Impact of gut–brain interaction in emerging neurological disorders

The central nervous system(CNS)is a reservoir of immune privilege.Specialized immune glial cells are responsible for maintenance and defense against foreign invaders.The blood–brain barrier(BBB)prevents detrimental pathogens and potentially overreactive immune cells from entering the periphery.When the double-edged neuroinflammatory response is overloaded,it no longer has the protective function of promoting neuroregeneration.Notably,microbiota and its derivatives may emerge as pathogen-associated molecular patterns of brain pathology,causing microbiome–gut–brain axis dysregulation from the bottom-up.When dysbiosis of the gastrointestinal flora leads to subsequent alterations in BBB permeability,peripheral immune cells are recruited to the brain.This results in amplification of neuroinflammatory circuits in the brain,which eventually leads to specific neurological disorders.Aggressive treatment strategies for gastrointestinal disorders may protect against specific immune responses to gastrointestinal disorders,which can lead to potential protective effects in the CNS.Accordingly,this study investigated the mutual effects of microbiota and the gut–brain axis,which may provide targeting strategies for future disease treatment.

Gut microbiota-astrocyte axis: new insights into age-related cognitive decline

With the rapidly aging human population,age-related cognitive decline and dementia are becoming increasingly prevalent worldwide.Aging is considered the main risk factor for cognitive decline and acts through alterations in the composition of the gut microbiota,microbial metabolites,and the functions of astrocytes.The microbiota–gut–brain axis has been the focus of multiple studies and is closely associated with cognitive function.This article provides a comprehensive review of the specific changes that occur in the composition of the gut microbiota and microbial metabolites in older individuals and discusses how the aging of astrocytes and reactive astrocytosis are closely related to age-related cognitive decline and neurodegenerative diseases.This article also summarizes the gut microbiota components that affect astrocyte function,mainly through the vagus nerve,immune responses,circadian rhythms,and microbial metabolites.Finally,this article summarizes the mechanism by which the gut microbiota–astrocyte axis plays a role in Alzheimer’s and Parkinson’s diseases.Our findings have revealed the critical role of the microbiota–astrocyte axis in age-related cognitive decline,aiding in a deeper understanding of potential gut microbiome-based adjuvant therapy strategies for this condition.

The Gut Brain Connection

The gut-brain connection is a bidirectional communication system that links the gut microbiome to the central nervous system (CNS). The gut-brain axis communicates through a variety of mechanisms, including the release of hormones, neurotransmitters, and cytokines. These signaling molecules can travel from the gut to the brain and vice versa, influencing various physiological and cognitive functions. Emerging therapeutic strategies targeting the gut-brain connection include probiotics, prebiotics, and faecal microbiota transplantation (FMT). Probiotics are live microorganisms that are similar to the beneficial bacteria that are naturally found in the gut. Prebiotics are non-digestible fibers that feed the beneficial bacteria in the gut. FMT is a procedure in which faecal matter from a healthy donor is transplanted into the gut of a person with a diseased microbiome. Probiotics, prebiotics, and FMT have been shown to be effective in treating a variety of gastrointestinal disorders, and there is growing evidence that they may also be effective in treating neurological and psychiatric disorders. This review explores the emerging field of the gut-brain connection, focusing on the communication pathways between the gut microbiome and the central nervous system. We summarize the potential roles of gut dysbiosis in various neurological and psychiatric disorders. Additionally, we discuss potential therapeutic strategies, research limitations, and future directions in this exciting area of research. More research is needed to fully understand the mechanisms underlying the gut-brain connection and to develop safe and effective therapies that target this pathway. However, the findings to date are promising, and there is the potential to revolutionize the way we diagnose and treat a variety of neurological and psychiatric disorders.

The Role and Significance of Brain-gut Peptide and Its Receptor's Expression in the Mechanism's Explanation of Cleaning Away Heat and Dampness

Cleaning away Heat and Dampness is one of the general methods in treating the syndrome of the Spleen and Stomach’s damp heat in Febrile Diseases,and its efficacy of invigorating the spleen regulating the stomach is involved in regulation of gastrointestinal motility.Many factors and systems act as the regulation,including Brain-gut peptide,which quantitative change in the gastrointestinal tissues and plasma can reflex the functions of gastrointestinal motility.So carrying on an investigation into the relation between brain-gut peptide and its receptors and gastrointestinal dyskinesia in the syndrome of damp heat in the spleen and stomach has its relevant to the explanation of the mechanism of cleaning away Heat and Dampness.

Functional gastrointestinal disorders and gut-brain axis: What does the future hold?

Despite their high prevalence, lack of understanding of the exact pathophysiology of the functional gastrointestinal disorders has restricted us to symptomatic diagnostic tools and therapies. Complex mechanisms underlying the disturbances in the bidirectional communication between the gastrointestinal tract and the brain have a vital role in the pathogenesis and are key to our understanding of the disease phenomenon. Although we have come a long way in our understanding of these complex disorders with the help of studies on animals especially rodents, there need to be more studies in humans, especially to identify the therapeutic targets. This review study looks at the anatomical features of the gut-brain axis in order to discuss the different factors and underlying molecular mechanisms that may have a role in the pathogenesis of functional gastrointestinal disorders. These molecules and their receptors can be targeted in future for further studies and possible therapeutic interventions. The article also discusses the potential role of artificial intelligence and machine learning and its possible role in our understanding of these scientifically challenging disorders.

Polyphenols-gut microbiota interplay and brain neuromodulation

Increasing evidence suggests that food ingested polyphenols can have beneficial effects in neuronal protection acting against oxidative stress and inflammatory injury. Moreover, polyphenols have been reported to promote cognitive functions. Biotransformation of polyphenols is needed to obtain metabolites active in brain and it occurs through their processing by gut microbiota. Polyphenols metabolites could directly act as neurotransmitters crossing the blood-brain barrier or indirectly by modulating the cerebrovascular system. The microbiota-gut-brain axis is considered a neuroendocrine system that acts bidirectionally and plays an important role in stress responses. The metabolites produced by microbiota metabolism can modulate gut bacterial composition and brain biochemistry acting as neurotransmitters in the central nervous system. Gut microbiota composition can be influenced by dietary ingestion of natural bioactive molecules such as probiotics, prebiotics and polyphenol. Microbiota composition can be altered by dietary changes and gastrointestinal dysfunctions are observed in neurodegenerative diseases. In addition, several pieces of evidence support the idea that alterations in gut microbiota and enteric neuroimmune system could contribute to onset and progression of these age-related disorders. The impact of polyphenols on microbiota composition strengthens the idea that maintaining a healthy microbiome by modulating diet is essential for having a healthy brain across the lifespan. Moreover, it is emerging that they could be used as novel therapeutics to prevent brain from neurodegeneration.

Focus on the gut-brain axis: multiple sclerosis, the intestinal barrier and the microbiome

The brain-gut axis serves as the bidirectional connection between the gut microbiome, the intestinal barrier and the immune system that might be relevant for the pathophysiology of inflammatory demyelinating diseases. People with multiple sclerosis have been shown to have an altered microbiome, increased intestinal permeability and changes in bile acid metabolism. Experimental evidence suggests that these changes can lead to profound alterations of peripheral and central nervous system immune regulation. Besides being of pathophysiological interest, the brain-gut axis could also open new avenues of therapeutic targets. Modification of the microbiome, the use of probiotics, fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers are all promising candidates. Hopefully, pre-clinical studies and clinical trials will soon yield significant results.

Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide

Long-acting glucagon-like peptide-1(GLP-1) analogues marketed for type 2 diabetes(T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2 D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors(GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions(e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2 D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation(thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2 D, stroke and Alzheimer disease(AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biomarkers. Herein, we discuss the GLP-1 action through the gut-brain axis, the hormone's regulation of some autonomic functions and liraglutide's neuroprotective potential.

Brain-gut-microbiota axis in Parkinson's disease

Parkinson's disease(PD) is characterized by alphasynucleinopathy that affects all levels of the braingut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological,neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding.Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gutmicrobiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.

Brain-gut axis in the pathogenesis of Helicobacter pylori infection

Helicobacter pylori (H. pylori) infection is the main pathogenic factor for upper digestive tract organic diseases. In addition to direct cytotoxic and proinflammatory effects, H. pylori infection may also induce abnormalities indirectly by affecting the brain-gut axis, similar to other microorganisms present in the alimentary tract. The brain-gut axis integrates the central, peripheral, enteric and autonomic nervous systems, as well as the endocrine and immunological systems, with gastrointestinal functions and environmental stimuli, including gastric and intestinal microbiota. The bidirectional relationship between H. pylori infection and the brain-gut axis influences both the contagion process and the host’s neuroendocrine-immunological reaction to it, resulting in alterations in cognitive functions, food intake and appetite, immunological response, and modification of symptom sensitivity thresholds. Furthermore, disturbances in the upper and lower digestive tract permeability, motility and secretion can occur, mainly as a form of irritable bowel syndrome. Many of these abnormalities disappear following H. pylori eradication. H. pylori may have direct neurotoxic effects that lead to alteration of the brain-gut axis through the activation of neurogenic inflammatory processes, or by microelement deficiency secondary to functional and morphological changes in the digestive tract. In digestive tissue, H. pylori can alter signaling in the brain-gut axis by mast cells, the main brain-gut axis effector, as H. pylori infection is associated with decreased mast cell infiltration in the digestive tract. Nevertheless, unequivocal data concerning the direct and immediate effect of H. pylori infection on the brain-gut axis are still lacking. Therefore, further studies evaluating the clinical importance of these host-bacteria interactions will improve our understanding of H. pylori infection pathophysiology and suggest new therapeutic approaches.

Effect of amitriptyline on gastrointestinal function and brain-gut peptides: A double-blind trial

AIM: To study the effects of low-dose amitriptyline (AMT) on gastrointestinal function and brain-gut peptides in healthy Chinese volunteers. METHODS: This was a double-blind, randomised, placebo-controlled, two-period cross-over trial. Twentyeight healthy volunteers were randomised and administered 1-wk treatments of AMT (12.5 mg tid) or placebo. Before and during the final two days of treatment, gastric emptying, proximal gastric accommodation and visceral sensitivity were measured by drinkingultrasonography test; the orocecal transit time (OCTT) was measured by lactulose hydrogen breath test, and fasting blood was collected. Plasma levels of ghrelin, motilin and neuropeptide Y (NPY) were measured by enzyme-linked immunosorbent assay kits.RESULTS: AMT slowed the OCTT (109.2 ± 29.68 min vs 96.61 ± 23.9 min, P = 0.004) but did not affect liquid gastric emptying and had no effect on proximal gastric accommodation. AMT resulted in decreases in the visual analogue scale (VAS) for difficulty in drinking 600 and 800 mL of water (3.57 ± 0.94 vs 2.98 ± 0.85, 5.57 ± 0.82 vs 4.57 ± 0.98, P < 0.01 for both), although it had no significant effect on the VAS for difficulty in drinking 200 mL and 400 mL of water. AMT significantly increased the plasma ghrelin level (442.87 ± 176.79 pg/mL vs 526.87 ± 158.44 pg/mL, P = 0.04) and the neuropeptide-Y level (890.15 ± 131.46 pg/mL vs 965.64 ± 165.63 pg/mL, P = 0.03), whereas it had no effect on the MTL level. CONCLUSION: Low-dose AMT could slow OCTT, make the stomach less sensitive and increase the plasma levels of ghrelin and NPY. Thus, we recommend the use of low-dose AMT for functional gastrointestinal disorders.

Microbiota-gut-brain axis and its affect inflammatory bowel disease:Pathophysiological concepts and insights for clinicians

Despite the bi-directional interaction between gut microbiota and the brain not being fully understood,there is increasing evidence arising from animal and human studies that show how this intricate relationship may facilitate inflammatory bowel disease(IBD)pathogenesis,with consequent important implications on the possibility to improve the clinical outcomes of the diseases themselves,by acting on the different components of this system,mainly by modifying the microbiota.With the emergence of precision medicine,strategies in which patients with IBD might be categorized other than for standard gut symptom complexes could offer the opportunity to tailor therapies to individual patients.The aim of this narrative review is to elaborate on the concept of the gutbrain-microbiota axis and its clinical significance regarding IBD on the basis of recent scientific literature,and finally to focus on pharmacological therapies that could allow us to favorably modify the function of this complex system.

Healthy axis: Towards an integrated view of the gut-brain health

Despite the lack of precise mechanisms of action, a growing number of studies suggests that gut microbiota is involved in a great number of physiological functions of the human organism. In fact, the composition and the relations of intestinal microbial populations play a role, either directly or indirectly, to both the onset and development of various pathologies. In particular, the gastrointestinal tract and nervous system are closely connected by the so-called gut–brain axis, a complex bidirectional system in which the central and enteric nervous system interact with each other, also engaging endocrine, immune and neuronal circuits. This allows us to put forward new working hypotheses on the origin of some multifactorial diseases: from eating to neuropsychiatric disorders (such as autism spectrum disorders and depression) up to diabetes and tumors (such as colorectal cancer). This scenario reinforces the idea that the microbiota and its composition represent a factor, which is no longer negligible, not only in preserving what we call “health” but also in defining and thus determining it. Therefore, we propose to consider the gut-brain axis as the focus of new scientific and clinical investigation as long as the locus of possible systemic therapeutic interventions.

Neuroimaging the brain-gut axis in patients with irritable bowel syndrome

AIM:To summarize and synthesize current literature on neuroimaging the brain-gut axis in patients with irritable bowel syndrome(IBS).METHODS:A database search for relevant literature was conducted using Pub Med,Scopus and Embase in February 2015.Date filters were applied from the year2009 and onward,and studies were limited to those written in the English language and those performed upon human subjects.The initial search yielded 797articles,out of which 38 were pulled for full text review and 27 were included for study analysis.Investigations were reviewed to determine study design,methodology and results,and data points were placed in tabular format to facilitate analysis of study findings across disparate investigations.RESULTS:Analysis of study data resulted in the abstraction of four key themes:Neurohormonal differences,anatomic measurements of brain structure and connectivity,differences in functional responsiveness of the brain during rectal distention,and confounding/correlating patient factors.Studies in this review noted alterations of glutamate in the left hippocampus(HIPP),commonalities across IBS subjects in terms of brain oscillation patterns,cortical thickness/gray matter volume differences,and neuroanatomical regions withincreased activation in patients with IBS:Anterio cingulate cortex,mid cingulate cortex,amygdala anterior insula,posterior insula and prefrontal cortex.A striking finding among interventions was the substantia influence that patient variables(e.g.,sex,psychologica and disease related factors)had upon the identification of neuroanatomical differences in structure and con nectivity.CONCLUSION:The field of neuroimaging can provide insight into underlying physiological differences that distinguish patients with IBS from a healthy population.

Role of the brain-gut axis in gastrointestinal cancer

Several studies have largely focused on the significant role of the nervous and immune systems in the process of tumorigenesis, including tumor growth, proliferation, apoptosis, and metastasis. The brain-gut-axis is a new paradigm in neuroscience, which describes the biochemical signaling between the gastrointestinal (GI) tract and the central nervous system. This axis may play a critical role in the tumorigenesis and development of GI cancers. Mechanistically, the bidirectional signal transmission of the brain-gut-axis is complex and remains to be elucidated. In this article, we review the current findings concerning the relationship between the brain-gut axis and GI cancer cells, focusing on the significant role of the brain-gut axis in the processes of tumor proliferation, invasion, apoptosis, autophagy, and metastasis. It appears that the brain might modulate GI cancer by two pathways: the anatomical nerve pathway and the neuroendocrine route. The simulation and inactivation of the central nervous, sympathetic, and parasympathetic nervous systems, or changes in the innervation of the GI tract might contribute to a higher incidence of GI cancers. In addition, neurotransmitters and neurotrophic factors can produce stimulatory or inhibitory effects in the progression of GI cancers. Insights into these mechanisms may lead to the discovery of potential prognostic and therapeutic targets.

Prion-like propagation of α-synuclein in gutbrain axis

Parkinson disease(PD) is a progressive degenerative disease of the nervous system,which is characterized by movement disorders,such as static tremor,rigidity,and bradykinesia in advanced patients.Gastrointestinal(GI) dysfunction,such as gastric dysmotility,constipation,and anorectic dysfunction,is common non-motor symptom in the early stage of PD.The progression of PD includes the degenerative loss of dopaminergic neurons and aggregation ofα-synuclein in the substantia nigra.Interestingly,both of them are also present in the enteric nervous system of PD patients.In this review,we describe the relationship between non-motor symptoms particularly GI dysfunction and the pathogenesis of PD,aiming to show the powerful evidences about the prion-like propagation of α-synuclein and support the hypothesis of gut-brain axis in PD.We then summarize the mechanism of the gut-brain axis and confirmα-synuclein as a potential target for drug design or new clinical treatment.

Inhibition of the cGAS–STING pathway:contributing to the treatment of cerebral ischemia-reperfusion injury

The cGAS–STING pathway plays an important role in ischemia-reperfusion injury in the heart,liver,brain,and kidney,but its role and mechanisms in cerebral ischemia-reperfusion injury have not been systematically reviewed.Here,we outline the components of the cGAS–STING pathway and then analyze its role in autophagy,ferroptosis,cellular pyroptosis,disequilibrium of calcium homeostasis,inflammatory responses,disruption of the blood–brain barrier,microglia transformation,and complement system activation following cerebral ischemia-reperfusion injury.We further analyze the value of cGAS–STING pathway inhibitors in the treatment of cerebral ischemia-reperfusion injury and conclude that the pathway can regulate cerebral ischemia-reperfusion injury through multiple mechanisms.Inhibition of the cGAS–STING pathway may be helpful in the treatment of cerebral ischemia-reperfusion injury.

Effects of electroacupuncture on c-Fos expression in the spinal cord and brain of rats with chronic visceral hypersensitivity

BACKGROUND： Visceral hypersensitivity is the main cause of irritable bowel syndrome, c-Fos is a marker of visceral hypersensitivity in the central nervous system. Electroacupuncture can relieve chronic visceral hypersensitivity in rats, but the mechanism is still unknown. OBJECTIVE： To identify c-Fos expression in the spinal cord and cerebral cortex of rats with chronic visceral hypersensitivity, and to test the effects of electroacupuncture on pain sensitivity in rats with chronic visceral hypersensitivity. DESIGN, TIME AND SETTING： A randomized controlled animal experiment was performed at the Animal E：~perimental Center, Shanghai University of Traditional Chinese Medicine, from January to April, 2007. MATERIALS： A total of 24 neonatal, male, Sprague Dawley rats, aged five days old, were equally and randomly assigned into a normal group, a model group, and an electroacupuncture group. Rabbit anti-rat c-Fos antibody and Evision secondary antibody kits （Sigma, USA）, diaminobenzidine kit （Dako, Denmark）, and an LD202H electroacupuncture apparatus （Huawei, Beijing, China） were used in this study. METHODS： Neonatal rats from the model and electroacupuncture groups were used to establish rat models of chronic visceral hypersensitivity by the saccule stimulation method. After model establishment, 0.25 mm diameter electric needles were inserted into Tianshu （ST 25） and Shangjuxu （ST37） at a depth of approximately 0.5 cm, with an square wave （alternating current frequency at 100/20 Hz, amplitude ranged 0.2-0.6 ms, intensity at 1 mA） once for 20 minutes, once a day, for seven days. Rats in the normal and model groups were not treated. MAIN OUTCOME MEASURES： Following 7 days of treatment, c-Fos expression in the spinal cord and cerebral cortex was detected by immunohistochemistry. After the first electroacupuncture treatment, abdominal withdrawal reflex scores were investigated to evaluate the pain threshold for chronic visceral hypersensitivity in rats. RESULTS： Visceral hypersensitivity increased c-Fos staining （P 〈 0.05）, and electroacupuncture significantly decreased the number of these cells to near normal levels （P 〉 0.05）. Abdominal withdrawal reflex scores were significantly lower in the electroacupuncture and normal groups than in the model group （P 〈 0.05） and were similar between the electroacupuncture and normal groups （P 〉 0.05）. CONCLUSION： Electroacupuncture decreases c-Fos expression in the spinal cord and cerebral cortex and increases pain threshold in a chronic visceral hypersensitivity model in rats.

Gut Microbiota and Metabolic Diseases

In this review, the characteristics of gut microbiota changes in 11 metabolic diseases, as well as the research progress on their interventions, are summarized. The gut microbiota contributes to metabolic diseases through intestinal mucosal dysfunction, chronic metabolic inflammatory response, gut brain axis imbalance, gene regulation, insulin resistance, and the action of its metabolites. The researches of cause effect relationship and mechanism are relatively few, need further study, expecting a breakthrough in the future to be a new path in the treatment of some metabolic diseases.

Clinical Treatment of Functional Pain Syndromes along the Microbiome-Gut-Brain-Axis: Combined Approach with Neuromodulation-Neurofeedback and Multispecies Probiotic

Functional pain syndromes are very common diseases that negatively impact the quality of life of patients with important socio-economic repercussions. The clinical alterations associated with these pathologies are multiple and have a complex psycho-organic character that moves along the micorobiome-gut-brain-axis. For the present study, 45 patients of both sexes (19 male, 26 female) aged 30 - 59 years were enrolled because of a diagnosis of Functional pain syndromes (FPS) that lasted for more than 6 months. All patients underwent pre-treatment clinical assessments (T0) for anxiety disorder, multidimensional assessment of pain, monitoring of baseline values of Alpha-Theta cerebral rhythm in occipital region and monitoring of salivary cortisol levels. All the patients underwent a clinical treatment combined with central neuromodulation with neurofeedback—Alpha Theta increase protocols (once a week for three months), administration of multispecies probiotic (one dose per day for 3 months) and clinical psychological interviews (once a week for three months). At the end of treatment (T1), patients were re-evaluated. Results show statistically relevant improvements of each feature considered: the Relief from Pain provided by the medication increases on average from 36.6% to 87.3%, the salivary Cortisol level at 11 pm decreases from 6.4 ng/ml to a physiological value of 1.2 ng/ml, and the anxiety rating score is reduced from 28 to 12. Moreover, the 23.9% increase in α-θ relative power shows the positive outcome of the brain autoregulation. This study highlights that the combined approach of Neurofeedback with drugs and multispecies probiotic results in great improvements in the patients’ life.