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Psicologia e pratica degli sport di squadra
di Leano Cetrullo

GUT MICROBIOTA AND MENTAL DISORDERS

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17 luglio, 2018 - 08:39
di Leano Cetrullo
Over the past decade, research has shown that diet and gut health affects symptoms expressed in stress related disorders, depression, and anxiety through changes in the gut microbiota. Psycho-behavioral function and somatic health interaction have often been ignored in health care with resulting deficits in treatment quality and outcomes. While mental health care requires the professional training in counseling, psychotherapy and psychiatry, complimentary therapeutic strategies, such as attention to a nutritional and diverse diet and supplementation of probiotic foods, may be integrated alongside psychotherapy treatment models. Development of these alternative strategies is predicated on experimental evidence and diligent research on the biology of stress, fear, anxiety-related behaviors, and the gut-brain connection 1. The constitution of intestinal microbiota in humans is determined by the type of delivery at birth, gene tendency, age, nutrition, physical activity, environmental factors, stress, infection, other disease and the usage of antibiotics. Genes of the brain and intestinal tract are quite similar, especially related to the formation of the neuronal synapse, thus some gene mutations can lead to abnormalities in both the brain and gut 2. Recent data show the strong correlation between dysbiosis and conditions such as obesity, allergies, autoimmune disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and psychiatric disorders 3. In the last few years, much research has been done in this direction, underlying the importance of dysbiosis in the etiopathogenesis of pathology such as autism, dementia and mood disorder. The evidence of the inflammatory state alteration, highlighted in disorders such as schizophrenia, major depressive disorder and bipolar disorder 4, strongly recalls the microbiota alteration and highly suggests an important role of the alteration of GI system also in neuropsychiatric disorders. Alterations in bidirectional brain-gut microbiota interactions are believed to be involved in the pathogenesis of well-known brain-gut disorders such as irritable bowel syndrome (IBS) and related functional gastrointestinal (GI) disorders and have more recently been implicated as a possible mechanism in the pathophysiology of several brain disorders including autism spectrum disorders (ASDs), Parkinson’s disease, disorders of mood and affect, and chronic pain. However, there is considerable controversy over the magnitude as well as the sites, pathways, and molecular mechanisms within the gut/brain axis that are responsible for these alterations. The intestinal microbiota and its metabolites have been shown to be involved in modulating GI functions, given their ability to affect intestinal permeability, mucosal immune function, intestinal motility and sensitivity, and activity in the enteric nervous system (ENS). Additionally, preclinical evidence suggests that the microbiota and its metabolites are likely to be involved in modulating behaviors and brain processes, including stress responsiveness, emotional behavior, pain modulation, ingestive behavior, and brain biochemistry 5In the Westernized world today, anxiety and depression are the most frequently diagnosed disorders 6The rise in the pathogenesis of anxiety and depression is concomitant with an epidemic of metabolic and auto-immune diseases, and may not be traceable to one or even a few etiologies. Instead, physiological and psychological comorbidities are likely reflective of a more insipid sweep of toxic changes permeating the lifestyles of people within urban-industrial societies. If the shared axis of psycho-behavioral function and somatic health continues to be ignored, then the future ramifications could be rather daunting. Therefore, while mental health is necessarily the domain of psychotherapy and psychiatry, and requires the specialized care that is afforded by mental health professionals, complimentary therapeutic strategies should be coopted alongside standard models of care. Development of these alternative strategies is non-random. Instead, they are predicated on extensive experimental evidence and diligent research on the biology of stress, fear, anxiety-related behaviors, and the gut-brain connection.This article provides an overview of the scientific and academic literature on biological markers of anxiety, briefly summarizing the expanding nutritional literature on brain health so as to connect the neuroendocrine routes and pathways of anxiety that can be manipulated or directly activated by the gut microbiome. The predictable consequence to traumatic and anxiety provoking incidents involves hyper-arousal in the nervous system, leading to the amygdala-mediated fight, flee, freeze, hypervigilance, or submission reactions. Freeze has been considered the more severe psychological price of earlier stressful or traumatic experiences and has been the major predictor of post-traumatic stress disorder (PTSD). This array of responses, especially freeze, compromises brain development and necessary neuro-endocrine functions 7. The ENS is directly connected to the CNS through descending ANS nerves, ascending vagus nerve, and epithelial capillaries that carry hormones and other humoral signals 8. Microbiota living in the colon comprise either an autochthonous (resident) or allochthonous (transient) population, both of which have important and influential functions for maintenance of the enteric ecosystem and for the host health 9. Inflammation in the gut is operationally contributive to inflammation in the brain and somatic tissues. The role of microbiota in behavior was originally suggested by observations that a variety of mental illnesses, such as anxiety, depression, schizophrenia, and cognitive developmental disorders such as autism spectrum disorder (ASD) are co-expressed with gut dysfunction 10 and linked to autoimmune disorders and neuroinflammation via detection of serum cytokines such as IL-6. Therefore, inflammatory markers are implicit in the GBA signaling complex alongside mental illness, particularly of anxiety and depression, incorporating the activity of inflammasomes and innate host-mediated pathogen awareness in the gut-brain connection 11. Gut microbiome remodeling through pro- or anti-biotics has also been shown to affect behavioral phenotypes in mice and in human patients 12. Brain to gut signaling is transduced through chemical crosstalk engaged through a variety of way points: (1) Host enterocytes such as the enterochromaffin cells (ECC) and immunocytes such as dendritic and mast cells (DC and MC respectively) secrete hormones and cytokines directly into the lumen and in return, can receive signals from mucosal and luminal microbiota in the form of metabolites, neuropeptides, peptide hormones, and neurotransmitter-like molecules; (2) Microbial molecules such as lipopolysaccharides and lipoproteins can leak into the host circulation through gaps in the epithelial tight junctions, termed “leaky gut”, stimulating a host immune response; (3) Efferent adrenergic and NA signals from capillaries and nerve terminals within the gut wall “spill” into the lumen during stressful or traumatic events (including physical trauma) and disrupt enteric homeostasis; and (4) Interkingdom signaling, particularly through adrenergic homologs that cross-activate bacterial and host adrenergic receptors. Additionally, the gut is directly innervated by the ANS, with the sympathetic NA system exerting a restrictive signal on gut function and digestion. Through NA, the sympathetic system is able to halt intestinal motor function and fluid secretion, which restricts lumen motility and alters microbial activity such as gene expression and metabolite production. Therefore, anxiety and stress increase NA and glucocorticoid production in the body, which translates into a disturbed enteric environment that promotes pathogenicity through decreasing motility and shifting microbial composition in favor of opportunistic pathogens. In turn, the gut reciprocates the brain with its own panoply of signals derived from microbial metabolites, which reach the brain through intermediary enterocytes and dendritic cells or directly through endocrine and neural signaling 13. Candidate microbial metabolites that are implicated in GBA communication as well as behavioral modulation are an open area of investigation, with good evidence for the production and impact of short chain fatty acids (SCFAs), catecholamines (serotonin and dopamine), and neurotransmitters 14. Microbial metabolites can influence enteric and systemic health in both a pro- and anti-inflammatory fashion. Microbial strains of Escheria, can disrupt gut motility by the release of peptides, which creates and imbalance in the population structure 15. Pro-inflammatory members of Clostridiales such as Lachnospiraceae and Ruminococcaceae have also been associated with social avoidance behaviors in mice 16. Pro-inflammatory and anxiogenic factors of microbial origin are often found in the bloodstream, suggestive of compromised epithelial function and intestinal permeability. Evidence for microbiome-related factors in mitigation, alleviation, or even prevention of disease are mainly limited to probiotic studies using just a few strains of Bifidobacteriaceae and Lactobacillaceae, and often in the presence of a pathogen-induced disease state 17. Still, these results are critical to formulating a baseline of therapeutic approaches. Recent work demonstrates that butyrate and propionate SCFAs strongly affect monocyte-derived DC gene expression, as well as reduce pro-inflammatory chemokines and inhibit lipopolysaccharide-induced cytokines 18. On the other hand, microbially-derived uremic toxins such as 4EPS and cresol are strongly associated with autism-like behaviors in mice 19, and recently, cresol was found to inhibit myelin gene expression in oligodendrocytes, implicating the microbiome in early developmental and long-term plasticity brain processes that directly affect stress tolerance and resilience. Studies on probiotic supplementation in mice and in humans provides compelling evidence of microbial regulation over stress and anxiety induced neuroendocrine signaling. In particular, strains of Lactobacillus and Bifidobacterium are found to exert a profound anxiolytic influence through the production of γ-aminobutryic acid (GABA), 5-HT, and SCFAs, and by dampening HPA adrenergic reaction 20. Moreover, the regression of anxiety after treatment in these studies was often associated with positive neurological changes such as increased BDNF, altered expression of PFC and hippocampal GABAA and GABAB receptors, increased circulating glutathione, and a reduction in inflammatory markers. Therefore, Lactobacillus and Bifidobacterium strains that are commonly found or enriched in foods that undergo lactic fermentation may be the critical factor in the potency of dietary probiotics towards supporting a reconfiguration of the enteric environment to supplant anxiogenic activity with anxiolytic regulation. “Psychobiotics”, which are live organisms, when ingested may produce health benefits in patients suffering from mood disorders 21. In a study of 124 healthy volunteers (mean age 61.8 years), those who consumed a mix of specific psychobiotics (Lactobacillus helveticus and bifidobacterium longum) exhibited less anxiety and depression 22. Symptoms of “depression” were reported to decrease following probiotic treatment in the rat 23. Additional studies showed beneficial effects of probiotics in animal models with altered behavioral phenotypes, as they reduced vagal-dependent activation of GABA receptors in response to physical and psychological stress 24. Interestingly, dysregulation of carbohydrate digestion and metabolism is also linked to clinical disorders such as depression, hyperactivity, and autism, though these associations require further empirical testing to clarify their mechanistic effect. Curiously though, there seems to exist a relationship between fructose malabsorption and circulating lipopolysaccharide (LPS), which could be abolished by administration of an antibiotic, thus implicating microbial activity 25. Even further, fructose malabsorption is linked to depression and mood disorders 26 in which observable behaviors strongly implicate a dysregulation of the tryptophan and 5-HT production cycle that has direct impact on mood control in the brain. Even so, one can speculate upon the contextual factors that surround what, how, and when an individual manages food selection and ingestion. Consideration of environmental and social factors is often ignored in the medical treatment of physical, infectious, and affective disorders, and yet may be the focal point of disease etiology and prognosis for recovery, and shows promise for immediate application in psychotherapy. Depression is a major form of mood disorder characterized by depressed mood and/or recurrent thoughts of death and/or loss of interest or pleasure in life activities present over a period of at least 2 wk, accompanied by at least five additional symptoms that cause clinically significant impairment in social, work, or other important areas of functioning 27<. It results from neuro-psychiatric disturbance, immunological deregulation, genetic factors and environmental influences; nevertheless, a correlation with gut microbiota is emerging 28; Through humoral route, microbiota can also influence CNS neurotransmission: it has been demonstrated that in GF mice anxiety-like behavior is reduced and modulated after restoration of the intestinal microbiota 29. In particular, administration of Lactobacillus sp, Bifidobacteria sp, L. helvetucys, B. longum, L. rhamnosus and Lactobacillus farciminis in murine sample lay to an improvement of depression and anxiety symptoms 30. In particular, an alteration of intestinal permeability, causing high level of LPS into the bloodstream, lead to the activation of inflammatory and immune response; these processes have been hypothesized as causative factors in psychiatric disorders such as depression 31. Moreover, as support to this hypothesis, it has been demonstrated that the administration of LPS in healthy subject is associated to increase of pro-inflammatory cytokines and plasma norepinephrine, whit higher depression rates 32. Among clinical studies conducted, gut microbiota has been characterized, showing an overexpression of Alistipes in patients affected by depression disorder 33. The overexpression of this bacterium, a genus in the phylum of Bacteroidetes, has been demonstrated in other disorders, such as chronic fatigue syndrome and in IBS 34. This evidence lead to speculate about a gut microbiota alteration as common mechanism of action in the genesis of these disorders. In summary, the focus on the neurobiology of anxiety and the CNS connectivity in the gut has illuminated likely mechanisms where microbial interference can induce signals that govern emotions and behaviors through the fear and reward anticipation circuits. Importantly, medical and mental health professionals can and should use these insights to develop informed models of therapy for the treatment of anxiety symptoms in a professional setting. The NA and adrenergic systems seem to be the core activators of anxiety symptoms. In fact, the mammalian executive system of fear consists of the lateral and central nuclei of the amygdala, the ventral anterior and medial hypothalamus, and the mesencephalic periaqueductal gray (PAG) 35. Therefore, their inhibition should be the goal of anxiolytic treatments, which is possible by dampening the HPA response to stress, improving immune function, and facilitating proper nutritional acquisition and absorption. The prescription is simple: rest, digest, exercise, practice mindful relaxation, and eat a nutritionally rich and varied diet. Through the gut microbiota, it is apparent that GABA and 5-HT are produced by specific bacterial strains 36, and that supplementation with these bacteria correspondingly attenuates presentation of anxious behaviors in animal models. Anxiolysis is also accomplished by reinstating normal gut function and community structure, suggesting that mitigating perception of anxiety is also possible by directly promoting gut health and treating dysbiosis through dietary modifications, specifically also adding a daily consumption of fermented foods. In this regard, diet, extenuating gut issues, and the contextual factors of eating behavior should be reviewed and treated before the application of psychotropic medication. This may also involve not only the treating medical and psychotherapy professional to educate oneself regarding gut issues, but also providing this information to the patient so as to increase cooperation in the dietary aspects of the treatment plan. Multiple vectors of psychological well-being and pathos exist. Early trauma may instate long-term anxiety, which modulates neuroendocrine signaling to and from the gut microbiota, effectively entrenching an anxiety phenotype. Models of physical and mental health treatment can use psychotherapy approaches such as CBT, Rational Emotive Behavior Therapy (REBT), Emotionally Focused Therapy (EFT), and Dialectical Behavioral Therapy (DBT), and mindfulness strategies to mitigate anxiety symptoms. These treatments prompt patients to identify and learn to manage the factors that contribute to anxiety and also teach patients to use relaxation and deep breathing to counteract the physical symptoms of anxiety. Indeed, these therapeutic strategies are designed to calm amygdalic activity and strengthen the cortical (cognitive) input and rationalization of emotion. However, it is no longer sufficient to use psychotherapeutic approaches alone, particularly where emotional trauma may play a role in the etiology of the presenting problem. With much evidence supporting the relation of systemic wellness in mental health, and in particular the status of the enteric ecosystem of the colon, health care must incorporate bottom-up as well as top down approaches towards treating anxiety disorders among other mental and physical health concerns. The search for the neurobiological substrates of fear and anxiety has had resounding success over decades of research, leaving no doubt that cognitive and emotional processes are merely one branch of an integrated systemic circuit, inclusive of the gut microbiota. Continued research and clinical application are essential to refine treatment strategies that will optimize enhancements in physical and mental health as well as engender long-term compliance for dietary and mental wellness related lifestyle changes 37.
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