Microbes and brain share neurochemistry

Certain bacteria produce neurochemicals and have the same receptors as our brain cells. So it is plausible that the microbiome – especially of the gut -- is important to mental health. But if we want to manipulate the gut microbiome therapeutically, we need to better understand the mechanisms that underlie the gut-brain connection. 

Many mammalian neurohormones and neurochemicals are found in organisms that do not have nervous systems, including bacteria.Microbes produce dopamine, GABA and acetylcholine,2  and via the same biosynthetic pathways found in humans. Many bacteria have the same neurochemical receptors as our brain cells.

Professor Mark Lyte explains that many bacteria share with humans a common language of neurochemistry.  Evolution of cell-cell signaling in animals may be due in part to late horizontal gene transfer from bacteria.

Bacteria are not “dumb bugs”

It is uncertain why bacteria have these features, though neuroactive compounds may have had a role in signaling from one bacterial cell to another. However, the fact that these systems have been conserved through evolution presents an opportunity for distant phylogenetic kingdoms to communicate with each other and influence each other’s behavior. Our common neurochemical “language” means that the gut microbiome affects the host, and what the host does affects the gut microbiome.

Microbiology, neurology and immunology are linked through a common language of neurochemistry

A simple example is that oral drugs reach our intestinal flora before they have the chance to act on us, and many non-antibiotics have antibiotic-like effects on human gut bacteria. Antipsychotics, for example, might change the microbiome.3

In short, bacteria are not “dumb bugs”: they are neuroendocrine organisms; and this realization has given rise to the field of microbial endocrinology. Neurochemicals are not restricted to us, or even to our microbiome. They are found in the food we eat. Bananas contain dopamine and norepinephrine, and tomatoes dopamine and tyramine, while the beans from certain legumes contain physiologically active amounts of L-dopa.4

Along with physical health, our mental health is therefore likely to be influenced by complex interactions between our microbiome, our diet, and host factors such as stress. The complex interplay of factors is shown in Figure 1.

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Figure 1

Microbes and Brain share Neurochemistry.  It shows possible routes for the bidirectional interaction between microbiota and brain, including mediation by the enteric nervous system. The figure also shows the influence of nutrition on microbiota, and the (as yet unproven) suggestion that bacteria themselves may influence eating behavior, creating a complex feedback loop which enables them to obtain preferred substrates. (Figure adapted from Lyte, 2014)

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Immunological and neural connections between gut and brain

Interactions between stress, the immune system and disease are complex.5,6 If a mouse experiences social defeat, phagocytosis is increased. This makes evolutionary sense since infection is a likely consequence of injury. Paradoxically, however, defeated mice survive less well than non-defeated controls when challenged orally with the common food pathogen Yersinia enterocolitica

A possible mechanism, involving shared neurochemistry, is suggested by in vitro work showing that growth of Yersinia enterocolitica is enhanced when a medium resembling conditions in the gut is supplemented with norepinephrine, and by a further study showing that pre-treatment with the neurochemical dramatically increases the virulence of the pathogen.7

Among much that is uncertain, it is clear that the gut, and particularly the villi, are extensively innervated, offering the possibility of a two-way flow of information between the CNS and mucosa that is in close contact with luminal bacteria. It had been thought that enteroendocrine cells communicated with nerve cells only through secretion of hormones, but there is now evidence of direct contact between them and neurons innervating the small intestine and colon.8

Anxiety-like behavior can be induced by inoculation of the mouse gut with Campylobacter

An early demonstration that the brain can be influenced by the presence of certain bacteria in the gut is found in the work of Lyte et al (1998).9 Subclinical oral infection of mice with Campylobacter jejuni that did not activate the immune system nevertheless caused a decrease in maze exploration that indicated anxiety. Evidence that this phenomenon is due to direct activation of neural pathways is provided by the subsequent studies of Klarer et al (2014) showing that selective vagal deafferentation consistently reduced anxiety-like behavior.10

Gaykema et al (2004) provided direct evidence that the presence of Campylobacter can be sensed by brain areas processing information from the gut.11 In the absence of immune marker activation, subclinical infection led to increased expression of c-Fos in the hypothalamic paraventricular nucleus, showing neuronal activation. 

Ways of explaining gut-brain interaction

Can processes in brain and in bacteria be so closely linked?  An indication of how this is possible is provided by evidence that we share with bacteria the same uptake mechanism for neuroactive biogenic amines.12 Using specific fluorescence-based assays, Lyte et al showed that Lactobacillus salivariusbiofilms appear capable of both plasma membrane monoamine transporter (PMAT)- and organic cation transporter (OCT)-like uptake of transporter-specific fluorophores.

The enteric nervous system is extensive and allows bidirectional flow of information between gut and brain. But the nature of the information exchanged is still largely unknown. 

We need more hypothesis-driven studies

Since PMAT and OCT mechanisms are a target of drugs used to treat depression and anxiety, their presence in bacteria is – at the very least – intriguing. This is especially so given that the strain of Lactobacillus used in these studies is regarded as a probiotic, and several studies have shown that probiotics can influence anxiety-like behaviors.2 Part of the explanation may be that probiotics are acting as delivery vehicles for neurochemicals. 

We should not think that this idea is new; it is not even recent. In 1914, Bond Stow (in the Medical Record Journal of Medicine and Surgery) wrote of the potentially helpful role of Bacillus bulgaricus– which is still of great interest as a probiotic in yogurt – in nudging our bacterial flora in a direction helpful to regulation of mood. 

There is a danger, however, that the field is being overwhelmed by masses of data derived from bioinformatics and by analysis that is not hypothesis-driven. The field is rich in studies that have established correlations, but still poor in terms of insight into potentially causative mechanisms. 

Quigley (2017) argues that we should be cautious in implicating certain profiles of gut microbiota in disease pathogenesis since we still have a very incomplete understanding of the role of the microbiome, its bidirectional interaction with the host, and the many potentially confounding factors that may affect both gut microbial signature and human health.13  

Acknowledgement

We would like to thank Professor Mark Lyte (Iowa State University College of Veterinary Medicine, Iowa, USA) for sharing his expertise and insights surrounding links between the microbiota-gut-brain axis and brain function and for providing feedback in the development of this article.

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References
  1. Mazzoli R, Pessione E. The Neuro-endocrinological role of microbial glutamate and GABA signaling. Front Microbiol. 2016;7:1934
  2. Lyte M. Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial endocrinology in the design and use of probiotics. Bioessays. 2011;33(8):574-81.
  3. Maier L, Pruteanu M, Kuhn M et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018 Mar 29;555:623-628. 
  4. Lampariello LRA, Cortelazzo A et al. The magic velvet bean of Mucuna pruriens. J Tradit Complement Med. 2012; 2(4):331–339.
  5. Dréau D, Sonnenfeld G, Fowler N, Morton DS, Lyte M. Effects of social conflict on immune responses and E. coli growth within closed chambers in mice. Physiol Behav. 1999;67(1):133-40. 
  6. Freestone PP, Sandrini SM, Haigh RD, Lyte M. Microbial endocrinology: how stress influences susceptibility to infection. Trends Microbiol. 2008;16(2):55-64.
  7. Lyte M, Ernst S. Catecholamine induced growth of gram negative bacteria. Life Sci. 1992;50(3):203-12.
  8. Bohórquez DV, Shahid RA, Erdmann A et al. Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells. J Clin Invest. 2015;125(2):782-6 
  9. Lyte M, Varcoe JJ, Bailey MT. Anxiogenic effect of subclinical bacterial infection in mice in the absence of overt immune activation. Physiol Behav. 1998;65(1):63-8.
  10. Klarer M, Arnold M, Günther L, et al. Gut vagal afferents differentially modulate innate anxiety and learned fear. J Neurosci. 2014;34(21):7067-76. 
  11. Gaykema RP, Goehler LE, Lyte M. Brain response to cecal infection with Campylobacter jejuni: analysis with Fos immunohistochemistry. Brain Behav Immun. 2004;18(3):238-45.
  12. Lyte M, Brown DR. Evidence for PMAT- and OCT-like biogenic amine transporters in a probiotic strain of Lactobacillus: Implications for interkingdom communication within the microbiota-gut-brain axis. PLoS One. 2018 Jan 11;13(1):e0191037.
  13. Quigley EMM. Gut microbiome as a clinical tool in gastrointestinal disease management: are we there yet? Nat Rev Gastroenterol Hepatol. 2017;14(5):315-320. 
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