The fungal microbiome in obese individuals

We hear mostly about the bacterial microbiome but there are other microbiomes out there like the virome (virus microbiome) and mycobiome (fungal microbiome). The mycobiome is an important part of the gastrointestinal tract and fungal microorganisms make up between .03-2% of the total microorganisms in the gut. A recent study out of Spain characterized the mycobiome of obese individuals and compared them to non-obese individuals.

The scientists used sequencing technologies to analyze the diversity of fungal organisms in the gut of 52 Caucasian individuals who were recruited for the study. After fecal sampling and sequencing, they found that diversity was lower in obese subjects than in non-obese subjects and they could be stratified depending on their mycobiome composition. Ascomycota and Basidiomycota were not significantly different between the two groups, however, the minor phylum Zygomycota was represented less in obese patients.

Interestingly, they found that the relative abundance of fungus in the Eurotiomycetes class of the Ascomycota phylum were similar between obese individuals and non-obese individuals but obese subjects with low levels of Eurotiomycetes had worse metabolic profiles. These subjects were identified as more “unhealthy” obese subjects than those with a higher abundance of Eurotiomycetes. 

This was the first study to look at the human mycobiome in relation to obesity and associated metabolic disorders. Further knowledge of these interactions between the mycobiome, microbiome, and metabolic disorders may elucidate new methods for treating obesity and metabolic syndromes.  

Associations between the microbiome and blood lipids

Cholesterol molecule

It is well known that we have to be careful with what foods we eat, remembering to stay healthy and eat our fruits and vegetables. Diets high in fat can create serious health issues such as obesity, high cholesterol, and possibly Type 2 diabetes. Also on that list of related health problems is cardiovascular disease, which is characterized by blood clots, due to fat and plaque build-up in blood vessels, and can lead to a heart attack or stroke. Previous research has implied a connection between the microbiome and cardiovascular disease, due to the microbiome’s effect on production of a molecule called trimethylamine N-oxide (TMAO). As of yet, no research has been done to track the association between the microbiome and lipid (fat) build-up, so this is precisely what researchers published in Circulation Research set out to do.

The scientists located in The Netherlands, Poland, and Massachusetts, collected blood cholesterol measurements from 1500 LifeLines-DEEP subjects. LifeLines-DEEP is a collection of subjects used for assessing various health issues. Ethnic outliers and genetically related participants were removed from the study. Fecal samples were collected from 1180 participants, and sequenced. By the end of the data collection, 99 participants were excluded for reasons such as antibiotic use, or use of potentially microbiome-altering medications. In total there was a final number of 893 participants (380 men and 513 women) for which cholesterol samples, microbiome samples, and genotypic information was obtained. The participants included a wide range of age, BMI, and blood lipid levels.

The researchers found that gut microbiome species richness was significantly higher in women, and increased with age. Microbial richness was positively correlated with high density lipoproteins (HDL, the 'good cholesterol'), not correlated with low density lipoproteins (LDL, the bad cholesterol), and negatively correlated with body mass index (BMI). For example, the study confirmed that lower abundances of kingdom Archaea, families Christensenellaceae and Rikenellaceae, class Mollicutes, and genus Dehalobacterium are associated with high BMI. It was estimated that the microbiome could explain 4.57% to 65 of variation in BMI, triglyceride and HDL. No link was found between the gut microbiome and genetic predisposition to obesity of high blood lipid levels.

One hypothesis raised by the researchers is that bacteria potentially try to correct lipid imbalances, thereby helping to prevent cardiovascular disease. The strong associated between the gut microbiome and BMI and blood lipid levels – regardless of age, sex, and genetics – suggests that the microbiome does indeed play a role, if indirectly, in cardiovascular disease and other fat-related issues. 34 gut bacteria were found to be associated with BMI and blood lipids. There is a real potential for the utilization of this information in health therapies, such as blood clot and stroke prevention.

The effect of various treatments for juvenile Crohn’s disease on the microbiome

CT scan showing Crohn's disease in the fundus of the stomach

Crohn’s disease is a type of inflammatory bowel disease that is characterized by an autoimmune response in the colon.  It is generally thought that the bacteria in the gut elicit this immune response and cause the disease.  In otherwords, Crohn’s is caused by a shift in the microbiome from a healthy state, to a dysbiotic one, although the ultimate cause of the disease is still unknown.  The standard of care for Crohn’s in adults is combinations of immunosuppressive drugs, although in children this is not normally recommended.  Instead, children take either a prescribed diet, normally something like Soylent that involves only essential nutrients, or antibiotics.  Scientists from UPenn recently monitored the microbiomes of children with Crohn’s that were put on various courses of treatment, as well as the progression of the disease.  They discovered the changes that occurred in the microbiome that yielded a therapeutic response, and many new associations between the microbiome and Crohn’s disease.  They published their results in Cell Host and Microbe.

The scientists measured the microbiomes and inflammatory markers of 90 children before and after entering therapy for Crohn’s: 52 taking anti-TNF (an immunosuppressant), 22 taking the enteral nutrition exclusively (i.e. something like soylent), and 16 taking the enteral nutrition along with any other food they wanted.  The scientists also took samples from 26 healthy children.  They discovered that of the 45 most abundant bacteria in each child, 14 were different between the Crohn’s children and the healthy children.  These included bacteria such as Prevotella and Odoribacter that were largely absent from the Crohn’s group, and Streptococcus, Klebsiella, and Lactobacillus that were in higher abundances in the diseased group.  Overall diversity was also higher in healthy patients compared to those with Crohn’s.  The researchers also discovered that high levels of fungi, such as Saccharomyces cerevisiae, in the stool were high associated with Crohn’s.  When the researchers monitored the response of Crohn’s patients to treatment they saw that in many patients the microbiome shifted rapidly to a healthier state, with less inflammation, within a week of treatment for all three therapies involved.

This study helped further define the dysbiosis that is associated with Crohn’s disease, as well as demonstrate how this dysbiosis is altered using treatment.  It was especially useful that treatment naïve children were used in the study, as many adult studies are unable to remove confounding variables of various previous courses of treatments.  IBD is a difficult disease to study because of its complexity, but this study supports the hypothesis that a dysbiosis is at the root of the problem.

Fungal infection in brain highly associated with Alzheimer’s disease

Common example of fungi hyphae

Alzheimer’s disease is a brain disease in which slow and irreversible neuronal deterioration occurs. It is characterized by the accumulation and aggregation of proteins in the brain and central nervous system (CNS), although no one knows the cause of this protein aggregation, or if these amyloids are even responsible for the neurodegeneration that occurs, rather than just associated with it.  More recently, some scientists believe that Alzheimer’s is a disease caused by inflammation, because sufferers of the disease have high levels of many inflammatory signals in their brains.  Indeed, some infections that would drive inflammation have been found in Alzheimer’s patients, but nothing convincing as of yet.  This week though, scientists from Spain discovered that a fungal infection in the brain is highly associated with the disease.  They published their results in Nature Scientific Reports.

The scientists made histological sections from the brains of 10 patients with Alzheimer’s and 10 healthy controls, and stained them for the presence of fungi.  Remarkably, all 10 of the patients with Alzheimer’s showed signs of various fungi, whereas none of the healthy controls did.  The fungi were seen both intracellularly and extracellularly, meaning that in some cases the fungi actually entered the neurons in the brain.  The fungi included both yeasts, such as Sachromyces cerevisae, as well hyphae forming fungi such as Neosartorya hiratsukae. In addition, the scientists found traces of these fungi in the blood of the Alzheimer’s patients as well, suggesting that they may originate through common pathways, and spread into the brain.

While this study does not in any way prove these fungi are causing the disease, it certainly is compelling data that they are primary culprit for the disease.  As the authors state, if one were to assume that the etiology of the disease is caused by the fungi, all the symptoms of the disease can be explained.  For example, the slow progression and inflammatory nature of the disease.  Fortunately, If the fungi are responsible there could be many possible therapeutic approaches, including antifungals.

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.

Microbiome metabolite in urine predicts severity of graft versus host disease

Molecular structure of indoxyl-sulfate

People that suffer from blood cancers, such as acute myeloid leukemia, often times receive hematopoietic stem cell transplants (HSCT) as part of their therapy.  This procedure typically replaces the sick person’s white blood cells with those of a healthy donor.  While this is a life-saving procedure it does carry a type of transplant ‘rejection’ risk.  While in a normal organ transplant a person’s own white blood cells will attack the foreign organ, in this case the new, donor white blood cells begin attacking parts of the recipient’s body.  This is called graft versus host disease (GvHD), and can often times be fatal.  One of the primary areas that are attacked by the new blood cells is the gut microbiome.  This is not surprising because the ‘replacement’ immune system is not programmed to tolerate and accept the bacteria in the gut, because they are so different from the bacteria it was originally adapted for.  Therefore, GvHD, is often considered a microbiome disease, and there have even been studies to investigate whether matching microbiomes decreases risk for the disease. 

An important area of research is focused on detecting GvHD before it begins so that it can be treated early.  While normally GvHD is diagnosed by symptoms, it may be possible to use the microbiome itself for early detection of the disease.  A group out of Germany recently showed that by monitoring a specific metabolite produced in the gut, indoxyl sulfate, one could predict the severity of GvHD.  This molecule is only produced by bacteria, mostly in the gut, by breaking down the amino acid tryptophan.  Moreover, indoxyl sulfate is an important signaling molecule that is thought to modulate the gut epithelial function, and may cause inflammation.  They published the results of their study in the journal Blood last week. 

The scientists measured the indoxyl sulfate concentration in the urine of 131 individuals undergoing HSCT over the course of 28 days following the treatment.  After, the ranked the patients in terms of indoxyl sulfate level during the first ten days after transplant, and compared their outcomes.  Remarkably, the people that had the lowest levels of indoxyl sulfate had a statistically significant higher risk of dying of GvHD after 12 months.  Next, the scientists attempted to relate the gut microbiome composition of the patients with the indoxyl sulfate levels.  They realized higher diversity microbiomes were related to higher indoxyl sulfate levels, and healthier outcomes.  In addition, higher levels of Clostridia and lower levels of Bacilli led to higher indoxyl sulfate.

This study may go a long way in informing clinicians about GvHD risk in their patients.  Not only does it show that monitoring indoxyl sulfate may predict GvHD severity, but it also points to specific bacteria that may be important in controlling its levels.  HSCTs are a highly effective treatment for blood cancer, that often times have a higher efficacy/safety profile compared with traditional cancer therapies.  Understanding the microbiome’s role in GvHD, one of the most important risks of HSCT, will hopefully lead to improved therapies and better overall cancer outcomes.