Evidence of gut/brain connection piles up, but actual products are a ways off, researcher says

This idea has catapulted onto the scene in just the last few years, said neuroimmunologist John Bienenstock, PhD, of McMaster University in Hamilton, Ontario. One observation that is often made is that serotonin is present in both the brain and the gut. Changes in bowel habits are a frequent side effect of the use of selective serotonin reuptake inhibitors, a popular category of drugs used to treat depression.  Could this common effect of SSRIs point to sertonin as a primary mechanism in the brain/gut communication?

“We would have to say at this point that that is highly speculative,”​ Bienenstock told NutraIngredients-USA. “ None of us has any real evidence of the role serotonin plays in the gut. Where there is more evidence is how some bacteria might be in communication with the nervous system.” ​

 Mounting evidence, some conducted by Bienenstock, from rodent studies has shown that alterations of the gut microbiome can affect the animals neural development, brain chemistry, mood and behavior.  He has focused his research one bacterial species, Lactobacillus rhamnosus​, and one neural pathway, the vagus nerve.

In one trial Bienenstock and his fellow researchers looked into how Lactobacillus rhamnosus​ affected GABA production in mice brains​.  GABA is the main central nervous system inhibitory neurotransmitter and is involved in regulating many physiological and psychological processes. Alterations in GABA receptor linked with anxiety and depression, which in turn are linked with functional bowel disorders.  

“These findings highlight the important role of bacteria in the bidirectional communication of the gut–brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression,”​ the researchers concluded.

In that trial, one group of mice had their vagus nerve, a central neural pathway connecting the enteric nervous system to the central nervous system, severed.  These mice did not show the same results as the others, pointing to the vagus nerve as a primary conduit. But that’s not the end of the story, Bienenstock said. Colleagues at McMaster have shown that some of these effects still occur in the systems they were studying even in the absence of a functioning vagus nerve connection.

“The bottom line appears to be that different bacteria are using different systems. They could be having metabolic effects and there could be factors circulating that are bypassing the vagus. We focus on the vagus because it happens to be a system that we know works for a particular bacteria and may help us dissect out what the factors that are involved in this communication,” ​Bienenstock said.

Epithelial signaling​

Bienenstock said his research has shown that the epithelium, the layer of cells lining the gut, is of prime importance in this connection.  Placing the bug on epithelial cells will generate a signal, the precise nature of which is not yet known. Putting the microbial cells on an exposed nerve fiber does not have the same effect.  That ephithelial signal could involve a transmitter like serotonin, he said, but the evidence is not there yet.

“All we can say now is the transduction of the signal seems to involve the epithelium,” ​he said.

Bienenstock also emphasized that the reductionism he and his fellow researchers are forced into so that they can formulate research questions they can get their arms around shouldn’t blind people to the larger picture.  Bacterial cells are present in many locations in the body, and they are all (invaders aside) probably doing something important.

“The fact is that it is one system, a unified system. Clearly the bacteria in the gut, the lung, the vagina, the skin, all of these places harbor a collection of bacteria that are important.  There is nothing to say that skin bacteria aren’t just as important as the bacteria in the gut,”​ he said.

Endocrine signalling​

Another way the gut bacteria connect to the brain is through the endocrine system.  One of Bienenstock’s colleagues at McMaster, Mark Lyte, PhD has coined the term “microbial endocrinology”​ to capture the idea. Lyte has observed that the microbiome produces a wealth of neurologically active compounds such as catecholamines, histamine and others.  These could affect the brain, either through direction connection via the nervous system or by diffusion into the blood via the gut wall.

In a paper published late last year​, Lyte said the brain/gut connection likely consists of a number of pathways, with the endocrine system being just one. The makeup of the gut itself is a confounding factor, Lyte said.  The enteric nervous system differs at different points in the gut, and the microbiome does, too, with a different population breakdown of species at different locations.  There is still a lot to learn, Lyte said.

“Recognition of the neuroendocrine-hormone-producing capacity of microbes will hopefully spur new investigation into the ability of members of the microbiome to produce neuroactive compounds that have specific targets within the host neurophysiological system,”​ he wrote.

Product formulation​

Bienenstock and his research partners focus on a particlar strain of Lactobacillus rhamnosus​.  Connecting results to a strain is critical for efficacy, he said. Unfortunately, while there is a significant amount of data connecting certain probiotic strains to effects on gut health, there is still no way to make a viable claim that would say that a certain strain might alleviate mild depression, for example.

“There is no question that some of the products of fermentation are important in the immunoregulatory system and have other positive effects.  Butyrate (a byproduct of fermentation), for example, is an effective antidepressant in animal models​. The Holy Grail would be to find the exact pathway.  We could have a bug that has a known behavioral effect,” ​Bienenstock said.

“That will be part of the final story.  But right now it is really not possible to buy a probiotic product that can claim to affect your anxiety or your stress,”​ he said.

Ancient relationship​

The interaction of living cells in symbiotic ways seems as old as life.  For example, one of the main theories of the origins of mitchondria, the energy factories within cells, is that these arose from smaller microorganisms that were incorporated into a larger cell. Mitochondria have their own DNA that is separate from the nuclear DNA that the layman is familiar with. Even today, some species of paramecium, largely unchanged for hundreds of millions of years, play host to smaller symbiotic microorganisms within their cytoplasm. So is this brain/gut interaction only “new” from the standpoint of human understanding?

How these systems may have coevolved is the subject of some current research, Bienenstock said.  The question is still unresolved whether the communication observed between the brain and the gut had to await the formation of a brain in mammals capable of emoting and so be subject to the first cases of chronic depression or anxiety.  While the evidence is lacking, Bienenstock said it seems clear that the nervous system and the gut lumen evolved in a way that they lean on each other, so to speak.

“It is a very interesting question. It is very unlikely in my opinion that the things we are looking at are not in fact very ancient. These systems where the bacteria are involved in homeostatis and regulation of the nervous system must have evolved very early,”​ he said.