By Hidaya Aliouche, Biochemistry BSc (Hons)

The human body possesses a diverse and abundant repertoire of microorganisms, termed microbiota, occupying distinct internal and external niches. In numerical terms, the bacterial component alone approaches 50 phyla of 1000 species that cover 10¹⁴ bacteria per gram of luminal content. Collectively, their genomes form the microbiome which encompasses bacteria, archaea, viruses, and eukaryotes.

The Optimal Microbiota

There is a well-established body of evidence that suggests that the co-evolution of microbes in the host has resulted in a symbiotic relationship. Whereby the host fulfils several requirements for the microbiota, and reciprocally, the latter perform biochemical and metabolic functions advantageous for human health. An optimally functioning microbiome is one which is varied and able to dynamically adapt to changes, called perturbations, in the gut. Variety is key; it is evident that a diverse microbial community will possess a large functional potential.

The dynamics of this relationship can however, go awry, with their role in the pathogenesis of disease becoming increasingly prominent. Most notable in recent years is the accumulation of evidence to implicate the gut microbiota in brain function and behaviour.  They do so by affecting the lines of communication between our gut and brain.

What is the Gut-Brain Axis?

The bidirectional communication between the enteric nervous system (ENS) and the central nervous system (CNS) is called the Gut-brain axis (GBA). As such, peripheral intestinal functions are connected to emotional and cognitive processes. This occurs through direct and indirect pathways and result from numerous signalling molecules that bacteria release. These molecules may act through the immune system via stimulation of immune cells to produce chemokine and cytokines, the endocrine system, and the autonomic nervous system (ANS).

The primary constituents of the GBA are the sympathetic and parasympathetic arms of the ANS which process both the afferent signals of the gut and efferent signals of the brain. The main nerve of the parasympathetic arm is the vagus nerve, the longest cranial nerve, and the most important pathway in bidirectional communication between the gut microbiota and the brain.

The principal endocrine system component is the hypothalamic-pituitary-adrenal axis (HPA), which controls reactions to stress in the ‘fight-or-flight’ response. In the CNS, the HPA activates in the limbic system of the brain which is the centre of cognitive and emotional processes.

The influence of the Microbiota on the GBA

The gut microbiota act alongside the neuro-immuno-endocrine mediators of the GBA that influence intestinal function. Work done in the past decade has demonstrated that the microbiota are principal regulators of this axis. The clearest experimental evidence for the role of the gut microbiota in the GBA originates from research in germ-free mice where abnormal brain development and behaviours occurs in the absence of the gut microbiota.

The mechanisms through which they act are varied. For example:

• Pro-inflammatory cytokines that are produced by immune cells are strongly implicated in the pathophysiology of psychiatric illnesses. The composition of the microbiota can indirectly influence this through their effect on the balance of pro- and anti-inflammatory cytokines.
• Bacterial species produce neurotransmitters such as gamma-aminobutyric acid (GABA), serotonin, catecholamines and dopamine. They may also produce their precursor, tryptophan or indirectly influence cognition by, for example, synthesising short chain fatty acids that are able to influence neural signalling and neurotransmitter production in the limbic system, therefore affecting mood and cognition.
• Gut bacteria can induce serotonin production in specialised gut cells called enterochromaffin cells. Serotonin (5-HT) operates in the gut to induce digestive secretion, peristalsis and pain perception. In the brain, 5-HT influence emotion and cognition. Additionally, tryptophan by bacteria can augment circulating serotonin levels as it is the precursor to its production.
• Bacterial endotoxins: Gram-negative bacteria present endotoxins, such as lipopolysaccharide (LPS) on the cell membranes, these are the cause of chronic low-grade inflammation which has been linked to stress-associated behaviours, for example activating immune cell activation.
• Control of gut movement and information communication from the gut to the limbic system occurs through the afferent and efferent fibres of the vagus nerve. Bacteria can stimulate the afferents through metabolite production and thus directly influence the host of processes controlled by the limbic system, including mood, emotions, stress, and hunger.

The association between the microbiota and the brain are still in their relative infancy, with the mechanistic links still not fully unearthed. The knowledge accumulated so far indicates a potential for therapeutic treatments for a range of emotional and cognitive disorders. Indeed, ‘psychobiotics’ may emerge as the future of mental health treatment. To date, research has been mined from exploratory animal studies; until rigorous randomised clinical trials in humans with psychiatric disorders are conducted, widespread therapeutic applications are a while away.

About Me 

I am a postgraduate student at the University of Manchester. Having completed a degree in Biochemistry, I am now pursuing a career in the field of science and medical communications. In my spare time, you can find me sweating it out outdoors, crocheting in a corner and baking up a storm (not necessarily in that order…or at the same time).