A brief summary of a recent review of the gut-brain axis

Comparison of a normal aged brain (left) and the brain of a person with Alzheimer's (right). 

The gut-brain axis refers to the interplay between the gut microbiome and our behavior.  There are a few mechanisms by which the gut microbiome can affect the brain, such as by directly communicating with it via the vagus nerve, by producing hormones or other metabolites that influence brain function, and by eliciting a systemic inflammatory response.  This past month researchers Timothy G. Dignan and John F. Cryan, both of the University College Cork, in Cork, Ireland, published a review of the recent advances in the gut-brain axis literature.  Many exciting scientific developments have occurred in the past few years, including new advances that connect the microbiome with depression, autism, Alzheimer’s disease, and schizophrenia.  Here, we discuss some of those studies and summarizing the review.

Depression: Studies have shown a possible association between the microbiome and feelings of depression.  It is not clear, however, if these changes are due to drugs that are being taken.  Other studies have shown that probiotics can reduce thoughts of depression, and a separate study showed that eating yogurt improved the moods of oil workers.

Autism:  Again, research has shown a correlation between the microbiome and autism, but not any sort of cause or relation with symptoms.  Multiple studies in mice have shown that a dysbiotic microbiome can lead to autism like symptoms, and that altering the microbiome can alleviate them.  Again, however, there are few mechanistic links between the microbiome and the disease.

Alzheimer’s disease:  Very few studies have linked Alzheimer’s and the microbiome.  Some studies have seen a broad decline in microbiome diversity amongst Alzheimer’s patients, but decreased diversity is known to be associated with many other phenotypes.  Smaller studies on mice have shown some symptoms of Alzheimer’s, such as memory loss, can be somewhat reversed using probiotics, but the results are hardly robust and do not necessarily imply a link with Alzheimer’s.

Schizophrenia:  Like Alzheimer’s, very few studies have linked the microbiome and schizophrenia.  Like all of the above, various associations have been made between the disease and the microbiome, but no strong correlations have been measured.  In mouse models of schizophrenia, antibiotics can alleviate symptoms of the disease.  In addition, there is evidence that antibiotics can also improve the mental state of humans. 

Taken collectively, there is a compelling reason to believe that the microbiome is important to each of these indications, and that it is critical to a healthy mind.  It is still early days though, and much more research is needed to prove mechanisms and pathways.  

The oral microbiome of schizophrenics differs from controls

Self-portrait of Vincent van Gogh, who likely had schizophrenia

The gut-brain axis is a very intriguing field that offers a lot of promise in making progress in neurological diseases.  The science is still very new, though, so much work needs to be done in establishing any connections between the microbiome and these diseases.  The reason the gut is normally explored is because of the strong connection between the gut and the brain via the vagus nerve, which in initial studies has been shown to be an important pathway for afferent and efferent connections.  Other body microbiomes’ connections to the brain have not yet been studied.  A new study that came out last week makes a connection between the oral microbiome and schizophrenia, a disease which had previously been linked to the gut microbiome.  The results were published in the journal PeerJ.

The scientists performed whole genome sequencing on the oropharyngeal microbiomes of 16 people with schizophrenia and 16 healthy people.  Importantly, the scientists note that the people with schizophrenia were more likely to be smokers and to be overweight, two qualities that are already associated with alterations of the oral microbiome.  The results showed that the schizophrenics had lower overall diversity of their oral microbiomes compared to controls.  Specifically, lactic acid bacteria, and especially Lactobacillus gasseri, were more abundant in the mouths of those with schizophrenia, even after controlling for other variables such as age and smoking status.

While this paper does not attempt to explain why these differences occur, they are quite interesting nonetheless.  If somehow the disease state can be characterized by the oral microbiome this could be important for diagnostics.  The next step is to actually establish if any of the connections between the bacteria in the body (including the mouth) and the brain are partly responsible causing the disease.  If this is the case then not only would it help explain the environmental causes of schizophrenia, but it would also lend itself to possible microbiome treatments for the disease, such as pro- or pre-biotics.

Schizophrenia and the virome

Schizophrenia PET scan

Schizophrenia is a mental health disorder in which people cannot recognize reality, suffer from hallucinations, and experience social withdrawal.  The causes of schizophrenia are unknown, but it is thought to include genetic, environmental, psychological, and social risk factors.  As we have written about extensively in this blog, the bacteria and viruses in our body have an important connection to our brain and behavior, in what has been termed the ‘gut-brain axis’.  Considering the gut-brain axis, a team of scientists from Johns Hopkins University wondered if the microbiome, and specifically the virome, was somehow related schizophrenia.  They recently published their findings in Schizophrenia Bulletin.

The scientists sampled the throat microbiome from 74 people in the Baltimore, MD area, 41 of whom suffered from schizophrenia and 33 of whom did not.  They discovered that a specific bacteriophage (virus that infects bacteria), Lactobacillus phage phaidh, was linked to schizophrenia, which was found in 17 of the 41 schizophrenia patients, but only 1 of the 33 control individuals.  In addition, 9 of those 17 schizophrenics had a comorbid immune disorder, such as diabetes or Crohn’s disease, whereas only 2 of the remaining schizophrenics without the phage had these diseases.  The scientists also found a loose link between taking the drug valproate and occurrence of the phage.  Interestingly, this drug has been previously shown to affect the microbiome.  Finally, the existence of the phage coincided with higher levels of the bacteria that the phage attacks, Lactobacillus gasseri.  This is an unsurprising result because a phage and its target are usually found together.

The scientists acknowledge that the results of this study do not prove any real association between the microbiome and schizophrenia, but based on the results, they suggest that further research is warranted.  Notably, Lactobacillus gasseri is sometimes included in probiotics to supposedly relieve gastrointestinal issues.  However, if gasseri’s phaidh phage goes along with it, then according to this study, it may cause more harm than good.

A recreational drug may cause memory loss due to the microbiome

There is a common method to induce schizophrenia-like symptoms in mice that is often used in research.  The method involves dosing the mice with a molecule called phenylcyclidine (PCP), better known as the drug angel dust.  There are neurological reasons why this drug should cause schizophrenia-like symptoms in mice, and one consequence of its administration is memory loss.  Researchers from Denmark recently tested if this memory loss was connected to the microbiome and published their results in Physiology and Behavior.

The researchers devised an experiment where groups of mice were either given PCP or a control.  All the mice had their microbiomes tested and underwent a memory test.  The scientists discovered that the PCP did heavily change the microbiome, with many genera increasing in abundance, like Roseburia, Dorea, and Odoribacter.  In addition, the memory performance also seemed to correlate with the microbiome.  As the microbiome rebounded after a 3 week time frame, so did the memory of the mice, even though some other symptoms of the PCP persisted.  Finally, the researchers gave some of the mice that were given PCP antibiotics so as to decrease the population of the microbiome.  The antibiotics were effective in restoring the memory of the mice even within 3 weeks, suggesting a microbiome connection.

The researchers hypothesize that stress caused from taking PCP may be the root cause of the microbiome shifts and memory loss.  Interestingly, some of the bacteria that they identified in the PCP microbiomes had been associated with stress in previous studies.  Here at the AMI we don’t like to preach to our readers, but if any of you use PCP and have a big exam coming up, you may want to consider stopping, or at least taking a probiotic.