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The gut-brain axis is a bidirectional communication system between the central nervous system (CNS) and the gastrointestinal tract. Regulation of the microbiota-brain-gut axis is essential for maintaining homeostasis, including that of the CNS. The routes of this communication are not fully elucidated but include neural, humoral, immune, and metabolic pathways.

Interest in the potential involvement of gut microbiota in brain function emerged, in part, due to the well-described pathways of communication between the brain and the GI tract (brainegut axis) which has been heavily studied in the area of food intake, satiety, and the regulation of the digestive tract.

Together, it is clear that the gut microbiota can be a key regulator of mood, cognition, pain, and obesity. Understanding microbiotaebrain interactions is an exciting area of research which may contribute new insights into individual variations in cognition, personality, mood, sleep, and eating behavior, and how they contribute to a range of neuropsychiatric diseases ranging from affective disorders to autism and schizophrenia.

Interestingly, the catalogue of microbial genes living in the human gut contains 3.3 million microbial genes which amount to 150-fold more than the human gene complement


(Burokas et al., 2015)

Recently, the microbiota-gut-brain axis is becoming recognized in biomedical research, creating multidisciplinary approach in the fields of neuroscience, psychiatry, gastroenterology, immunology, and microbiology

Neural Pathways

The neuronal control of the braine-gut axis transits between the CNS and the ENS via the ANS and peripheral nervous system.

The ENS constitutes a secondary sensory, interneuronal, and motoneuronal network working on its own, allowing to be referred to as the “brain of the gut” or the “second brain” (Galligan, 2002). The ENS is important for good coordination of gut functions and maintaining the general homeostatic state of the organism (control of colon motility, the GI blood flow, and interaction with intraluminal and epithelial gut cells signaling) in order to maintain the optimal performance even in situations of threat (Galligan, 2002; Holzer, 2007). This continuous communication with the brain is facilitated by neurotransmitters, such as acetylcholine, noradrenaline, adrenaline, gamma-amino butyric acid (GABA), neuropeptides, such as substance P, neuropeptide Y, and opioids.

Serotonin and Tryptophan Metabolism

Serotonin [5-hydroxytryptamine] is a biogenic amine that functions as a neurotransmitter in the body, both in the CNS and the gut. Approximately, 95% of serotonin in the body is contained within the gut, specifically, in the enterochromaffin cells of the mucosa and in the nerve terminals of the ENS neurons. Peripheral serotonin is involved in the regulation of GI secretion, gut motility, and pain perception (Costedio, Hyman, & Mawe, 2007; McLean, Borman, & Lee, 2007) and it plays an important role in maintaining mood and cognition (Cryan & Leonard, 2000). Alterations in serotonin transmission may underlie the pathological symptoms of both GI and some psychiatric disorders, and may explain their high comorbidity (O’Mahony, Clarke, Borre, Dinan, & Cryan, 2015). Actually, selective serotonin reuptake inhibitors and tricyclic antidepressants modulating serotonergic neurotransmission, have been shown to be effective in the treatment of both affective and GI disorders such as irritable bowel syndrome (IBS).

Serotonin synthesis in the brain depends on the availability of its precursor, tryptophan which is an essential amino acid and must be supplied in sufficient quantities in the diet (Le Floc’h, Otten, & Merlot, 2011). The evidence of a relationship between the microbiota and tryptophan metabolism has emerged from germ-free mice studies, whereby the absence of the microbiota in early life resulted in increased plasma tryptophan concentrations, reduced kynurenine:tryptophan ratio, and induced increases in hippocampal serotonin levels in adulthood. Moreover, these effects were restored following the introduction of bacteria in germ-free mice postweaning (Clarke et al., 2013). Furthermore, inhibition of the enzyme that initiates the first and rate-limiting step of tryptophan breakdown along the kynurenine pathway indoleamine-(2,3)-deoxygenase, in rats resulted decreased concentrations of serotonin in brain and associated change in anxiety behavior in the elevated plus maze, demonstrating that peripheral tryptophan can influence brain activity and, more importantly, behavior (Naslund, Studer, Nilsson, Westberg, & Eriksson, 2013). The enzymes indoleamine-(2,3)-deoxygenase and tryptophan 2,3-dioxygenase are regulated by inflammatory mediators like proinflammatory cytokine IFN-c and corticosteroids, respectively (Ruddick et al., 2006; Taylor & Feng, 1991). Excessive immune-mediated tryptophan degradation may induce depressive symptoms when the availability of tryptophan is insufficient for normal serotonin synthesis.

The below visual demonstrates how up regulation in the enzymes IDO and TDO, via inflammation or elevations in cortisol, influence tryptophan metabolism and this serotonin production. This can influence both gut and cognitive function.


(Mahoney et al., 2015)

Gut Hormonal Response

The gut can also communicate with the brain via hormonal signaling pathways that involve the release of gut peptides from enteroendocrine cells, which can act directly on the brain (Forsythe & Kunze, 2013). Gut peptides, such as ghrelin, gastrin, orexin, galanin, pancreatic polypeptide, cholecystokinin, and leptin, modulate feeding behavior, energy homeostasis, circadian rhythm, sexual behavior, arousal, and anxiety.

The idea that changes in enteric microbiota composition can alter gut hormone release is supported by probiotic studies

Not only do bacteria in the gut produce hormone-like substances and regulate hormonal output, they can also potentially respond to the hormonal secretions of the host (Lyte, 2013). Elevations in noradrenaline concentrations after acute stress can, for example, stimulate the growth of nonpathogenic commensal E. coli as well as other gram-negative bacteria.

Bacterial Metabolites: Short-Chain Fatty Acids

Under the anaerobic conditions of the large intestine, undigested carbohydrates are fermented mainly to SCFAs (such as butyrate and acetate) and gases (hydrogen, carbon dioxide, methane, and hydrogen sulphide).


Prebiotics are nondigestible food ingredients that selectively stimulate the growth of probiotic bacteria such as Lactobacilli and Bifidobacteria in the gut (Saulnier et al., 2013). Increasing the proportion of these bacteria with prebiotics such as galactooligosaccharides or fructooligosaccharides has many beneficial effects on the gut, the immune system, and on brain function, specifically, increased BDNF expression and NMDA receptor signaling, providing initial support for further investigations of the utility of prebiotics in mental health and potential treatment of psychiatric disorders (Burokas et al., 2015).


It is pertinent to note that, not all probiotics even within bacterial genera, will produce positive effects. Moreover, the status of the host itself is critical for the efficacy of probiotics in that some probiotics will only exhibit beneficial effects in disease states such as IBS and may show no positive effects in healthy individuals.

There are some studies showing effects of probiotics on brain function in healthy humans. For example, women who had taken a fermented milk product containing four probiotics (Bifidobacterium animalis subsp. lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp. lactis) showed reductions in brain responses to an emotional task, particularly in sensory and interoceptive regions that were measured with functional magnetic resonance imaging.

The below visual highlights disorders of the microbiota-gut-brain axis. The microbiotaegutebrain axis plays an important role in maintaining homeostasis and its dysfunction has been linked to various psychiatric and nonpsychiatric disorders.


(Burokas et al., 2015)


One of the principal mechanisms proposed to underlie stress-induced alterations is the “leaky gut” phenomenon, which has been described by inmajor depression (Maes, Kubera, & Leunis, 2008). Thus, increased intestinal permeability and the consequent translocation of gram-negative bacteria across the mucosal lining to sites where direct interaction with immune cells and the ENS can occur (Gareau, Silva, & Perdue, 2008). This may lead to activation of an immune response characterized by increased production of inflammatory mediators. Indeed, it has been shown that patients with major depression had higher serum concentrations of IgM and IgA against lipopolysaccharide of enterobacteria than healthy controls.


It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. Since the gut contains at least 400 times more melatonin than the pineal gland, a review of the functional importance of melatonin in the gut seems useful, especially in the context of recent clinical trials. These receptors can be found in the gut and their involvement in the regulation of GI motility, inflammation and pain has been reported in numerous basic and clinical studies.

Presently, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials.


This article includes large extracts from the article: Burokas et al., (2015) Microbiota Regulation of the Mammalian GuteBrain Axis; Advances in Applied Microbiology, Volume 91