The human brain is made up of billion of neurons that are constantly firing electrical signals back and forth to tell you what to do, what to think and how to feel. But the human body actually has a second brain that controls you much more than you might realize and most people have no idea it exist (Fiona,2016).
Buried around the gut or digestive system is a second brain “The gut brain” also called “The enteric brain” which has a mind of its own (Dorland, 2012). The gut (digestive system of the body) has close to 500 million neurons, five times as many as the one hundred million neurons in the human spinal cord (Hall, 2011). Not only that the gut “talks” with the brain chemically (by releasing chemicals that are then taken to the brain by blood) but it also sends electrical signals via the vagus nerve. Vagus nerve is one of the longest nerves inside the body whose central purpose is to relay information and status of internal organs like gut and heart to the brain (Mastone, 2011). It starts from the head and after going through the entire organs end near the anus.
Most of the gut neurons are used in the daily grind of digestion (Hadhazy, 2010). Gut system is an extremely complex chemical processing machine which breaks down the food, absorbs nutrient and moves the waste down (via muscular contraction) towards anus for expelling it. Thus, the autonomous nervous system of gut allows it to work independently of the brain. Nevertheless recent researches have revealed that there is tremendous amount of information flow from the gut to the brain via the vagus nerve and this flow is mostly one sided – almost all of it is from the gut to the brain and not the other way round (Hadhazy, 2010). This is how it should be since gut works continuously whether we are aware or not.
The reverse interaction (from the brain to the gut) is when we get hunger pangs and the brain tells the body to get food or when something goes wrong in the gut like pain or diarrhea, necessitating medicines for its cure.
Recent scientific evidence also suggests that big parts of our emotions are probably influenced by the chemicals and nerves in the gut. For example, 95% of body’s serotonin is found in the gut (Hadhazy, 2010). Serotonin is an important neurotransmitter that is well known contributor towards feelings of well being. Sometimes it is also called a “happiness hormone”.
A deeper understanding of this mass of neural tissue, filled with important neurotransmitters, is revealing that it does much more than merely handle digestion or inflict the occasional nervous pang. The little brain in connection with the big one in the skull partly determines our mental state and plays a key role in certain diseases throughout the body (Hadhazy, 2010).
Functioning much like the brain in your head, this system is able to sense and receive impulses. It records and remembers experiences and responds to all kind of emotions (Romesh, 2017). Its neuron or nerve cells are affected by the same neurotransmitters as the high brain (Romesh, 2017).
“Structurally and neurochemically, the enteric nervous system is a brain unto itself. Within the yards of tubing lies a complex web of microcircuit driven by more neurotransmitters and neuromodulators that cannot be found anywhere else in the peripheral nervous system” – Dr Micheal Gershon, professor of Anatomy and cell Biology at Columbia-Presbyterian medical center in New York
What makes the enteric nervous system so special is that it controls the entire digestive system, from the esophagus to the anus, and is able to function completely on its own even when completely cut off from the brain. In addition to controlling our digestive system, the enteric nervous system also has a surprising effect on our mood and behaviour (Dovey, 2016).
The enteric nervous system or intrinsic nervous system is one of the main divisions of the autonomic nervous system and consist of a mesh-like system of neurons that govern the function of the gastrointestinal tract. The ENS is called the second brain because it is capable of acting independent of the sympathetic and parasympathetic nervous systems, although can be influenced by them (Dorland, 2012).
The ENS in humans consists of some 500 million neurons (Young, 2015) five times as many as the 100 million neurons in the human spinal cord. The enteric nervous system is embedded in the lining of the lining of the gastrointestinal tract (Hall, 2011).
The neurons of the ENS are collected into two main ganglia; the myenteric plexus (Auerbach’s) located between the inner and outer layers of the muscularis externa and submucosal plexus (Meissner’s) located in the submucosa. The Myenteric plexus provides motor innervations to both layers of the muscular layer of the gut, having both parasympathetic and sympathetic input. It arises from the cells in the vagal trigone which is the nucleus of the origin for the tenth cranial nerve (vagus nerve) located in the medulla oblongata. The fibers are carried by both the anterior and posterior vagal nerves. The myenteric plexus is the major nerve supply to the gastrointestinal tract and controls GI tract motility. The nerve bundles of the submucous plexus are finer than those of the myenteric plexus. Its function is to innervate cells in the epithelial layer and the smooth muscle of the muscularis mucosa. 14% of submucosal plexus neurons are sensory neurons (Costa & Brookes, 2000). The ENS is capable of autonomous functions (Dorland, 2012) like coordination of reflexes; although it receives considerable innervations from the autonomic nervous system, it can and does operate independently of the brain and spinal cord (Gershon, 1998). Its study is the main focus of neurogastroenterology.
This gut-brain axis is a biochemical signaling that takes place between the gastrointestinal tract (GI tract) and the central nervous system (Sudo & Chida, 2004). Broadly defined, the gut-brain axis includes the central nervous system, neuroendocrine and neuroimmune systems, including the hypothalamic–pituitary–adrenal axis (HPA axis), sympathetic and parasympathetic arms of the autonomic nervous system, including the enteric nervous system and the vagus nerve, and the gut microbiota (Dinan & Cryan, 2015). The term “gut–brain axis” is occasionally used to refer to the role of the gut flora in the interplay as well, whereas the term “microbiome–gut–brain axis” explicitly includes the role of gut flora in the biochemical signaling events that take place between the GI tract and CNS (Mayer, 2014). The gut-brain axis comprises a network of autonomic neurons that connect the central nervous system (CNS)—specifically, the caudal brainstem and spinal cord—to the esophagus, gastrointestinal tract, liver, and pancreas (Furness, 2006). The axons of these neurons travel through the vagus, splanchnic, mesenteric and pelvic spinal nerves to innervate the abdominal viscera. While the general organization of the gut-brain axis appears relatively simple compared to that of the CNS, the neurochemical, anatomical and functional relationships between different populations of gut-brain axis neurons can be highly complex (Anlauf et al, 2003). Notably, the anatomical study of gut-brain axis has a remarkably long history. However, the detailed anatomy of the gut-brain axis remained inaccessible to biologists for a long time because the nerves immediately cease to be distinguishable as they penetrate into peripheral organs. Thus, it was not until the late nineteenth century that Auerbach and Meissner (Meissner, 1857; Auerbach, 1863) discovered postganglionic neurons located in the gastrointestinal wall (also known as enteric neurons). Enteric neurons, along with postganglionic neurons in the gallbladder and pancreas, are part of the gut-brain axis, as they receive direct input from, and transmit information to, the rest of the autonomic nervous system; however, enteric neurons are also capable of operating independently of the gut-brain axis (Gershon, 1981). Studies with humans – measuring variations in gut flora between people with various psychiatric and neurological conditions or when stressed, or measuring effects of various probiotics (dubbed “psychobiotics” in this context) – had generally been small and were just beginning to be generalized (Braun & Enck, 2016). Whether changes to gut flora are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut-brain axis, remained unclear (Schneiderhan & Locke, 2016).
Serotonin is a key element of this axis, acting as a neurotransmitter in the CNS and in the enteric nervous system that is present in the wall of the gut. In addition, serotonin is produced by endocrine cells and as a paracrine hormone in the gut and as an endocrine hormone, carried through the blood to the platelets. Its role as a hormone acts to link the two ends of the brain-gut axis as well as having systemic effect such as bone density and metabolism (Sansone, 2012). The synthesis of serotonin involve hydroxylation of tryptophan by the enzyme tryptophan hydroxylase. Serotonin synthesis occurs in the periphery within the gut neurons and enterochromaffin cells and centrally within the neurons of the raphe in the brainstem. The peripheral endocrine synthesis pathway only differs from the central and enteral neuronal pathway by the utilization of tryptophan hydroxylase type 1 instead of type 2 (Amireault et al, 2013). Degradation of serotonin is via monoamine oxidase but in the periphery glucuronidation plays an important role(Sakakibara et al, 2015). Another piece of the serotonin puzzle involves the resident community of microorganism that have colonized the digestive tract. The gut microbiota is primarily found in the large intestine, but smaller numbers can be found throughout the gastrointestinal tract (Janddhyala et al, 2015). Cross-talk between the gastrointestinal epithelium and enteric flora contributes to functions such as immune responses and regulation of hormones, and is proving to be critical to the maintenance of both homeostasis and health. A balance is needed between bacterial utilization of tryptophan and the tryptophan necessary for serotonin synthesis in both the enteric and central nervous system (O’Mahony et al, 2015).
There is both direct and indirect regulation of tryptophan and serotonin in the gut by the resident microbiota. Indirect regulation of tryptophan availability and serotonin formation by the gut microbiota is primarily via the kynurenine pathway. As noted, the synthesis of kynurenine accounts for approximately 90% of tryptophan metabolism (Stone & Darlington, 2002)
The gut flora is the complex community of microorganisms that live in the digestive tracts of humans and other animals. The gut metagenome is the aggregate of all the genomes of gut microbiota (Saxena & Sharma, 2016).The gut is one niche that human microbiota inhabit (Sherwood, 2013). In humans, the gut microbiota has the largest numbers of bacteria and the greatest number of species compared to other areas of the body (Quigley, 2013). In humans, the gut flora is established at one to two years after birth, and by that time, the intestinal epithelium and the intestinal mucosal barrier that it secretes have co-developed in a way that is tolerant to, and even supportive of, the gut flora and that also provides a barrier to pathogenic organisms (Faderl, 2015). The relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship (Sherwood, 2013). Human gut microorganisms benefit the host by collecting the energy from the fermentation of undigested carbohydrates and the subsequent absorption of short-chain fatty acids (SCFAs), acetate, butyrate, and propionate (Clarke, 2014). Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics (Clarke, 2014). The systemic importance of the SCFAs and other compounds they produce are like hormones and the gut flora itself appears to function like an endocrine organ and dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions (Quigley, 2013). The composition of human gut flora changes over time, when the diet changes, and as overall health changes (Shen & Wong, 2016).
From a viewpoint of the human body as a self-sufficient individual, to a perception of our bodies as super-complex ecosystems. This change of perspective has included a reappraisal of the role of microorganisms within our bodies (i.e., endosymbionts). While the popularly-held belief is that any microorganism found within the human body must have a detrimental effect on its health, emerging research has renewed an emphasis on the fact that many microorganisms have mutually beneficial relationships with their hosts (Archie and Theis, 2011), acting as a probiotic: a live microbe with a beneficial effect on the host via modifications of host-associated microbial communities, enhancing the host’s response toward disease, its nutrient-exploitation capacity, or improving its environment (Verschuere et al., 2000). Recent research suggests how microbiota, i.e., a microbial community occupying a particular habitat (e.g., the gut microbiota), can serve its host by protecting it against pathogens, metabolizing complex lipids and polysaccharides that otherwise would be inaccessible nutrients, neutralizing drugs and carcinogens, modulating intestinal motility, and affecting visceral perception. Across evolution, endosymbionts have established important feedback channels with the central nervous system (CNS), some of which are crucial for maintaining homeostasis. For example, as microbial life was increasingly tolerated across generations of organisms, its presence has shaped the evolution of the immune system (Kelly and Mulder, 2012). The recognition that the gut microbiota influences several signaling pathways led to the suggestion of the concept of a microbiota–gut–brain (MGB) axis, a topic covered by extensive reviews (Cryan and Dinan, 2012). The proposal of a MGB axis suggests that through a dynamic alignment, microbiota inhabiting the intestinal lumen affects its host’s CNS activity (including vegetative and cognitive functions), and vice versa brain activity impacts microbiota development and composition. Clinical and experimental evidence indicate that this is also the case of human subjects, with such relationship playing a pivotal role in the development of metabolic and mental diseases. According to the World Health Organization, metabolic and mental disorders lead the global burden of disease, urging researchers and clinicians to set research priorities, and to governments, public agencies and private funds to apply urgent actions and investment (Mathers et al., 2008). In this regard, understanding the bidirectional signaling between the microbiota, gut and brain, underlie potential and significant impacts on global health, opening new preventive and therapeutic opportunities. Based on the above, the first section of our work provides an overview of the neurobiology supporting such interactions, focusing on key experimental and clinical data of the MGB axis and its potential impact on relevant metabolic and mental human disorders. While recent years have witnessed an increasing interest in proximate questions regarding different aspects of microbiota, the co-evolutionary interactions of animals and bacteria have been relatively unattended. This, in spite of the possibility that a focus on the evolution of the MGB axis could provide new theoretical frameworks for understanding complex evolutionary relationships involved in mutualisms between hosts and commensal bacteria. This includes the possibility that such mutualisms could influence the evolution of immunological systems, shape higher cognitive functions at the individual level, and work as a selective force promoting socialization and social structures, with an influence on the psychobiological basis of gregariousness, social perception, mate choice, and sexual behavior (Neuberg et al., 2011).
Multiple direct and indirect pathways maintain intensive and extensive bidirectional interactions between the gut microbiota and the CNS; involving endocrine, immune and neural pathways (Grenham et al., 2011), and form the basis of the so called MGB axis. For instance, under stress, the brain may influence the composition of the gut microbiota (Bailey and Coe, 1999) via the hypothalamus–pituitary–adrenal (HPA) axis, which regulates cortisol secretion, affecting immune cells activity; both locally in the gut and systemically. When the organism suffers an injury, the first immunological reaction is characterized by redness, pain and heat. These responses are constrained by neuronal regulation of inflammation process, carried out by the HPA axis via catecholamine (Sternberg, 2006) production. The necessary communication processes are based on neurotransmitters, neuropeptides, cytokines, hormones, growth factors (among others), which mediate the relationship between the immune system and the CNS. A feedback process leading to homeostasis (Downing and Miyan, 2000). Yet, disorders like stress (Glaser and Kiecolt-Glaser, 2005)can impact such equilibrium, leading to disease, allergic reactions, inflammatory disease and predisposition to infection. Additionally, cortisol can alter gut permeability and barrier function, and thus contribute to variations in gut microbiota composition (O’Mahony et al., 2011). Vice versa, experimental evidence indicates that the gut microbiota, and pre- and probiotic agents can alter the levels of circulating cytokines, which in turn can have a marked effect on several brain functions (Forsythe and Bienenstock, 2010). Additionally, both the afferent branch of the vagus nerve (Bravo et al., 2011) and modulation of systemic tryptophan, precursor of the neurotransmitter serotonin (Desbonnet et al., 2009), are strongly implicated in relaying the influence of the gut microbiota to the brain.

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