Starch rich diets can influence the gut-microbiome and subsequently behavior

The microbiome’s role in modulating the gut-brain axis has been well-supported by a large body of evidence.  Many experiments in the past have demonstrated this in preclinical models by administering probiotics with specific bacterial strains or by fecal microbiome transplant in rodent models, which were then associated with changes in behavior.  Diet has also been implicated in these modulations, as food intake can influence species diversity and composition.  Low-digestible carbohydrates, or resistant starch, have received attention as being beneficial toward health, as these components are not digested but rather fermented by resident microbiota to produce an array of beneficial metabolites.  In a recent study, researchers from Texas Tech University investigated whether a diet rich in resistant starches were also associated with changes in behavior.

48 mice were randomly assigned to 3 different treatment groups, with each group either fed normal corn starch diet, a resistance starch rich diet, or an octenyl-succinate diet for 6 weeks.  The animals were monitored for weight, were subject to robust behavioral tests, and fecal samples were examined for microbiota composition.  The animals on the resistant starch diet exhibited similar weight gains as compared to the normal corn starch diet, and the octenyl-succinate group demonstrated lower weight gain.  Fecal microbiota analysis revealed diet correspondence to specific diet, and that resistant starch diet groups displayed increases in Verrucomicrobia and Actinobacteria as compared to octenyl-succinate and normal corn starch group, respectively.  In all groups, mice displayed significant anxiety-like-behavior in an elevated plus maze, and in open-field tests the mice fed resistance starch rich and octenyl-succinate diet mice exhibited high-anxiety-like behaviors. 

This data again supports that diet manipulation can have marked influence on behavior, and that starch rich diets could perhaps induce undesirable behavioral effect via modulation of the gut-brain axis.  This could be an important drawback to the beneficial components provided for microbial fermentation.  

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.

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.

Early life stress implications on the gut microbiome

A growing body of evidence supports the significance of the gut microbiome with respect to behavioral disorders, as mediated by disruption to the gut-brain axis.  Importantly, there is a lack of understanding regarding associations between gut microbiome dysbiosis and behavioral phenotypic outcome.  Traumatic childhood events early-in-life can result in later-in-life behavioral consequences.  Maternal separation (MS) is an example of such an event that is represented with a well-established preclinical (i.e., animals) experimental model for early life stress.  In a recent study, researcher’s sought to investigate the precise role of MS in the induction of changes to the gut microbiomes of mice, and the potential behavior phenotypic consequences brought on by these changes. 

C57 mice were subject to three unique experimental groups: germ-free (GF) mice, specific pathogen-free mice (SPF, i.e. mice with microbiome compositions), and germ-free mice that were eventually subject to recolonization.  Mice were either left alone after birth or exposed to MS 3 days after birth.  Behavior was examined after 8 weeks, and the germ-free group was sacrificed after 9-10 weeks and the SPF group after 16-20 weeks.  The recolonization group was recolonized with microbiota at 12-13 weeks, followed by more behavioral tests and subsequent sacrificed. 

Corticosterone - a major stress hormone - was significantly elevated in both GF and SPF mice that were subjected to MS.  The researchers next wanted to define a relationship between the host microbiome and anxiety-like behaviors weeks after being separated from the mothers.  It was fist observed that MS did indeed alter microbiota composition in SPF mice.  Interestingly, MS-induced anxiety like behavior was observed in SPF mice, but not in GF mice, suggesting that the microbiome played a significant role in the development of these types of behaviors.  The experimenters then recolonized the guts of a subgroup of GF mice.  Indeed, behavior was altered in MS mice whose guts were colonized as compared to the MS mice that remained germ free.  Other physiological indicators demonstrated significant interactions between MS and the presence of gut microbiota, as gut microbiota presence had a significant impact on noradrenaline and serotonin levels. 

All told, the findings in this study suggest microbiome dysbiosis is a critical physiological driving force behind the behavioral phenotypes associated with early life stress events.  It will next be important to begin thinking about translate these preclinical findings in a clinical setting, in hopes of exploring ways to help those in need.