How the gut influences the brain: the intestinal microbiome as a new dimension for understanding mental health

Dinan TG
Cork University Hospital, Dept. of Psychiatry Unit GF, Cork, Ireland

Evidence is accumulating to suggest that gut microbes may be involved in neural development and function, both peripherally in the enteric nervous system and centrally in the brain. There is an increasing and intense current interest in the role that gut bacteria play in maintaining the health of the host. Altogether the mass of intestinal bacteria represents a virtual inner organ with 100 times the total genetic material contained in all the cells in the human body. However, a disordered balance amongst gut microbes is now thought to be an associated or even causal factor for many chronic medical conditions as varied as obesity and inflammatory bowel diseases.

While evidence is still limited in psychiatric illnesses, there are rapidly coalescing clusters of evidence which point to the possibility that variations in the composition of gut microbes may be associated with changes in the normal functioning of the nervous system. Studies in germ-free animals indicate aberrant development of the brain monoaminergic system together with memory deficits and autistic patterns of behaviour. These deficits can be partially normalised if there is early gut colonisation.

The gut is inhabited by 10¹³ – 10¹⁴ micro-organisms, which is ten times the number of human cells in our bodies and contains over 100 times as many genes as our genome. The estimated species number varies greatly but it is generally accepted that the adult microbiome consists of greater than 1,000 species and more than 7,000 strains. It is an ecosystem dominated by bacteria, mainly strict anaerobes, but also including viruses, protozoa, archae and fungi. The microbiome is largely defined by 2 bacterial phylotypes, Bacteroidetes and Firmicutes with Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia phyla present in relatively low abundance.

Colonisation of the infant gut commences at birth when delivery exposes the infant to a complex microflora and its initial microbiome has a maternal signature. The microbiome of unweaned infants is simple with high interindividual variability. The numbers and diversity of strict anaerobes increase as a result of diet and environment, and after 1 year of age a complex adult-like microbiome is emerging. Despite major individual variation in the enteric microbiota, there seems to be a balance that confers health benefits and an alteration in this ecosystem can negatively influence the wellbeing of the individual,increasing vulnerability to a range of diseases.

Recent pre-clinical studies suggest that certain Bifidobacteria may have anxiolytic or antidepressant activity while Bifidobacterium infantis has been found effective in treating patients with irritable bowel syndrome.

Metchnikoff was the first to observe the fact that those living in a region of Bulgaria who consumed fermented food in their diet tended to live longer. He first published his observations in 1908 and this gave rise to the concept of a probiotic or bacteria with a health benefit. That bacteria might have a positive mental health benefit is now becoming clear. Such bacteria may influence the capacity to deal with stress, reducing anxiety, perhaps positively impacting on mood and are now called psychobiotics. Whether, they are capable of acting like and in some circumstances replacing antidepressants remains to be seen.

At a time when antidepressant prescribing has reached exceedingly high levels, the emergence of effective natural alternatives with less side-effects would be welcome. It will be intriguing to investigate if psychobiotics [1] will be beneficial in other psychiatric domains. Indeed, very recently a Bacteroides fragilis given early in life was shown to correct some of the behavioural and gastrointestinal deficits in a mouse model of autism induced by maternal infection.

The mechanisms of psychobiotic action are gradually being unravelled. It has been shown that Lactobacillus rhamnosus has potent anti-anxiety effects in animals and does so by producing major changes in the expression of GABA receptors in the brain [2]. GABA is the most important inhibitory transmitter in the human brain and these are the receptors through which benzodiazepines such as diazepam and various anaesthetic agents act. The changes in these receptors are mediated by the vagus nerve which connects the brain and gut. When this nerve is severed no effect on anxiety or on GABA receptors is seen following psychobiotic treatment. An impact on obsessive compulsive disorder type symptoms has also been reported with a similar strain of psychobiotic.

Interestingly, Lactobacillus rhamnosus not only alters GABA receptors in the brain but has been shown to synthesise and release GABA. There is also evidence to support the view that gut bacteria may influence the brain in routes other than the vagus nerve, for example by immune modulation and by the manufacture of short chain fatty acids.

Communication between the brain and gut is bidirectional and complex. Increased understanding of this axis and the role of the gut microbiota may aid the development of therapies not just for functional bowel disorders but for mood disorders also.

References

1	Psychobiotics: a novel class of psychotropic Dinan TG, Stanton C, Cryan JF Biol Psychiatry 2013, 74:720–726
2	Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology Dinan TG, Cryan JF Psychoneuroendocrinology 2012, 37:1369–1378