels of GF CRS mice were decreased compared with SPF CRS mice. All results revealed that SPF mice exhibited more anxiety-like behavior than GF mice under the same external stress. Moreover, we also found that GF mice exhibited significant differences in, hormones, and hormone receptors compared with SPF mice. In conclusion, Imbalances of the HPA axis caused by intestinal microbes could affect the neuroendocrine system in the brain, resulting in an anxiety-like behavioral phenotype. This study suggested that intervention into intestinal microflora may provide a new approach for treating stress-related diseases.

[Gut microbiome and major depressive disorder : The other side of ourselves]. / Dickdarmmikrobiom und Depression : Die andere Seite unseres Selbst.

Microbiological ecology and its ambition to describe the complete genome of complex living communities as a whole, have given us powerful tools to characterize the human gut microbiome on a genetic and, hence, taxonomic and abundance level; for a decade now, they have become sufficiently inexpensive, fast and feasible. Thus, opportunities arose to have a fresh and closer look at the microbiota-gut-brain-axis and its impact on human health; this axis comprises a complex multisystemic network of multidirectional interactions between brain and gut including influences beyond one generation. Gnotobiotic animal models have become essential for specific research targets. Combining gut microbiome analysis with observations on the hypothalamus-pituitary-adrenal axis and various aspects of inflammation helped to gain first insights into the role of the microbiota-gut-brain-axis in depressive disorders. Therapeutic endeavors with psychobiotics have not yet shown their value in clinical studies.

Prospective investigation of the hypothalamo-pituitary-adrenal axis in patients with tularemia.

BACKGROUND/AIM: To investigate prospectively the hypothalamo-pituitary-adrenal (HPA) axis by adrenocorticotropic hormone (ACTH) stimulation test. MATERIALS AND METHODS: Tularemia was diagnosed according to guidelines. An ACTH stimulation test (1 µg) and a dexamethasone suppression test (DST; 1 mg) were performed in patients in the acute phase of tularemia before antibiotic treatment and in the chronic phase. RESULTS: Nineteen patients (mean age: 41.0 ± 13.2 years; 57.9% female) with tularemia were enrolled in the study in 2011 and 2012. Cortisol response to ACTH stimulation test was sufficient in all patients during the acute phase. After the DST, the cortisol was not suppressed during the acute phase in only one patient. The median control time of 11 patients after acute tularemia was 13 months. During the chronic phase, cortisol response to ACTH stimulation was normal in all patients, and after DST cortisol was suppressed in all patients. The peak cortisol level after the ACTH stimulation test in the acute phase was higher than that in the chronic phase, but the difference was not statistically significant. CONCLUSION: The HPA axis of patients with tularemia was not significantly affected in the acute and chronic phases.

Factors in Early-Life Programming of Reproductive Fitness.

Fertility rates have been declining worldwide, with a growing number of young women suffering from infertility. Infectious and inflammatory diseases are important causes of infertility, and recent evidence points to the critical role of the early-life microbial environment in developmental programming of adult reproductive fitness. Our laboratory and others have demonstrated that acute exposure to an immunological challenge early in life has a profound and prolonged impact on male and female reproductive development. This review presents evidence that perinatal exposure to immunological challenge by a bacterial endotoxin, lipopolysaccharide, acts at all levels of the hypothalamic-pituitary-gonadal axis, resulting in long-lasting changes in reproductive function, suggesting that disposition to infertility may begin early in life.

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.

Role of microbiome in regulating the HPA axis and its relevance to allergy.

There has been an increasing and intense interest in the role that gut bacteria play in maintaining the health of the host. Gut microbiota have an estimated mass of 1-2 kg, number 100 trillion and together possess 100 times the number of genes in the human genome. In addition to their well-established role in the postnatal maturation of the mammalian immune system, they are also responsible for an enormous array of metabolic activities that include effects on the digestion of food and the production of a host of biologically active substances. Moreover, it is also rapidly becoming apparent that the gut microbiome plays a major role in the development and regulation of neuroendocrine systems such as the hypothalamic-pituitary-adrenal axis, a central integrative system crucial for the successful physiological adaptation of the organism to stress. In fact, our previous study on gnotobiotic mice demonstrated that exposure to gut microbes is a postnatal environmental determinant that regulates the development of the hypothalamic-pituitary-adrenal axis stress response and also the set point for this axis.

[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.