The human gut contains a diverse community of bacteria which colonize the large intestine in the days following birth and vastly outnumber our own cells. These intestinal microflora constitute a virtual organ within an organ and influence many bodily functions. Among other things, they aid in the uptake and metabolism of nutrients, modulate the inflammatory response to infection, and protect the gut from other, harmful micro-organisms. A new study by researchers at McMaster University in Hamilton, Ontario now suggests that gut bacteria may also influence behaviour and cognitive processes such as memory by exerting an effect on gene activity during brain development.
Jane Foster and her colleagues compared the performance of germ-free mice, which lack gut bacteria, with normal animals on the elevated plus maze, which is used to test anxiety-like behaviours. This consists of a plus-shaped apparatus with two open and two closed arms, with an open roof and raised up off the floor. Ordinarily, mice will avoid open spaces to minimize the risk of being seen by predators, and spend far more time in the closed than in the open arms when placed in the elevated plus maze.
This is exactly what the researchers found when they placed the normal mice into the apparatus. The animals spent far more time in the closed arms of the maze and rarely ventured into the open ones. The germ-free mice, on the other hand, behaved quite differently – they entered the open arms more often, and continued to explore them throughout the duration of the test, spending significantly more time there than in the closed arms.
The researchers then examined the animals’ brains, and found that these differences in behaviour were accompanied by alterations in the expression levels of several genes in the germ-free mice. Brain-derived neurotrophic factor (BDNF) was significantly up-regulated, and the 5HT1A serotonin receptor sub-type down-regulated, in the dentate gyrus of the hippocampus. The gene encoding the NR2B subunit of the NMDA receptor was also down-regulated in the amygdala.
All three genes have previously been implicated in emotion and anxiety-like behaviours. BDNF is a growth factor that is essential for proper brain development, and a recent study showed that deleting TrkB, the receptor to which it binds, alters the way in which newborn neurons integrate into hippocampal circuitry and increases anxiety-like behaviours in mice. Serotonin receptors, which are distributed widely throughout the brain, are well known to be involved in mood, and compounds that activate the 5HT1A subtype also produce anxiety-like behaviours.
The finding that the NR2B subunit of the NMDA receptor down-regulated in the amygdala is particularly interesting. NMDA receptors are composed of multiple subunits, but those made up of only NR2B subunits are known to be critical for the development and function of the amygdala, which has a well established role in fear and other emotions, and for learning and memory. Drugs that block these receptors have been shown to block the formation of fearful memories and to reduce the anxiety associated with alcohol withdrawal in rodents.
The idea of cross-talk between the brain and the gut is not new. For example, irritable bowel syndrome (IBS) is associated with psychiatric illness, and also involves changes in the composition of the bacterial population in the gut. But this is the first study to show that the absence of gut bacteria is associated with altered behaviour. Bacteria colonize the gut in the days following birth, during a sensitive period of brain development, and apparently influence behaviour by inducing changes in the expression of certain genes.
Exactly how gut bacteria might exert such influences is unclear, but they may do so via the autonomic branch of the peripheral nervous system, which controls functions such as digestion, breathing and heart rate. A better understanding of cross-talk within this so-called ‘brain-gut axis’ could lead to new approaches for dealing with the psychiatric symptoms that sometimes accompany gastrointestinal disorders such as IBS, and may also show that gut bacteria affect function of the mature brain.
Neufeld, K., et al. (2011). Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. DOI: 10.1111/j.1365-2982.2010.01620.x