How much sway can a microbe hold?
The gut has defenses against pathogens, but, at the same time, it encourages the survival and growth of "healthy" gut bacteria.
The vast majority of these single-celled visitors are based in the colon, where no less than 1 trillion reside in each gram of intestinal content.
Estimating the number of bacterial guests in our gut is challenging; to date, the best guess is that 40 trillion bacteria call our intestines home - partially dependent on the size of your last bowel movement (poop's major ingredient is bacteria).
To put that unwieldy number into perspective, our bodies consist of roughly 30 trillion cells. So, in a very real sense, we are more bacteria than man.
Most of our gut bacteria belong to 30 or 40 species, but there can be up to 1,000 different species in all. Collectively, they are termed the microbiome.
Of course, bacteria do benefit from the warmth and nutrition in our bowels, but it is not a one-way relationship - they also give back.
Some species benefit us by breaking dietary fiber down into short-chain fatty acids that we can then absorb and use. They metabolize a number of compounds on our behalf and play a role in the synthesis of vitamins B and K.
The microbiome's role in health and disease is only slowly giving up its secrets. The latest and perhaps most remarkable finding is the ability that gut bacteria have to moderate our brain and behavior.
Why should the gut and brain be linked?
The goings on in our guts are a matter of life or death. If the gut is empty, our brain must be told; if there is a problem with our gut that will hinder food processing and therefore nutrition absorption, the brain will need to be informed. If our gut is facing a pathogen attack, our brain should be kept in the loop.
The links between our gut and brain are hormonal, immunological, and neural, via the central nervous system and the enteric nervous system, which governs the function of the gut. Collectively, they are termed the gut-brain axis.
Although, at first glance, the connections between the gut and brain might seem surprising, we have all experienced it in action. The relationship between stress, anxiety, and a swift bowel movement are no stranger to anyone.
These gut-brain conversations have been studied for some time. However, a new level to this partnership has recently been glimpsed; researchers are now considering the influence of our microbiome on the gut-brain axis. In other words, researchers are asking: do the bacteria in our gut affect our psychology and behavior?
Termed, rather clumsily, the brain-gut-enteric microbiota axis or microbiome-gut-brain axis, researchers are only beginning to scratch its surface.
Stress and the gut
In humans, the hypothalamic-pituitary-adrenal (HPA) axis is the primary responder to stresses of any kind. It is one of the major players in the limbic system and is heavily involved in emotions and memory.
Stress activates the HPA axis and eventually results in the release of cortisol - the "stress hormone" - which has a variety of effects on many organs, including the brain and gut.
In this way, the brain's response to stress has a direct influence on the cells of the gut, including epithelial and immune cells, enteric neurons, interstitial cells of Cajal (the pacemakers of the bowels), and enterochromaffin cells (serotonin synthesizing cells).
Conversely, these cell types are also under the influence of our resident army of bacteria. Although the mechanisms by which the microbiota regulate the brain are less clear, evidence is mounting that there is, indeed, a two-way dialogue.
What a difference a microbe makes
The first clues that microbes might have some control over our mental activity came more than 20 years ago. Patients with hepatic encephalopathy - a decline in brain function due to severe liver disease - were found to improve substantially after taking oral antibiotics.
Later studies provided further hints that the microbiome had more than a passing influence on states of mind; it was found to impact anxiety and depressive-like behaviors.
"We suspect that gut microbes may alter levels of neurotransmitter-related metabolites, affecting gut-to-brain communication and/or altering brain function. [...] Correlations between gut bacteria and neurotransmitter-related metabolites are stepping stones for a better understanding of the crosstalk between gut bacteria and autism."
Researchers in 2004 noted that mice bred to have no gut bacteria had an exaggerated HPA axis response to stress. Further investigations using similar germ-free mice have demonstrated that their lack of gut bacteria alters memory function.
Germ-free mice have been a useful tool to study the microbiome-gut-brain axis. They have helped prove that something is going on, but the results are impossible to extrapolate into humans. They replicate no natural situation known to man - there is no such thing as a germ-free human.
Other studies have used different approaches; some investigated the effects of the neuroactive compounds that gut flora produce; others still have looked at the differences in the gut flora of individuals with psychiatric or neurological differences.
Research, in general, has not been conclusive. Even if changes in gut flora are seen, the eternal chicken or egg question persists: was the psychiatric condition caused by the change in gut flora, or did the psychiatric condition and its altered behavior patterns cause the gut flora to change? Or, is there a two-way interaction?
How can gut flora moderate the brain?
Bacterial influence over human psychology is slowly coming into focus.
Stress is known to increase the permeability of the intestinal lining; this gives bacteria easier access to both the immune system and the neuronal cells of the enteric nervous system.
This may be one of the ways in which bacteria find a way to influence us. However, another, more direct route has also been demonstrated.
One study, using food-borne pathogens, provided evidence that bacteria in the intestines can activate stress circuits by directly activating the vagus nerve - a cranial nerve supplying a number of organs, including the upper digestive tract.
A more direct route still might involve direct contact of the microbiome with the sensory neurons of the enteric nervous system. Studies have shown that these sensory neurons are less active in germ-free mice, and, once the mice have been given probiotics to restock their microbiome, the activity levels of the neurons return to normal.
Probiotics influencing psychology
If germ-free mice show differences in behavior, the next question is whether adding gut bacteria to an animal can make similar changes. A meta-analysis, published in the Journal of Neurogastroenterology and Motility, collated the results of studies looking at the effects of probiotics on central nervous system function in both humans and animals.
They examined 25 animal and 15 human studies, most of which used Bifidobacterium and Lactobacillus over a 2-4-week period. Although, as the authors mention, translating animal studies like this into human terms is a dodgy game. They concluded:
"These probiotics showed efficacy in improving psychiatric disorder-related behaviors including anxiety, depression, autism spectrum disorder, obsessive-compulsive disorder, and memory abilities, including spatial and non-spatial memory."
Another study, published in PLOS One, found that age-related decline in memory could be reversed in rats by altering the levels of Actinobacteria and Bacterioidetes in their gut with probiotics.
The authors conclude: "The data support the notion that intestinal microbiota can be manipulated to positively impact on neuronal function."
The future of the microbiome-gut-brain axis
There is a long and winding path ahead of those scientists brave enough to investigate the strange reality of the microbiome-gut-brain axis. No doubt a multitude of molecules are involved in various ways to differing degrees.
In the far-flung future, perhaps medicines specifically targeting the microbiome will be created for psychiatric conditions; the microbiome may become an early warning system for certain diseases or even a diagnostic tool.
For now, all we can do is ponder the influence that bacteria have on our everyday state of mind. We should also be amazed and amused that humans, as intelligent as we consider ourselves, are partially under the control of single-celled lifeforms.
Perhaps we would do well to remember that bacteria predate us by billions of years and are highly likely to outlive our species by billions more.