Did you know that humans, in terms of cell number, are mostly bacteria? The ten trillion ‘self’ cells that make a human body are outnumbered 10 to 1 by the bacteria residing in our guts. Emerging research suggests that these intestinal bacteria populations (our gut “microbiota”) not only influence their local enteric (intestinal) niche but can modulate host brain function, behaviour and even mental health. The opportunity to medically manipulate this interaction thus provides a novel therapeutic avenue for treating psychiatric disorders. Mind-blowing stuff!
Humans healthily co-exist in this state because these bacteria live with us – or rather, we live with them – in a largely commensal agreement: we scratch their (usually peptidoglycan) backs and they neither scratch ours nor harm us in return. This is a biological relationship which goes back over many evolutionary millennia, and to a certain extent the existence of each organism now relies on the other. The ability of gut microbiota to chemically communicate with the brain, via what is commonly labelled the microbiota-gut-brain (MGB) axis, is being increasingly acknowledged in the scientific community. Indeed, through this pathway gut bacteria may even regulate the development of the brain itself. So how might the MGB axis work?
Mechanisms of microbiota-brain communication
The precise mechanisms by which gut bacteria interact with the brain are currently unclear, but two intermediary systems have been suggested. Perhaps obviously, the first is the nervous system, wherein bacteria produce (and possess receptors for!) chemicals which modulate the activity of neurons, such as serotonin and dopamine. The fact that bacteria secrete and recognise neurochemicals has been known for many years, but it is only recently that mouse model findings are demonstrating the capacity of the microbiota to generate significant neurophysiological change within the gut. These chemicals can act on the enteric nervous system (often referred to as the body’s “second brain”), neurons within which predominantly communicate with the actual brain via sensory axons of the vagus nerve (the tenth of twelve cranial nerves – yes, it goes all the way down to your gut!). Interestingly* however, a recent study showed that cutting out the vagus nerve (vagotomy) in mice did not abolish the effect of microbiota-altering drugs on brain chemistry and behaviour. It seems as though bacteria must be finding other ways to communicate with the brain.
The second of the two major players likely mediating the MGB axis is the immune system. It is well documented that both commensal and probiotic bacterial residents of the gut can directly modulate host immunity, and also that there exists two-way communication between the central nervous system (CNS: the brain and spinal cord) and the immune system. Immune signalling is therefore an ideal conduit through which the microbiota could converse with the CNS.
Mental microbiota medicine?
So what kind of effect does this biochemical discussion have on our minds? Early experimental studies in animals have shown that oral inoculation of mice with just a single type of bacterium (Campylobacter jejuni) can lead to increased activation of brain regions receiving sensory input from the gut (via the vagus nerve). This effect was accompanied by alterations in mouse behaviour indicative of increased anxiety. Later studies have demonstrated that faecal microbiota transplantation (nice) between mouse strains can transfer the behavioural traits of the donor to the recipient. Who’d have thunk it!
These mouse data are certainly remarkable, but you might be thinking (and rightly so**): where are the humans? The link between gut microbiota and human health is well-established, and it is evident that this connection extends to mental wellbeing as well. As an example, patients with liver cirrhosis have a much-altered mucosal microbiota compared to healthy controls, and this difference associates with the poor cognition often observed in this patient population. But experimental research probing beneficial psychiatric outcomes after microbiota modification is limited.
Unpublished data presented at the annual meeting of the Society for Neuroscience this year showed that in a small cohort of healthy men, a daily dose of probiotic bacteria (Bifidobacterium longum 1714) reduced self-reported anxiety and lowered morning levels of the stress hormone cortisol, whilst also improving tested memory. In the study, a total of 22 healthy male*** volunteers were assigned randomly to receive either a daily probiotic pill for four weeks, and then a placebo for a further four weeks, or vice versa. In medical research terms this was a randomised (random allocation), controlled (uses a control group), balanced (each participant receives all treatments) crossover trial. Measurements were made at baseline and after each treatment regime, and despite the probiotic effects being objectively small, they were large enough to be perceived. It is exciting preliminary work – watch this space!
In summary, it seems that the bacteria within our guts have the capacity to effect change in our mental state, but the mechanisms through which they act are not fully clear. This opens up the possibility of orally manipulating the microbiota to cause positive psychological adjustments, as has been demonstrated in promising – albeit preliminary – human studies. Perhaps probiotic prescriptions for particular psychiatric disorders will be a clinical reality in the not-too-distant future. What do you think? Let us know!
A. (Twitter: @AB_Munster)
** We are unaware of any non-human readers of Bio Detectives. If you are non-human and wish for your voice to be heard, please get in touch!
*** According to one of the researchers, women were excluded because the menstrual cycle can modulate cortisol production, which would have complicated the study significantly.
A recent paper on this topic not only has an amazing title but also provides an in-depth review of current research studies related to how the microbiota communicate with the nervous systems of the body (both enteric and central).