Can we promote neural regeneration through microbiota-targeted strategies? Introducing the new concept of neurobiotics.

Biological models for psychiatric disorders, such as anxiety and depression, emphasize the role of neurochemical changes in the development and maintenance of the disorders. The past decade, however, has shown increased evidence for the role of the microbiota-gut-brain axis in psychiatric disorders. Although much of this research is still in its preclinical stages and has largely been based on animal models, the findings in this area have potential implications for the conceptualization and treatment of psychiatric disorders. A number of excellent in-depth systematic and narrative reviews have been published on the topic of the microbiota-gutbrain axis and psychopathology recently (Collins, Surette & Bercik, 2012; De Angelis et al., 2015; Foster & Neufeld, 2013; Montiel-Castro et al., 2013; Wang & Kasper, 2014), many of which have been written by our research group at McMaster University. However, one of the limitations of these reviews is that they are published in basic science journals and tend to provide a very in-depth, detailed, and technical review of the basic science literature as it relates to the microbiota-gut-brain axis with limited focus on clinical implications. Therefore, the goal of the current article is to increase the visibility and accessibility of this research by providing an introduction to the topic with a strong focus on theoretical and clinical implications. Moreover, this article brings together ideas on the topic from a multidisciplinary team, including clinical psychologists, psychiatrists, gastroenterologists, and primary researchers, which highlights an interdisciplinary perspective on the topic with ideas for future research.The Gut MicrobiomeThe human body consists of a number of microbial environments that are predominantly made up of bacteria but also includes archaea, fungi, protists, and viruses. The intestinal or gut microbiome is the largest with approximately 100 trillion bacteria, most of which are located in the distal gut (Gill et al., 2006; Qin et al., 2010). The gut microbiome consists of over 1,000 distinct bacterial species (Qin et al., 2010) and its genetic material outnumbers human DNA by 10-fold. Although a core microbiome is shared by all humans, there is variability and fluctuation in the microbiota throughout the life span. This variability and fluctuation is influenced by factors such as diet, stress, infections, and antibiotic use (Cryan & O'Mahony, 2011; Forsythe, Sudo, Dinan, Taylor, & Bienenstock, 2010; Turnbaugh, Ridaura, Faith, Rey, Knight, & Gordon, 2009; Wu & Hui, 2011). The gut microbiome changes rapidly during the first 2 years of life and is influenced by a number of factors including genetics, method of birth delivery, maternal characteristics, nutrition, infections, use of antibiotics, and stress (Collado et al., 2010; Dominguez-Bello et al., 2010; Harmsen et al., 2000; Palmer et al., 2007; Penders et al., 2006).The Microbiota-Gut-Brain AxisThe microbiota-gut-brain axis is defined by the bidirectional communication between the digestive system and the central nervous system. The microbiota-gut-brain axis involves the central nervous system, the autonomic nervous system, and the enteric nervous system. The enteric nervous system consists of approximately 100 million neurons that line the gastrointestinal tract and is often referred to as the second brain because it can function autonomously (Pocock & Richards, 2006). Early research focused on the role of the gut-brain axis in digestion, metabolism, and immune functioning (Konturek, Konturek, Pawlik, & Brzozowski, 2004; Tache, Vale, Rivier, & Brown, 1980), with a strong focus on the role of the central nervous system in regulating these functions (i.e., a top-down model). More recently, there is growing appreciation for the bidirectional communication between the central nervous and digestive systems. The gut is not only influenced by the brain, but also influences the brain. …

Gastrointestinal symptoms and gut dysbiosis may occur before the onset of motor symptoms in Parkinson's disease (PD). Prediagnostic and prodromal features, such as constipation and α-synuclein pathology, can be detected several years before the clinical diagnosis of PD and have the potential to develop as early PD biomarkers. Environmental toxins and gut dysbiosis may trigger oxidative stress and mucosal inflammation, and initiate α-synuclein accumulation in the enteric nervous system, early in PD. Chronic gut inflammation can lead to a leaky gut and systemic inflammation, neuro inflammation, and neuro degeneration via gut-vagus-brain signaling or through blood-brain barrier permeability. Concepts regarding the gut-brain signaling in PD pathogenesis are changing rapidly and more investigation is required. The gut microbiota interacts with the human body by modulating the enteric and central nervous systems, and immune activity. Understanding the immune responses between gut microbiota and human body might help in elucidating the PD pathogenesis. As changes in gut microbiota composition might be associated with different clinical phenotypes of PD, gut microbiota-modulating interventions, such as probiotics and fecal microbiota transplantation (FMT), have the potential to restore the gut dysbiosis, reduce inflammation, and possibly modulate the clinical PD phenotype.

The brain and the gut are linked together with a complex, bi-path link known as the gut-brain axis through the central and enteric nervous systems. So, the brain directly affects and controls the gut through various neurocrine and endocrine processes, and the gut impacts the brain via different mechanisms. Epilepsy is a central nervous system (CNS) disorder with abnormal brain activity, causing repeated seizures due to a transient excessive or synchronous alteration in the brain’s electrical activity. Due to the strong relationship between the enteric and the CNS, gastrointestinal dysfunction may increase the risk of epilepsy. Meanwhile, about 2.5% of patients with epilepsy were misdiagnosed as having gastrointestinal disorders, especially in children below the age of one year. Gut dysbiosis also has a significant role in epileptogenesis. Epilepsy, in turn, affects the gastrointestinal tract in different forms, such as abdominal aura, epilepsy with abdominal pain, and the adverse effects of medications on the gut and the gut microbiota. Epilepsy with abdominal pain, a type of temporal lobe epilepsy, is an uncommon cause of abdominal pain. Epilepsy also can present with postictal states with gastrointestinal manifestations such as postictal hypersalivation, hyperphagia, or compulsive water drinking. At the same time, antiseizure medications have many gastrointestinal side effects. On the other hand, some antiseizure medications may improve some gastrointestinal diseases. Many gut manipulations were used successfully to manage epilepsy. Prebiotics, probiotics, synbiotics, postbiotics, a ketogenic diet, fecal microbiota transplantation, and vagus nerve stimulation were used successfully to treat some patients with epilepsy. Other manipulations, such as omental transposition, still need more studies. This narrative review will discuss the different ways the gut and epilepsy affect each other.

ABSTRACTIntroductionThe microbiota‐gut‐brain axis (MGBA), a complex two‐way connection between the gut microbiota and the brain, has become a key regulator of neurological and neuropsychiatric disorders. Neurological disorders and gut microbiota dysbiosis are linked to these diseases. Changes in gut microbiota can lead to neurotransmitter imbalances, oxidative stress, and neuroinflammation. Gut dysbiosis may contribute to the development of diseases such as depression, autism, schizophrenia, bipolar disorder, Parkinson's disease, Alzheimer's disease, dementia, multiple sclerosis, epilepsy, anxiety, and autism spectrum disorders through immunological regulation, neuroinflammation, and neurotransmitter metabolism changes.MethodThis review systematically sourced articles related to microbiota gut brain axis, neurological disorders, neuropsychiatric disorders and clinical studies from major medical databases, including Scopus, PubMed, and Web of Science.ResultsThis review explores the molecular processes underlying MGBA interactions, including vagus nerve signaling, systemic immunological responses, and metabolites produced by microorganisms. The discussion explores the potential of microbiome‐targeted treatments like fecal microbiota transplantation, probiotics, and prebiotics as effective treatment methods. The comprehension of the MGBA can revolutionize neurology and psychiatry, introducing innovative diagnostic and therapeutic approaches. Multiple elements, including diet, metabolism, age, stress, and medications, shape the human gut microbiota, and intestinal imbalances can lead to CNS diseases. The MGBA interacts with gut bacteria, and gut dysbiosis is associated with neurological disorders.ConclusionsThe review demonstrates the correlation between gut microbiota and neurologically associated diseases, highlighting its importance in neurogenesis, mental development, emotions, and behaviors. MGBA, mediated by microbial metabolites, affects brain function and neuroinflammation. Interventions like fetal microbiota transplantation, probiotics, and prebiotics can improve microbial balance, but more clinical research is needed.

Evidence for a gut-immune-vascular axis in the development of hypertension.

This review summarizes current advances in dental pulp stem cells (DPSCs) and their potential applications in the nervous diseases. Injured adult mammalian nervous system has a limited regenerative capacity due to an insufficient pool of precursor cells in both central and peripheral nervous systems. Nerve growth is also constrained by inhibitory factors (associated with central myelin) and barrier tissues (glial scarring). Stem cells, possessing the capacity of self-renewal and multicellular differentiation, promise new therapeutic strategies for overcoming these impediments to neural regeneration. Dental pulp stem cells (DPSCs) derive from a cranial neural crest lineage, retain a remarkable potential for neuronal differentiation, and additionally express multiple factors that are suitable for neuronal and axonal regeneration. DPSCs can also express immunomodulatory factors that stimulate formation of blood vessels and enhance regeneration and repair of injured nerve. These unique properties together with their ready accessibility make DPSCs an attractive cell source for tissue engineering in injured and diseased nervous systems. In this review, we interrogate the neuronal differentiation potential as well as the neuroprotective, neurotrophic, angiogenic, and immunomodulatory properties of DPSCs and its application in the injured nervous system. Taken together, DPSCs are an ideal stem cell resource for therapeutic approaches to neural repair and regeneration in nerve diseases.

The second brain in Parkinson's disease: fact or fantasy?

Previous studies have shown a bidirectional communication between human gut microbiota and the brain, known as the microbiota–gut–brain axis (MGBA). The MGBA influences the host's nervous system development, emotional regulation, and cognitive function through neurotransmitters, immune modulation, and metabolic pathways. Factors like diet, lifestyle, genetics, and environment shape the gut microbiota composition together. Most research have explored how gut microbiota regulates host physiology and its potential in preventing and treating neurological disorders. However, the individual heterogeneity of gut microbiota, strains playing a dominant role in neurological diseases, and the interactions of these microbial metabolites with the central/peripheral nervous systems still need exploration. This review summarizes the potential role of gut microbiota in driving neurodevelopmental disorders (autism spectrum disorder and attention deficit/hyperactivity disorder), neurodegenerative diseases (Alzheimer's and Parkinson's disease), and mood disorders (anxiety and depression) in recent years and discusses the current clinical and preclinical gut microbe‐based interventions, including dietary intervention, probiotics, prebiotics, and fecal microbiota transplantation. It also puts forward the current insufficient research on gut microbiota in neurological disorders and provides a framework for further research on neurological disorders.

Neurological disorders are diseases of the central and peripheral nervous systems. These disorders include Alzheimer's disease, epilepsy, brain tumor, and cerebrovascular diseases (stroke, migraine and other headache disorders, multiple sclerosis, Parkinson's disease, and neuroinfections). Hundreds of millions of people worldwide are affected by neurological disorders. Approximately 6.2 million people die because of stroke each year; over 80% of deaths take place in low- and middle-income countries. More than 50 million people worldwide have epilepsy. It is estimated that there are globally 35.6 million people with dementia with 7.7 million new cases every year. Alzheimer's disease is the most common cause of dementia and may contribute to 60–70% of cases. The prevalence of migraine is more than 10% worldwide. Therefore, repairing the damaged nervous system is one of the greatest challenges in medicine. Damage to the peripheral nervous system (PNS) can lead to the loss of sensation, motor function, and muscle weakness, but the PNS is capable of significant spontaneous regeneration and in many cases some function can be restored. In contrast, neuronal regeneration following damage to the central nervous system (CNS) is generally unsuccessful and the injuries of CNS can cause permanent paralysis and loss of sensation. Therefore, CNS injuries present significant therapeutic challenges. Current clinical options for CNS disorder treatment, including drug delivery and rehabilitation therapy, are limited and these treatment options do not fully restore the original functions. Recently, cellular therapy has emerged as a treatment option for repair and regeneration of nerve injuries. However, transplantation of stem cells to the injured sites showed poor cell survival and engraftment (Wu et al., 2011). In this regard, the combination of functional biomaterials and cell delivery is a favorable and promising strategy for CNS repair.

The Gut Microbiome in Health and Disease

Pruning that selectively eliminates inappropriate projections is crucial for sculpting neural circuits during development. During Drosophila metamorphosis, ddaC sensory neurons undergo dendrite-specific pruning in response to the steroid hormone ecdysone. However, the understanding of the molecular mechanisms underlying dendrite pruning remains incomplete. Here, we show that protein phosphatase 2A (PP2A) is required for dendrite pruning. The catalytic (Microtubule star/Mts), scaffolding (PP2A-29B), and two regulatory subunits (Widerborst/Wdb and Twins/Tws) play important roles in dendrite pruning. Functional analyses indicate that PP2A, via Wdb, facilitates the expression of Sox14 and Mical prior to dendrite pruning. Furthermore, PP2A, via Tws, governs the minus-end-out orientation of microtubules (MTs) in the dendrites. Moreover, the levels of Klp10A, a MT depolymerase, increase when PP2A is compromised. Attenuation of Klp10A fully rescues the MT orientation defects in mts or pp2a-29b RNAi ddaC neurons, suggesting that PP2A governs dendritic MT orientation by suppressing Klp10A levels and/or function. Taken together, this study sheds light on a novel function of PP2A in regulating dendrite pruning and dendritic MT polarity in sensory neurons.

Neuropathic pain (NP) is a chronic pain disorder arising from somatosensory nervous system impairment. Extensive evidence supports the notion that the gut microbiota (GM) is crucial in maintaining human health by performing vital tasks. At the same time, its disruption has been linked to the emergence and advancement of an expanding range of disorders, including NP, in which GM could play a role in its pathophysiology. The crosstalk between the nervous system and GM happens through immune mediators, metabolites, and nervous structures and involves both central and peripheral nervous systems. This literature review aims to thoroughly investigate the function of modulating GM in the treatment of NP. It will achieve this by integrating existing knowledge, identifying underlying mechanisms, and evaluating the possible clinical consequences of exploiting the gut-brain axis. We will cover the main therapeutic applications of the described GM-modulators, such as probiotics, faecal microbiota transplantation, dietary supplements and emotional support, to the main kinds of NP in which any evidence, even if only pre-clinical, has been unravelled in recent years. The explored NP areas include chemotherapy-induced peripheral neuropathy, diabetic neuropathy, trauma-induced neuropathic pain, trigeminal neuralgia, postherpetic neuralgia and low back pain.

As a common neurodegenerative disease, Parkinson’s disease (PD) is typified by α-synuclein (α-syn) aggregation and progressive degeneration of dopaminergic neurons within the substantia nigra. Clinical manifestations encompass motor symptoms and non-motor aspects that severely impair quality of life. Existing treatments mainly address symptoms, with no effective disease-modifying therapies available. The gut microbiota refers to the community of microorganisms that colonize the intestinal tract. The gut microbiota, gut, and brain are all connected via a complicated, mutual communication pathway known as the “gut microbiota-gut-brain axis.” Gut microbiota dysbiosis is strongly linked to the onset and course of PD, according to growing data. In individuals with PD, gut dysbiosis correlates with clinical phenotype, disease duration, severity, and progression rates. Mechanistically, gut dysbiosis contributes to PD through enhanced intestinal permeability, increased intestinal inflammation and neuroinflammation, abnormal α-syn aggregation, oxidative stress, and reduced neurotransmitter synthesis. Therefore, focusing on the gut microbiota is regarded as a potentially effective treatment strategy. Fecal microbiota transplantation (FMT) is an emerging approach to modulate gut microbiota, with the goal of recovering microbiota diversity and function by transferring functional intestinal flora from healthy individuals into patients’ gastrointestinal tracts. FMT is expected to become a promising therapy of PD and has a broad research and application prospect. Evidence suggests that FMT may restore gut microbiota, ease clinical symptoms, and provide potential neuroprotective benefits. However, the precise therapeutic mechanisms of FMT in PD remain uncertain, necessitating further research to clarify its effectiveness. This review examines alterations in gut microbiota linked to PD, mechanisms through which gut dysbiosis influences the disease, and the latest advancements in FMT research for treating PD, setting the stage for its clinical application.

Canine behavioral disorders have become one of the most common concerns and challenging issues among dog owners. Thus, there is a great demand for knowledge about various factors affecting dogs' emotions and well-being. Among them, the gut-brain axis seems to be particularly interesting, especially since in many instances the standard treatment or behavioral therapies insufficiently improve animal behavior. Therefore, to face this challenge, the search for novel therapeutic methods is highly required. Existing data show that mammals' gut microbiome, immune system, and nervous system are in continuous communication and influence animal physiology and behavior. This review aimed to summarize and discuss the most important scientific evidence on the relationship between mental disorders and gut microbiota in dogs, simultaneously presenting comparable outcomes in humans and rodent models. A comprehensive overview of crucial mechanisms of the gut-brain axis is included. This refers especially to the neurotransmitters crucial for animal behavior, which are regulated by the gut microbiome, and to the main microbial metabolites-short-chain fatty acids (SCFAs). This review presents summarized data on gut dysbiosis in relation to the inflammation process within the organism, as well as the activation of the hypothalamic-pituitary-adrenal (HPA) axis. All of the above mechanisms are presented in this review in strict correlation with brain and/or behavioral changes in the animal. Additionally, according to human and laboratory animal studies, the gut microbiome appears to be altered in individuals with mental disorders; thus, various strategies to manipulate the gut microbiota are implemented. This refers also to the fecal microbiome transplantation (FMT) method, based on transferring the fecal matter from a donor into the gastrointestinal tract of a recipient in order to modulate the gut microbiota. In this review, the possible effects of the FMT procedure on animal behavioral disorders are discussed.

Through the gut-brain axis, the microorganisms that reside in the gut are able to exert an important influence on the central nervous system. Preclinical and clinical evidence suggests that alterations in the composition of the gut microbiota are involved in gastrointestinal and neurological disorders. During critical neurodevelopmental time periods, such as the early life, changes in gut microbial composition may detrimentally impact neurodevelopment, and subsequently lead to neurological disorders in later life. The finding that neurological disorders persist suggests that epigenetic modifications may be involved in response to disruption of the microbiota-gut-brain axis. Through establishing epigenetic modifications, environmental (microbial) signals can interfere with the cellular gene expression patterns. These long-lasting modifications exert their effects even when the initial stimulus is removed. In this review, we discuss the pathways that provide bidirectional communication between the microbiota and the central and peripheral nervous systems. Furthermore, we summarize how these microorganisms in the gut exert their influence through changing the epigenome in the brain-gut axis.Impact statementAlterations in the composition of gut microbiota may influence the etiology of gastrointestinal and neurological disorders by disturbing the communication in the gut-brain axis. Epigenetic changes in the gut-brain axis may perpetuate these phenotypes even when the gut microbiota has been restored. The studies reviewed in this article provide an overview of the influence the microbiota exerts onto its host’s epigenome. First, we summarize the bidirectional pathways through which the microbiota and the gut-brain axis communicate. Second, we provide evidence for the epigenome-altering capacity of the gut microbiota. Finally, we address the existing knowledge gaps and highlight the potential role of the epigenome in the microbiota-gut-brain axis.