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Gut Feelings: Microbial influences on neurotransmitters and brain function

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With the growing focus on the human microbiome there has been a profound shift in our understanding of the role of the gut in health and disease. In particular, the numerous neurocrine and endocrine signalling mechanisms between the gut and the brain has been demonstrated as a key influence of the central nervous system. The gut and the brain are now recognised as being highly integrated and communicate in a bidirectional fashion largely through the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis. This complex cross-talk not only ensures the proper maintenance of gastrointestinal homeostasis and digestion, but is likely to have multiple effects on affect, motivation and higher cognitive functions, including intuitive decision making.[1

Of course, as a concept, the principle of a gut-brain axis is not new and is in fact, deeply rooted in our language. Our reference to long held expressions, such as ‘gut-instinct’ and ‘intestinal fortitude’, point to an intuitive appreciation of the relationship between the gastrointestinal and nervous systems.

In the middle of the nineteenth century, physiology and psychiatry had recognised this interaction and its role in abdominal pain syndromes[2] as well as possible emotional regulation.[3] By the early twentieth century Byron Robinson, an American physician noted for his extensive research on the nervous system of the abdomen, had published his seminal book The Abdominal and Pelvic Brain. His observations identified a vast and highly complex neuronal network contained within the abdominal viscera, which was shown to independently influence and regulate autonomic processes including: peristalsis, blood flow, secretion, and absorption.

It was Robinson’s contemporary, Johannis Langley, who coined the term enteric nervous system (ENS); and due to its communication with the central nervous system (CNS) via the vagus nerve and sympathetic nervous systems, has been described as the ‘second brain’. We now know that the ENS, consisting of some 500 million neurons, is not just capable of autonomy but also profoundly influences the brain.[4

Having developed from the same embryonic neural crest, the CNS and ENS share many similar features, including extensive glial support, neuronal diversity and semi-permeable membranes constituting a barrier to the passage of cells, particles, and large molecules. Both are also richly endowed with neurotransmitters and neuromodulators. 

The ENS makes use of more than 30 neurotransmitters, most of which are identical to the ones found in CNS. In fact, many of the neurotransmitters known to be critical to CNS communications were first discovered in the ENS. The adrenergic amines, adrenaline and noradrenaline are located only in the extrinsic sympathetic pathways, but acetylcholine, serotonin, gamma-aminobutyric acid (GABA) and nitric oxide are all found in the nerves of the ENS.[5] In addition, two dozen neuropeptides are present along with enkephalins and benzodiazepines.

The multitude of neurons in the enteric nervous system, along with this broad array of neurotransmitters and neuropeptides, are not only responsible for controlling the primitive motile, secretory, and absorptive behaviours of the gut, they also enables us to sense the inner world of our gut and its contents.[6

Nevertheless, it appears that this system is far too sophisticated to have evolved simply to exclusively ensure normal digestive function. The fact that about 90 per cent of the signals passing along the vagus nerve come from the gut to the brain and not the other way around suggest that a large part of our emotions and psychological states are influenced by the ENS.

This has been demonstrated through several studies involving vagus nerve stimulation. In 2006, Corcoran et al demonstrated that vagus nerve stimulation (VNS) may be an effective treatment for some individuals suffering from chronic treatment-resistant depression.[7] A previous study in 1995 showed that VNS significantly increased cerebrospinal fluid levels of GABA while also decreasing aspartate.[8

Another study published in 2011 showed that specific components of our food exert a direct effect on neurotransmitters in the gut that then signal the brain. By providing subjects with an intra-gastric infusion of fatty acid solution or saline during experimentally induced emotions, researchers found that behavioural and neural responses to sad emotion were attenuated by the fatty acid infusion. Within minutes after the fatty acids hit the stomach, MRI scans showed activation of those brain regions known to moderate emotions, with notably higher levels of blood flow in the brain stem and the limbic system.[9

The gut-brain interaction also seems to play a role in a range of neurological disorders. Researchers have investigated the prevalence of depression and anxiety disorders as a comorbidity in inflammatory bowel disease (IBD) and IBS. It was found that IBD and IBS patients are more likely to suffer from psychiatric disorders like depression and anxiety disorders in comparison to the general population.[10-12] When comparing the comorbidity of these GI disorders, significantly more IBS subjects were diagnosed with depression (IBS: 61%; IBD: 16%), generalised anxiety disorder (IBS: 54%; IBD: 11%), panic disorder (IBS: 61%; IBD: 11%), and agoraphobia (IBS: 25%; IBD: 25%) [13], with a higher prevalence for a lifetime diagnosis of these disorders compared to the general population.[12,13]

Other studies in mice have shown that serotonin released from the gut enterochromaffin cells may contribute to serotonin signalling in the brain.[14] Given that the gastrointestinal tract is responsible for producing 80 - 90% of the body’s total pool of serotonin, any disturbance to gut production could theoretically, have profound implications on mood.

Exactly how disturbances in the production of gastrointestinal serotonin (and other gut neurotransmitters) might occur may currently be uncertain, but accumulating evidence points to a critical role for the gut microbiome. In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important factor in such regulation. 

Given the substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission, therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders.[15]

A 2015 study has demonstrated just how important the microbiome is with regards to diverse serotonin-related functions. Researchers found that mice lacking gut bacteria had low levels of serotonin in the colon and blood compared to mice with normal gut bacteria. When the germ-free mice were colonised with native spore-forming microbes from other mice, serotonin in the blood and colon reached normal levels. Moreover, these microbes improved gut motility as well as platelet aggregation and blood clotting. Using metabolomic profiling, the researchers also found that spore-forming bacteria altered serotonin synthesis in the colon through metabolic signalling to enterochromaffin cells.[16]

In further research, demonstrating the effect of commensal gut bacteria on CNS function,  researchers showed that Lactobacillus rhamnosus increased GABA receptors in the cortical regions of the brains of mice. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression. Importantly, L. rhamnosus reduced stress-induced corticosterone as well as anxiety and depression-related behaviour. Furthermore, these effects were not found in mice that had their vagal nerve removed, identifying the vagus as a major modulatory communication pathway between the gut bacteria and the brain.[17]

This study is further supported by research using Bifidobacterium longum in mice with infectious colitis. Researchers used a model of chemical colitis to test whether the anxiolytic effect of B. longum involves vagal integrity and changes in neural cell function. Consistent with previous observations, chronic colitis was associated with anxiety-like behaviour, which was absent in vagotomised mice. B. longum normalised behaviour and it’s anxiolytic effect was dependant on vagal integrity. Given that  B. longum decreased excitability of enteric neurons, it was concluded that this may signal to the central nervous system by activating vagal pathways at the level of the enteric nervous system.[18]

In 2011, Neufeld and colleagues used female germ-free mice to demonstrate that conventional microbiota influences anxiety behaviour. The authors showed that the altered behaviour of germ free mice was accompanied by a decrease in aspartate receptor expression in the central amygdala, increased brain-derived neurotrophic factor (BDNF) expression and decreased serotonin receptor expression in the hippocampus. BDNF is crucial for supporting neuronal survival and encouraging the growth and differentiation of new neurons and synapses and thus is involved in the regulation of multiple aspects of cognitive and emotional behaviours.

In an attempt to translate the relevance of these studies to humans another group in 2013 investigated whether consumption of a fermented milk product containing probiotics (FMPP: Bifidobacterium animalis, Streptococcus thermophiles, Lactobacillus bulgaricus and Lactococcus lactis) for four weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks. Four-week intake of an FMPP by healthy women affected activity of brain regions that control central processing of emotion and sensation. This study is the first to demonstrate an effect of probiotics on gut–brain communication in humans. It was successful in showing that such communication exists and is modifiable, even in healthy women.[19]

In a more recent study published in August 2015, researchers examined 40 healthy young adults who had no mood disorders. In this triple-blind placebo-controlled, randomised trial, half the group consumed a probiotic supplement containing eight types of bacteria, while the other half took a placebo. The probiotic group noted improvements in their moods, reporting less reactivity and aggressive feelings to sad moods than those who took placebo.[20]

In light of this research, our understanding of the gut-brain axis is evolving at a very rapid pace. While the ENS and its connection to the CNS has been a basic tenet of physiology and medicine for the last one-hundred years, evidence is now accumulating that the gut microbiota plays a significant role in relaying information from the gut to the brain utilising microbiota-derived signalling molecules, neurotransmitters and gut hormones, as well as vagal and spinal afferent neurons. 

There is a growing realisation that disturbances to the gut microbiome can lead to alterations in mood and cognition, giving rise to anxiety-like behaviours as well as alterations in central neurochemistry. Changes in diet, certain medications, infections and stress can all impact the microbiome, which may in turn have a direct effect on brain function.

What is especially promising is that emerging studies are providing insights into the use of probiotics as novel treatment strategies for gastrointestinal disorders that are associated with an altered signalling from the bowel to the brain.[21] While future studies will provide further insight into the specific role of probiotics in neurological signalling, much evidence exists for it to be selected a safe and promising consideration.


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