The Microbiome Podcast returns: Episode 10 with Dr. John Cryan on the gut-brain axis

The Microbiome Podcast has been on a hiatus since June so we wanted to make sure that our first episode back was a good one.  Our conversation with Dr. John Cryan from University College Cork in Ireland was very informative and for anyone interested in how the microbiome and the gut may impact the brain during development or in later stages of life, this is a great listen. 

Listen to the episode on our website. On iTunes. On Stitcher. 

On this week’s episode we discussed: 

• (1:06) Our visit to the White House and the Office of Science and Technology Policy’s microbiome initiative.
• (3:30) A paper describing the “microbial cloud” that individuals emit. Read the paper.
• (6:18) A C. diff treatment that ReBiotix received breakthrough designation from the FDA. Read more. 
• (9:04) We were joined by Dr. John Cryan.  
• (9:20) What is the gut-brain axis?
• (12:00) The importance of the gut-brain axis during early stages of life.
• (13:35) Studies in humans that show how the microbiome may influence brain function. A study from Mike Baley's group on temperament during early childhood. 
• (15:20) Psychobiotics.
• (22:45) The gut-brain axis in neurodegenerative diseases like Parkinson’s and Alzheimer’s disease. A study from Denmark that showed if a person had their vagal nerve removed halved their chances of getting Parkinson’s disease. 
• (27:40) Microbiome mediating hunger and a specific hormone called ghrelin.
• (32:40) Research in the Cryan Lab. Read more. 
• (37:05) The APC Microbiome Institute at University College Cork. Learn more. 
• (41:00) On the aftershow, we discussed our opinions of iPhones and Apple products.

The anorexia nervosa gut microbiome differs from healthy controls and is related to mental health

Two photographs, before and after treatment for anorexia

Anorexia nervosa is devastating condition in which an individual purposely starves themselves leading to severely low weight.  In addition, most patients with anorexia have depression, and there is a definitely mental aspect to this disease.  The disease then, has both dietary and mental components, making it extremely interesting to microbiome scientists, because the microbiome is implicated with both of these facets.  Scientists from UNC recently conducted a preliminary study on both of these aspects of the disease by comparing the microbiomes and mental state of anorexic patients before and after treatment, along with healthy controls.  They published there results last week in the journal Psychosomatic Medicine.

Sixteen patients with anorexia nervosa who sought treatment for their disease had stool samples collected at admission to the hospital as well as their mental health assessed.  Ten of these individuals that made partial recoveries (improved body mass index) were discharged from the hospital and donated stool samples and had their mental health assessed upon leaving.  The researchers discovered that the patients’ microbiomes severely lacked diversity compared to aged matched controls, and that was true for both admission and discharge from the hospital.  The scientists noted though, that the patients that left the hospital had microbiomes that more resembled the control individuals than when they entered.  For example, the anorexic patients had very little Clostridia when they entered the hospital, but these populations rebounded during treatment.  In terms of the mental health aspect of anorexia and the microbiome, the researchers found a direct association between eating disorder psychopathology and microbiome diversity, with lower diversity corresponding to worse eating disorder psychopathology.  The same was true for depression, as the degree of depression was inversely correlated with bacterial diversity.  In terms of individual families of bacteria, a lack of Ruminococcaceae had the strongest association negative mental state.

This study shows that a lack of eating decreases gut flora diversity and negatively impacts the microbiome.  While not surprising, this lack of diversity will almost certainly cause a dysbiosis that detriments many other aspects of health.  One of these, in the case of anorexia, may be mental health, but of course it is not clear which causes which, or if there is any causation or merely just correlation.  In any event, disorders that have both mental and dietary components are extremely fascinating to investigate, as it is possible the microbiome is of primary importance to these diseases.

Fish oil may be important to altering the microbiome, reducing anxiety

Last week we published a blog on the gut-brain axis, and the various associations between brain health and the gut microbiome.  One of the ailments we discussed was depression, which is often studied in mice by inducing early life stress on the mice.  One way to do this is by separating mice from their mothers for hours at a time at a young age.  The Maternal Separation model, as it is known, causes stress and anxiety in these mice, but more importantly, research has shown that it creates a dysbiosis of their gut microbiomes as well.  Many scientists believe the dysbiosis may be implicated in causing some of the stress phenotypes, and so reversing this dysbiosis could have therapeutic value.  Researchers from the University College Cork, in Cork Ireland, experimented with N-3 polyunsaturated fatty acids (PUFAs), like those found in fish oil, in these maternally separated mice, and found they may be important to preventing the dysbiosis.  They published their findings in the journal PLoS ONE.

In the study, the researchers separated mice into two groups, one underwent maternal separation, and the other had a normal upbringing.  Within each group the mice were separated into two more groups, one that received fish oil supplements and the other that didn’t.  Over the course of 17 weeks each groups’ feces were sampled for their microbiomes.  The Maternal separation tended to decrease the bacteroidetes to firmicutes ratio of the mice’s microbiome, which has previously been linked to depression in humans.  Interestingly, supplementation with the fish oil increased this ratio in those maternally separated mice.  In addition, the fish oil also increased the concentration of bacteria that were higher in non-separated mice, such as populations of Rikenella.  Finally, the fish oil increased the amount of butyrate producing bacteria, and as we have seen many times before, butyrate and other short chained fatty acids (SCFAs) are often associated with health.

Overall this study showed that fish oil shifted stressed mice’s microbiome to a more natural state, presumably helping them in the process.  While the scientists did not directly measure stress levels in these mice to support the microbiome connection, hopefully that will be part of a follow up study.  The scientists noted that fish oil is clinically shown to reduce inflammation, and made it a point to connect the stress in the mice to systemic inflammation.  Systemic inflammation is also mediated by the microbiome.  Indeed, people that have inflammation from IBD, for example, do tend to have more stress and anxiety.  In the end, fish oil could make for an interesting prebiotic to shift the microbiome, counteract inflammation, and improve mental health. 

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.  

Probiotics may be able to prevent depression

Clinical studies have shown that probiotics can decrease anxiety, improve mental outlook, and induce positive mood changes and outlook.  In fact, some bacteria strains have been shown to reduce anxiety and depression in mice by directly modulating nerve firings associated with these cognitive maladies.  A recent study conducted by Leiden University in The Netherlands explored further in human subjects to assess whether or not probiotics, composed of various strains of Bifidobacteria and Lactobacilli could specifically modulate cognitive reactivity to sad mood, a well-characterized indicator for vulnerability to depression. 

In brief, cognitive reactivity is defined as a series of dysfunctional patterns of thinking prompted by subtle mood changes, such as rumination, aggression, and hopelessness.  It is thought that cognitive reactivity is central in the development, maintenance, and recurrence of depression episodes.  This behavioral reaction is considered to have significant predictive value in detecting vulnerability to developing clinical depression.  Due to this implication, cognitive reactivity is considered a target for therapeutic intervention to prevent depression onset, and was thus analyzed in this study. 

40 healthy, non-depressed adults were selected and split into two groups, each receiving a 4-week regiment of a probiotic or a placebo.  The participants filled out questionnaires before and after the regiment to assess cognitive reactivity and depression symptoms.  Of the several behavioral indicators of cognitive reactivity that were assessed, aggression and rumination were significantly modified according to the behavioral questionnaires.  Specifically, post-regiment scores in the probiotic group were significantly lowered from pre-regiment scores, and this was not observed in the placebo group.  All told, this suggests that a probiotic regiment eased cognitive reactivity to aggressive and ruminative thoughts.

This study is the first to show that probiotics can modulate an important cognitive process that determines vulnerability to clinically diagnosed depression.  These findings are additionally enlightening with respect to the gut microbiome’s role in overall cognitive health.  As is often the case however, there were some limitations.  Specifically, it would have been interesting to investigate biological underpinnings of these interactions in complementary animal models, especially in light of previous findings that indicate probiotics can facilitate microbiota to synthesize and release serotonin.  On Monday we highlighted work done by Professor Diane Hsiao’s group at Cal Tech that stressed the gut microbiome’s role in serotonin production.  As we mentioned, serotonin is implicated in many bodily functions, including a vast range of cognitive mechanisms.  Indeed, serotonin systems have been primary target for therapeutic treatment of depression.  Zoloft, one of the most highly prescribed antidepressants in the world, blocks serotonin metabolism to facilitate its endogenous mode of action in the brain. 

Not only do the current findings complement those from the Cal Tech lab, but they also highlight an exciting new potential toward therapeutic approach.  Conventional therapies that directly target serotonin systems can be ineffective and have many undesired side-effects and limitations.  Understanding the microbiome’s role in serotonin production can give us more insight and perhaps pave a way toward a more organic therapeutic approach aimed at preventing and/or treating depression.  

Research is needed on the role of the microbiome and anorexia nervosa

Sketches of Miss A before (top) and after (bottom) treatment for anorexia nervosa by William Withey Gull.  Dr. Gull was among the first people to be clinically establish and treat anorexia, and was responsible for naming the disease.

Yesterday we discussed the latest research on the microbiome and obesity.  Today we wanted to share some thoughts on the other end of the spectrum: the microbiome and anorexia nervosa.  This week in the International Journal for Eating Disorders there was a call for research by doctors from the University of North Carolina to investigate the microbiome’s role in this disease.

Anorexia nervosa is a neurological disease characterized by self-starvation.  It often occurs with depression and other affective disorders.  It has severe side effects such as heart disease and seizures, which makes it the deadliest neurological disease, with around 5% of cases becoming fatal.  The causes of anorexia are complex, but genetic, social, and environmental risk factors all exist. 

Anorexia nervosa is a disease that is very likely implicated with the microbiome, perhaps profoundly.  It coincides with our understanding of the so-called gut-brain axis, which has already been linked to depression, anxiety, and appetite, which are distinctly awry in anorexia sufferers.  The relationship between anorexia and the microbiome is largely unknown.  Studies have indicated those suffering from anorexia have very unique microbiomes with similar bacterial that are not commonly found in the gut, but these studies are hardly convincing and not robust. 

Treatment for anorexia always includes dietary interventions, but these are not always effective in reestablishing normal weight, and relapse occurs in around half of all patients.  Recovery and therapeutics should also consider the microbiome.  Research on malnourishment in Africa has produced a wealth of literature on the importance of a balanced, robust, and healthy microbiome to nutrition and weight.  Simply adding calories to a diet is often not enough to improve health in the malnourished because their dysbioses, and the same phenomenon may also occur in patients suffering from anorexia nervosa.

Because the microbiome may be fundamental to both the neurological and dietary aspects of the disease, the authors of the paper encourage further research.  They suggest that microbiome transplants may be important to both physical and mental healing.  Anorexia nervosa is a complex disease, but research on the microbiome is crucial to fully understanding it.