International Journal of Cardiovascular Sciences. 2020; 33(5):528-536 528 REVIEW ARTICLE The Gut Brain-Axis in Neurological Diseases Pedro Melo Barbosa and Egberto Reis Barbosa Departamento de Neurologia, Universidade de São Paulo, São Paulo, SP – Brazil Abstract evident when the digestive tract is considered. Commensal bacteria, which colonize the human gut shortly after birth, Recent evidence suggests that dysfunction of the gut- acquire nutrients from their hosts. In exchange, they assist brain axis may be an important factor contributing to many the digestive process and the production of metabolites diseases of the nervous system. Increased gut permeability that contribute to the host’s survival. The collective of host- associated with chronic gastrointestinal dysfunction, as associated microbes is denominated microbiota, and its well as changes in the composition of the gut microbiota genomic constitution, microbiome.1 could contribute to exposure of the enteric and central The enteric nervous system consists of approximately nervous system to pathogens and its metabolites, 200 million neurons that control the function of the including endotoxins and pro-inflammatory cytokines. entire digestive tract. It is composed of an intrinsic As a consequence, dysfunction of the host’s immune network of nervous fibers and ganglia, the myenteric system could contribute to an abnormal immunological and submucosal plexus. The myenteric plexus controls response leading to auto-immune conditions, such as mainly the motility of the digestive tract (peristalsis) and multiple sclerosis. So far, gut dysbiosis has been reported is located deeply between the longitudinal and circular in association with Parkinson’s disease, Alzheimer’s layers of the entire digestive tract. It is composed mainly disease, multiple sclerosis, neurodevelopmental and of a network of ganglia linked by unmyelinated fibers neuropsychiatric conditions, and cerebrovascular disease. connected to the vagus nerve and sympathetic ganglia. These findings suggest that the possibility of targeting the The submucosal plexus (Meissner plexus) is located more gut microbiota could become a future therapeutic option superficially and closer to the intestinal lumen from the to treat these conditions. However, before this knowledge stomach to the colon. It is composed mainly by nervous can be useful in the clinical setting, more data is needed to fibers and ganglia, and controls the mucosal secretions, establish clear causal relationships between dysfunction vascular flow and absorption.2 of the gut-brain axis and neurological diseases. The gut-brain axis is an information exchange platform which allows two-way communication between the gut Introduction and the host nervous system. Information can be exchanged via neural network, hormones and the immune system.3 Hundreds of millions of years of co-evolution have resulted Disruption of the delicate balance between host and gut in a complex symbiotic relationship between multicellular bacteria could be a contributing factor behind many diseases. life and bacteria. While it is very likely that more aggressive Following publications that have reported changes in the interactions predominated in the early days, survival in composition of the gut microbiome, in association with many the long run demanded a more harmonic relationship. digestive and non-digestive conditions, research interest in For modern humans, the benefits of this relationship are the gut-brain axis has significantly increased making it a research hot topic. This review will explore the physiology and pathophysiology of the gut-brain axis and its role in Keywords neurological diseases. Gastrointestinal Tract; Brain; Nervous System; Microbiome Gastrointestinal/complications; Neurobehavioral Manifestations. Egberto Reis Barbosa Assistant Doctor at Universidade de São Paulo Mailing Address: Egberto Reis Barbosa Universidade de São Paulo Av Dr. Arnaldo, 455. Postal Code: 05508-900, São Paulo, SP – Brazil. [email protected] E-mail: [email protected] DOI: https://doi.org/10.36660/ijcs.20200039 Manuscript received on March 08, 2020, revised manuscript on April 03, 2020, accepted on April 03, 2020. Barbosa & Barbosa Int J Cardiovasc Sci. 2020; 33(5):528-536 529 The Gut-Brain Axis Review Article Pathophysiology to affect the production of neurotransmitters, such as gamma-aminobutyric acid (GABA), acetylcholine and the serotonin precursor tryptophan.1 Commensal Normal functioning of the gut-brain axis gut bacteria are also capable of producing important nutrients, such as choline and SCFA, as well as the The intestinal epithelial barrier relies on tight hormones ghrelin and leptin. They are also able to alter junctions between cells to keep its integrity and to brain function through changes in the expression of separate the external (the gut microbiota) from the CNS receptors.9 Animal research using murine models internal environment (the gut immune and nervous have highlighted the importance of the gut bacteria, systems). The composition of the gut microbiota is not only for preserving the health of the brain, but also regulated by both extrinsic factors, such as diet, lifestyle for contributing to its normal development. Collins and early microbiota exposure; and intrinsic factors, et al.,10 have reported a decrease in nerve density, a such as genetic background, metabolism, and activity decrease in neuronal density in ganglia, and an increase of the host’s hormonal and immune systems.4 in the prevalence of nitrergic neurons in the myenteric One of the most studied extrinsic factors that is plexus of the jejunum and ileum of germ-free mice, able to alter the gut microbiota composition is diet. highlighting the importance of the gut microbiota in the Dietary fibers are degraded by commensal bacteria in normal development of the enteric nervous system.10 the gut and lead to the production of short-chain fatty Worse cognition and increased stress response have acids (SCFA), which are beneficial to the brain. On the been reported in germ-free mice, a different behavioral other hand, epidemiological studies have reported a phenotype compared to control animals.11 The gut positive correlation between increased risk of cognitive microbiota can also affect brain circuits responsible for decline and consumption of high-saturated-fat food, motor and behavioral control.12 Increased microbiota high intake of animal protein and refined sugars.5 diversity has been associated with improved structural The Mediterranean diet, known for its association with organization of the hippocampus, hypothalamus and longevity, is also able to influence the composition of the caudate nucleus.13 gut microbiome, resulting in higher levels of fecal SCFA and predominance of Prevotella and Firmicutes species, a composition that appears to be more favorable to the Dysfunction of the gut-brain axis host.6 SCFAs are important bacterial metabolites that A complex immune interplay is in place allowing can reduce inflammatory response and promote CNS the gut microbiota to co-exist peacefully with the host’s plasticity. A diet high in fructose has been associated cells. The gut immune system needs to be finely tuned with an exacerbated inflammatory response in the to maintain its vital defensive function in the presence hippocampus, which could be a consequence of changes of commensal bacteria. Diverse pathological forces in the gut bacteria.7 could break this delicate and complex relationship Patients with refractory epilepsy can benefit from a resulting in diseases. ketogenic diet. Olson et al8 have studied how this type The composition of the gut microbiota appears to be an of diet can influence the gut microbiota. Higher levels important factor contributing to diseases. An unbalanced of hippocampal GABA have been reported alongside composition of the gut microbiota, known as dysbiosis, an increase in Akkermansia and Parabacteroides species. has been implicated not only in diseases of the gut, This change appears to confer seizure protection, as it does but also in pathologies of distant organs/systems. The 8 not occur if germ-free mice were fed with a ketogenic diet. immune system can be affected by dysbiosis in many The vagus nerve is an important gut-brain axis ways. Activation of T-cells by changes in gut microbiota pathway that allows for direct connection between these has been associated with auto-immune uveitis14 and two organs. By controlling gut motility and secretion, the could have a role in other auto-immune conditions. vagus nerve is able to change the gut environment and Furthermore, systemic levels of pro-inflammatory to control the enteric immune system response with a cytokines can be affected by commensal gut bacteria direct consequence to the gut microbiota. Conversely, gut and could be implicated in different conditions. bacteria produce metabolites that are able to influence Lastly, allergies have also been associated with changes both the enteric and the central nervous system and in the composition of the gut microbiota.15 Int J Cardiovasc Sci. 2020; 33(5):528-536 Barbosa & Barbosa Review Article The Gut-Brain Axis 530 Another possible factor connecting dysbiosis to Neuropsychiatric symptoms and neurodevelopmental diseases is an increase in gut permeability (‘leaky conditions gut’), caused by local pathological processes. This Inducing gut dysbiosis by antibiotic use in animal could allow gut bacteria and/or its metabolites to models, researchers have reported that anxiety and