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Basheer, Samath, and Basheer: The gut–brain axis – a new key to understand mind–body connection


The enteric nervous system had been regarded as a digestive organ until the remarkable discovery made by Michael Gershon that 90% of the body’s serotonin is located within the walls of the gastrointestinal (GI) tract.1 This ignited the interest of various neuroscientists, including psychiatrists, regarding the GI nervous system. The enteric nervous system is composed of neuronal plexuses (e.g. Meissner’s plexus and Auerbach’s plexus), surrounded by a pool of more than 30 neurotransmitters (e.g. serotonin, dopamine, glutamate, noradrenaline and nitric oxide) and other chemical mediators (e.g. neuropeptides and enkephalins). It also contains glia-like supportive cells, and together contains nearly 100 million neurons, similar to the number of neurons in the spinal cord.2,3

The gut–brain axis describes the bidirectional neural pathways linking cognitive and emotional centres in the brain to the neuroendocrine centres, the enteric nervous system and the immune system.4 Emotional states, such as depression, and behavioural dispositions, ranging from hostility to psychosocial stress, can directly influence both physiological function and health outcomes in different ways;5 one such example is the gut–brain connection. The gut–brain connection is intimately involved in explaining how inflammatory response induced by psychosocial stress in the gut is modulated by bidirectional communication between the neuroendocrine and immune system of the gut with brain. Many areas of research have established multiple pathways by which the immune system and the enteric nervous system communicate bidirectionally with the brain.6

There are two types of gut flora. Normal gut flora is essential to maintain the gut–brain axis, thereby ensuring a good mood is maintained; the composition of normal gut flora varies from person to person. In addition, there is also variation based on the location of the gut microbes in the gut of different individuals. As a result of this variation, there is a diverse pattern of the enteric nervous system which differs between individuals, as these microbes are essential for the production of serotonin. Serotonin is vital for the development and maturation of the enteric nervous system in order to maintain a homeostatic gut–brain axis. Any disruption in the growth of normal microbes impairs cognitive and emotional balance7 whenever the gut is exposed to pathogenic microbes; secretory immunoglobulin A (IgA) is constantly produced (60 mg/kg) at the interface between GI mucus and lumen by plasma cells to prevent adhesion of these pathogens, thus maintaining a homeostatic gut–brain axis.8,9

When an individual is under stress, IgA production decreases, leading to activation of proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-α) and interleukins 1, 6 and 8, which spontaneously stimulate the hypothalamus to produce corticotropin-releasing hormone (CRH) by two routes: (1) crossing the blood–brain barrier via the bloodstream and (2) the vagus nerve, which carries 90% of information of immune status from the periphery to the central nervous system (CNS). Thus, CRH in turn stimulates adrenocorticotropic hormone from the anterior pituitary to produce cortisol from the adrenal cortex.1012 Under stress, TNF-α upregulates indoleamine 2,3-dioxygenase, a catabolic enzyme that degrades tryptophan in order to prevent bioavailability of tryptophan for microbes; serotonin formed from tryptophan is vital for elevation of mood and its deficiency leads to depression. Furthermore, the released cortisol stimulates tryptophan-2,3-dioxygenase to produce kynurenine, which further forms neurotoxic quinolinic acid (a N-methyl-D-aspartate receptor agonist), thereby impairing cognition.7,13

In conclusion, the enteric nervous system communicates with the CNS through neural, immune and endocrine pathways, which may help in understanding the mind–body connection.



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