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There is an important relationship between probiotics, psychobiotics and cognitive and behavioral processes, which include neurological, metabolic, hormonal and immunological signaling pathways; the alteration in these systems may cause alterations in behavior (mood) and cognitive level (learning and memory). Psychobiotics have been considered key elements in affective disorders and the immune system, in addition to their effect encompassing the regulation of neuroimmune regulation and control axes (the hypothalamic-pituitary-adrenal axis or HPA, the sympathetic-adrenal-medullary axis or SAM and the inflammatory reflex) in diseases of the nervous system.
- probiotics
- microbiota
- beneficial bacteria
- psychobiotics
- human health
1. Introduction
The skin and mucosal surfaces of vertebrates contain a wide collection of microorganisms (collectively named microbiota) which includes bacteria, fungi, parasites and viruses. The human gut harbors one of the most complex and abundant ecosystems composed of up to 1013–1014 microorganisms which is between 1 to 10 times more than the number of eukaryotic cells in the body [1,2]. The collective adult human gut microbiota is composed of a maximum of 500–1000 bacterial species [1,3,4].
Hundreds of years of co-evolution have led to a mutual symbiosis between the host and gut microbiome. Indeed, the gut is rich in molecules that can be used as nutrients by the microorganisms, favoring microbiota colonization [1]. Gut colonization begins at birth and is established in the first 3 years of life. The initial interaction between gut microbiota and the host is indispensable for the maturation of the nervous system, the immune system and for the developmental regulation of intestinal physiology [1,5,6]. At this stage, gut microbiota is also able to modulate the process of angiogenesis [7]. Furthermore, microorganisms also display anti-microbial activities, thus maintaining a stable gut ecosystem. Alterations in the process of microbial colonization of the human gut in early life have been shown to influence the risk of disease [8].
Later in life, microbial colonization of the intestine has a significant impact on the host neurophysiology, behavior and function of the nervous system [9,10,11]. Given the immunomodulatory properties of gut microbiota, it has been shown that different immune pathways, inside and outside the central nervous system (CNS) are involved in important mechanisms like microbial mediation of brain functions and behavior. It has been discovered that neuroimmune modulation by the microbiota is able to contribute to etio-pathogenesis or to display important signs and symptoms in neurodegenerative and behavioral disorders such as autism spectrum disorders (ASD), anxiety, depression, Alzheimer’s disease (AD) and Parkinson’s disease (PD) [9].
2. Axes of Neuroimmune Control and Regulation
It has been shown that there is an important neural control of the immune system [17]. A well-known principle of the physiology in mammals is that the nervous system is responsible for achieving homeostasis by modulating of the function of other systems in the body through the HPA axis, the inflammatory reflex, the enteric nervous system (ENS) and finally the brain-gut axis.
Microglia is the resident immune cell in the CNS which represents 5 to 20% of glial cells. It is a myeloid cell, phagocytic, and has the activity of an antigen presenting cell (APC). In addition, it releases cytokines and can activate inflammatory-type responses [18,19]. During the early development stage, the microglia “brand” and “clean” synapses through a process called “synaptic pruning”, promotes the “wiring” of neuronal circuits and releases cytokines and chemokines that assist and guide the process of neuronal differentiation [18,20]. The microbiota has a direct influence on the maturation and function of the microglia. In germ-free (GF)-animals, the microglia display a longer development process and with more derivations, with high levels in the expression of receptor-1 of the colony stimulating factor (CSF1R), F4/80 and CD31, factors that decrease in expression during development. This suggests that there is an important effect of the microbiota on the microglia, which depends on the stage of development and/or the time of microbial colonization.
The microglia of adult GF-mice can be functionally damaged when there are alterations caused by lipopolysaccharide (LPS) or by lymphocytic choriomeningitis virus, which in turn causes alterations in the correct activation of the immune system, including an increase in the release of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. These functional deficits are consistent with the concept that the naive microglia of adult GF-mice has a significant decrease in the expression of several genes important to interferon (IFN)-mediated responses, in genes for innate immune responses and genes for viral defense response and effector processes [9,21].
The mechanisms through which intestinal microbes exert their influence on microglia in the brain are not clear but it seems that there is a “microglial modulation” according to a specific type of bacteria [9]. This has raised the question of whether the effects of microbiota on microglia are not regulated by bacteria in general, by the microbiome, or if very specific microbial species are required [9]. The alterations in the morphology of the microglia in GF-animals and the alteration in the expression of genes can be normalized thanks to the post-natal supplementation with short-chain fatty acids (SCFAs), which are products of bacterial fermentation [22,23], suggesting that the bacterial species producing SCFAs are able to restore the alterations that occur in the microglia in GF-mice or treated with antibiotics [9].
The coordination of information between neurons, microglia and the responses at the central level with the periphery is carried out through the different axes of regulation and control; the HPA axis, and the inflammatory reflex (Figure 1). The coordination of these defense responses is mediated by signaling pathways related to the hypothalamus, the pituitary gland and the adrenal glands (e.g., HPA-axis), which causes the release of chemical molecules capable of altering behavior, including glucocorticoids, mineralocorticoids, and catecholamines. The activity of the HPA-axis is regulated by multiple sympathetic, parasympathetic and limbic circuits (amygdala, hippocampus and medial prefrontal cortex) that will directly or indirectly activate the hypothalamic paraventricular nucleus (PVN) [24]. Under normal conditions HPA-axis activity exhibits continuous oscillatory activity synchronized with circadian as well as ultradian rhythms [25,26].
Figure 1. Regulation and control of neuroimmune axes. The three systems of regulation and control of information between the central nervous system (CNS) and the periphery are the hypothalamic pituitary adrenal (HPA)-axis, the sympatho-adrenal medullary (SAM)-axis and the inflammatory reflex. These systems are permanently sensing through nociceptive receptors and send information in real time to the CNS. ACTH, adrenocorticotropic hormone; NST Nucleus of the solitary tract; LC Locus coeruleus; TNF, tumor necrosis factor; IL, interleukin.
3. The Interaction of Microbiota with Enteric Nervous System and Brain-Gut Axes
In the last 10 years the importance of the brain-gut axis has been highlighted [50,51,52]. A connection has been established between the gut and the CNS, which is essential to achieve host homeostasis. It has been called the “brain-gut axis” or “GB axis” [53] (Figure 2). The brain-gut axis includes: the CNS, neuroendocrine and neuroimmune systems, the sympathetic and parasympathetic “arms” of the autonomic nervous system (ANS), the enteric nervous system (ENS) and noticeably the intestinal microbiota [29]. All these components interact and form a very complex network of reflexes, with afferent fibers (input) that project towards integrative structures of the CNS and efferent fibers (output) with projections towards the smooth muscle. This bi-directional communication network enables the sending of signals from the brain and influences the motor, sensory and secretory part of the gut, and conversely, visceral messages from the intestine can influence brain functions, especially in areas dedicated to the regulation of stress at the hypothalamic level [29].
Figure 2. Brain-Gut Axis. The brain-gut axis is essential for the regulation established between the intestine and the brain. It includes the central nervous system and the endocrine and neuroimmune systems; as well as the enteric nervous system. CRH, corticotropin-releasing hormone; CRF, corticotropin releasing factor; SCFAs, short chain fatty acids; ACTH, adrenocorticitropic hormone; HPA, hypothalamic pituitary adrenal.
The sympathetic nervous system (SNP) enables the selective presentation of enteric bacteria to the mucosal immune system. Nerve fibers containing NE have been identified very close to the epithelium surrounding the lymphoid follicles in the jejunum of pigs; the administration of NE increases the reception of pathogenic bacteria inside the follicles [7]. In this sense, it has been suggested that the release of biogenic amines, such as NE, can influence the composition of the intestinal microbiota. For instance, it has been observed that this neurotransmitter stimulates the growth of both pathogenic and nonpathogenic Escherichia coli in vitro, in addition to influencing its adherence to the mucous membranes [48,54,55]. Changes in the physiology of the host that originated within the gut or from signals from the CNS, produce changes in the bacterial composition of the gut [7].
The ENS is a complex neuronal network that involves multiple neurotransmitters such as 5-HT, Ach and CRF, where a prominent role is given to the CRF that is mediating changes at the level of gastrointestinal function. At the ENS level, this CRF demonstrates that peripheral pathways also play a preponderant role in the local regulation of the intestine and its function in states of stress [56]. The activation of CRF-1 receptor (CRFR1) in the intestine induced by stress increases the motility of the colon, defecation, permeability of the intestine and the sensation of visceral pain [57]. The activation of CRFR2 inhibits gastric emptying, suppresses the motor function of stimulating the colon and prevents hypersensitivity generated by colorectal distension. It has been proposed that CRFR2 may have a key role in stress-induced patency dysfunction and in mucosal immune modulation and in inflammatory responses in the colon [58]. CRF can directly activate mesenteric neurons to increase motility, permeability and stimulate diarrhea in rodents [59].
The contrasting actions of CRFR1 and CRFR2 are associated with differential expression patterns. CRFR2 is present in anterior regions of the intestinal tract [60], whereas CRFR1 is mostly distributed in the colon, and is expressed in a very important way in the cells of the colon mucosa [56]. The presence of CRFR2 in the colonic mucus has been demonstrated and it has been proposed that in this area it may also have an important role in the stress-induced patency dysfunction in the modulation of immune and inflammatory responses within the colon mucosa [61]. The evidence shows that stress causes the recruitment and activation of CRF receptors in the colon, which induces changes related to the same stress in the intestinal function and in turn causes an increase in sensitivity to stress that results in an altered expression of receptors to CRF [29].
5-HT is recognized as the most important biological substrate in the pathogenesis of mood disorders [62]. There is evidence of the role of serotonergic signaling in the neurobiology of anxiety [63,64]. In GF-mice, altered levels of 5-HT have been reported in the striatum and in the hippocampus, which suggest an association between the microbiota and serotonergic signaling [62]. In addition to its role as a neurotransmitter in the brain, monoamine 5-HT is a potent regulator in the gut. More than 90% of all 5-HT in the body is synthesized in the intestine, where it activates 14 different types of receptors located in enterocytes [65,66], in enteric neurons [67] and in cells of the immune system [68]. In addition, circulating platelets sequester 5-HT from the gut and release it for the purpose of distributing it in different parts of the body [69]. 5-HT derived from the intestine regulates various functions including motor and secretory reflexes, platelet aggregation, regulation of immune responses, bone development, and cardiac function [69]. A dysregulation of peripheral 5-HT levels is implicated in the pathogenesis of diseases such as irritable bowel syndrome (IBS), cardiovascular diseases [70] and in osteoporosis processes. The molecular mechanisms that control the metabolism of 5-HT at the intestinal level are still unclear, but it has been shown to be synthesized by specialized endocrine cells called enterochromaffin cells (ECs), as well as by mast cells of the mucosa and by mesenteric neurons (Figure 3) [69].
Figure 3. Serotoninergic system. The serotoninergic system is involved in the pathogenesis of diseases at the intestinal level, as well as in the regulation of different functions at a systemic level, which includes the regulation of memory processes, cognition and humor, among others. CNS, central nervous system; 5-HT, serotonin; ENS, enteric nervous system.
4. Behavior, Cognition, and Emotion
It has been demonstrated that bi-directional communication exists between the intestine and the brain and that it involves neurological, metabolic, hormonal and immunological signaling pathways; and that disturbance or alteration in these systems can result in altered behavior [83]. A clear example is intestinal inflammation, which has been associated with changes in bowel-brain interactions, as well as a high morbidity between inflammatory bowel disorder and anxiety states (Figure 4) [84].
Figure 4. Brain-Gut Homeostasis. The relationship between the intestine and the brain involves signaling pathways at a neural, metabolic, hormonal and immune system levels. The alteration in these pathways is capable of causing changes in cognitive and behavioral processes, as well as inducing inflammatory processes at the periphery level.
The role of microbiota has not only focused on the impact it exerts on the brain and central nervous function but also on how it is intimately related to the constitutive modulation of nerve function at the peripheral central level [71].
Stress has been defined as a very complex dynamic condition in which homeostasis or the internal “resting state” is altered or threatened [85,86]. Throughout life all organisms are exposed to factors that exceed the homeostatic threshold, which results in a stress response, which may be physical, psychological or immunological. Evolution has armed most organisms with the necessary biological machinery to mount a defense response to acute stressors and restore the homeostatic balance once the stress or damage has subsided [85].
A significant number of animal studies provide abundant evidence that the medial prefrontal cortex (MPFC) plays an important role in the regulation of stress circuitry [28]. While the ventral part of the MPFC has been augmented with a stimulatory role, the more dorsal part in contrast has been described to possess an activity of HPA-axis inhibition. It has been also described that this negative feedback mechanism is mediated by the inhibition of glucocorticoid receptors (GRs) in the MPFC [28]. The amygdala is a key region in the process of stress responses in addition to being an important target for the inhibitory feedback system by the MPFC [87]. In humans, the MPFC area is involved in the modulation of amygdala activity during emotional conflicts and in the regulation of autonomic and affective responses [28,88].
Stress, particularly in the early stages of life, is one of the major predictors of the onset of major depression disorder (MDD) [89]. Early exposure to stress and MDD is associated with a significant de-regularization of the HPA-axis and the stress/cortisol response system. Exposure to stressors, HPA-axis deregulation, elevated corticosteroid levels and major depression states are related to structural alterations in the hippocampus and amygdala, key regions in the regulation of the HPA-axis [90,91].
In one study of early life maternal separation, a group of male rats were submitted to stress tests [79]. They all showed the typical pattern: poor forced swim performance while the group that was separated also showed records of high IL-6 blood levels, low NE levels in brain and higher expression of CRF gene in the amygdala [92]. By administering L. rhamnosus R011 plus L. helveticus R0052, the rats downregulated their HPA axis and normalized their corticosterone levels [16,92].
Psychobiotics are now considered key elements in affective disorders. In one experiment with mice that were administered with L. rhamnosus, they featured lesser signs of anxiety and depression in forced swim and plus elevated maze respectively than their control counterparts, even at the same levels of corticosterone [16,93]. This suggests that the probiotic had a downregulation effect over HPA axis [93]. In the presence of L. rhamnosus, mice showed a lower hippocampal expression of the GABAB1b receptor gene and a higher expression of it in the cingulated cortex and limbic regions. Since GABA is the main inhibitory neurotransmitter of the nervous system, it would appear that psycobiotics are able to modulate the local balance of inhibition/exciting in order to control the systemic responses to stress, anxiety and depression [93].
As previously described, GF-mice exhibit an exaggerated response to stressors, with the presentation of anxious-type behaviors and cognitive deficits [94,95]. This behavior is influenced by the amygdala and the hippocampus. The signaling between the basolateral amygdala (BLA) and the ventral hippocampus modulates anxiety behaviors and social behaviors [96]. Tune changes (structural changes) in the amygdala and hippocampus are associated with anxiety disorders in humans and in rodents in early stages of development. There is evidence of hypertrophy of the dendrites of excitatory neurons in the BLA area under a state of repeated (repetitive) stress that induces atrophy of the dendrites in hippocampal neurons [94].
The “germ-free” status induces dendritic hypertrophy in inhibitory interneurons, and the excitatory pyramidal neurons of the BLA area show increased density of spines type: “thin”, “stubby” and “mushroom”. The absence of intestinal microbiota induces dendritic atrophy in other areas of the CNS, as is the case of hippocampal pyramidal neurons and granular cells of the dentate gyrus. In GF-animals, there is a significant loss of “stubby” and “mushroom” spines in hippocampal pyramidal neurons [94].
It has been estimated that there are 32% fewer synaptic connections in hippocampal pyramidal neurons of GF-animals when the dendrite size decreases and this is combined with a smaller size in the same dendritic spines [94].
A characteristic shared by the animal models of autism and GF-mice is an important alteration in the processes of social behavior. This type of alterations is in turn associated with alterations in the volume of the hippocampus and the amygdala. Changes in the size of these structures have been well documented in experiments with rodents, subject to severe stressors. Prenatally stressed rats experience an increase in the volume of the lateral amygdala [97,98] whereas chronic stress or treatment with corticosteroids induces hippocampal atrophy [98]. Changes in these structures of the CNS are frequently observed in human patients with anxiety disorders or with autism, clearly indicating that the volumetric alterations of the limbic structures can in turn be the result of a maladaptive response to stress [94]. In chronically stressed mice, dendrite hypertrophy is observed in inhibitory GABAergic neurons of the prefrontal cortex area [99].
The amygdala has different “target” areas that are responsible for modulating neuroendocrine responses to stress. The BLA area is activated by psychological stressors, and lesions in this area significantly reduce the HPA-axis response efficiency [94]. While, on the other hand, the area of the central nucleus of the amygdala (CeA) is not involved in the signaling of the HPA-axis induced by stressors, it is an area that also regulates autonomic responses to stress [94]. GF-mice have a lower degree of anxiety and social cognitive deficit, and it has been mentioned previously that there is an important relationship between anxiety and social behavior; the amygdala and the area of the ventral hypothalamus are directly involved in the regulation of this type of behavior [100]. In addition to having a preponderant role in the regulation of anxiety, the ventral hypothalamus is also involved in processes of sociability, and an alteration or damage in this area leads to the appearance of abnormal responses to social situations [101]. Besides, this ventral hippocampus exhibits a very important reciprocal connection with the amygdala, another area involved in anxiety and sociability [100].
The different tonsillar sub-regions have different roles in the regulation of anxiety and social behavior. The areas of the lateral amygdala (LA) and the BLA area integrate sensory information and adverse situations and then send their projections to the CeA area [100]. The stimulation of the projections from the BLA to the CeA area induces an anxiolytic phenotype in mice [102]. This is in contrast to direct stimulation of the entire BLA area, where an opposite effect is generated, suggesting that most of the BLA neurons project towards areas that regulate anxiogenic effects [102].
It has been mentioned that chronic stress in the adult stage is also capable of affecting the composition of the gut microbiota [11]. It is clear that alterations in the brain-gut axis interactions are associated with intestinal inflammatory processes, syndromes of chronic abdominal pain, and with eating disorders [11,103]. This altered modulation of the brain-gut axis is associated with alterations in the regulation of stress responses and behavioral alterations. The high co-morbidity that exists between stress and some symptoms of psychiatric illnesses such as high anxiety, gastrointestinal disorders (included in irritable bowel syndrome, IBS) is clear evidence of the importance of this axis in the pathophysiology of certain types of diseases [11].
Chronic stress on the other hand breaks the intestinal barrier, causes filtrations and alters the ability of the HPA-axis to reverse the deleterious effects of stress (Figure 5) [93,94].
Figure 5. Chronic stress and HPA axis. A chronic stress process is capable of causing disruption at a level of the intestinal barrier and cause dysbiosis, which in turn induces the leakage of bacteria and the activation of the local immune system, leading to a significant alteration of the hypothalamic pituitary adrenal (HPA)-axis. IL, interleukin; MCP-1, monocyte chemoattractant protein; red arrow down mean decrease levels; blue arrow up mean increase levels.
GABA is the major inhibitory neurotransmitter in the CNS. Dysfunctions in GABA signaling are associated with anxiety and depression [104]. Lactobacilli and bifidobacteria are able to metabolize glutamate to produce GABA in vitro [62,104,105]. In an in vivo experiment in mice, a strain of Lactobacillus rhamnosus shows an effect and influence on depressive and ancestral behavior, and it can also alter the central expression of GABA receptors in key brain regions for stress management [62].
In 2006, Kamiya et al. [106] demonstrated that oral administration of Lactobacillus species for anesthetized rats is capable of completely suppressing colonic distension induced by pseudo-affective cardiac responses, which is reflected in the inhibition of visceral pain perception. This treatment is also effective in reducing electrical charges in fibers of the dorsal root of the ganglia [71]. The administration of these same strains of Lactobacillus to healthy adult rats is enough to activate calcium (Ca2+) and potassium (K+) channels in neurons-AH (after hyperpolarization) of the ENS in mesenteric plexus of the colon [71].
It has been shown that the oral administration of specific strains of Lactobacillus induces the expression of opioids-μ receptors and cannabinoids and promotes analgesic functions similar to effects of morphine. This suggests that intestinal microbiota can influence our visceral perception [107]. Altogether, these findings indicate that probiotics are able to modulate the function responsible for the visceral and somatic perception of pain [71].
Currently, there is evidence that supports the influence of intestinal microbiota on the behavior and health of SNC [1]. Patients with depressive symptoms show a significant improvement in the symptoms of depression accompanied by a reduction in plasma TRP after a fructose-restricted diet. Furthermore, fructose malabsorption provides the substrate for a rapid bacterial fermentation, which results in changes in gut motility [72]. The administration of a strain of Bifidobacterium infantis for 14 days increases the levels of plasma TRP, suggesting that commensal bacteria have the ability to influence the metabolism of TRP [93].
Intestinal bacteria are potent regulators of systemic and local immune responses such as that related to mucous membranes, in addition to contributing to the development of inflammatory disorders in the CNS. GF-animals or animals treated with antibiotics with an experimental autoimmune encephalomyelitis (EAE) process present reduced inflammation and a lower degree of disease compared to conventional mice, which suggest the existence of complex interactions between commensal bacteria and the inflammatory process in CNS [9,97,98]. For example, segmented filamentous bacteria (frequently associated with the intestinal epithelium) promote the development of Th17 helper T cells, which produce IL-17. They have been termed as Th17 cells in the small intestine of mice [99,108].
There is important evidence that the brain-gut axis can influence brain chemistry and is able to modulate behavior in adult mice [43]. A transient disturbance in the microbiota is able to increase the levels of BDNF in the hippocampus, as well as increase the exploratory behavior of animals. In the hippocampus, BDNF is associated with memory and learning processes and recent evidence indicates that this increase is associated with anxiolytic and antidepressant-like behavior [43]. On the other hand, the amygdala is also associated with memory and disorders in the mood and there has been an increase in the expression of BDNF in the amygdala during processes of “learning fear” [109]. Low levels of BDNF in the amygdala increase the exploratory behavior of the animals (Figure 6) [9,43].
Figure 6. BDNF release system. The brain-derived neurotrophic factor (BDNF) released via the activation of the brain-gut axis has been associated with cognitive and behavioral processes, as well as with anxiolytic and antidepressive effects. SCFAs, short chain fatty acids; red arrow up mean increase levels.
This entry is adapted from the peer-reviewed paper 10.3390/nu11040890
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