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Gut Microbiome Linked to Age-Related Cognitive Decline

Researchers studying the role of the gut-brain axis in aging have found that fecal transplants from old mice to young mice produce learning and memory impairments in the young mice. These results add to on a growing body of research linking age-related cognitive decline with gut microbiome changes. The gut microbiome changes throughout our lifetime, declining in diversity as we age, and gut microbiome changes have been found in in multiple neurological conditions, including Alzheimer’s disease and depression. Recently, the gut-brain axis, has emerged as an important pathway of communication between the brain and the gut. However, the causal relationship between cognition changes and the gut microbiome is largely unknown. We know that inducing strokes in mice causes changes in their gut microbiome, and metabolites produced by gut bacteria can travel to the brain and worsen certain neurological diseases. Thus, the relationship is complex and bidirectional. In an effort to further understand this link, researchers investigated the effects of transferring gut microbes from old mice to young mice on cognitive function. The researchers hypothesized that if the microbiome plays a role in age-associated changes in cognition, then a decline would be seen in young mice administered a fecal transplant from older mice. The young mice (3-months old) were first treated with antibiotics to deplete their microbiomes, then administered a fecal transplant collected from older (24 months) mice, and ultimately, subjected to a barrage of metabolic, cognitive and behavioral tests. Following the fecal transplants, the young mice displayed memory and spatial awareness impairments with no changes in exploratory behavior, locomotor activity or markers of anxiety. The mice also displayed altered expression of proteins associated with synaptic plasticity and neurotransmission in the hippocampus, which has previously been linked to age-related cognitive decline. The young mice began to display the same cognitive functional changes as seen in old mice. It is still early in the field of gut-brain axis research, but there are promising signs that treatments focused on the gut microbiome could help maintain cognitive health as we age. Reference: D’Amato, A., Di Cesare Mannelli, L., Lucarini, E. et al. Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients. Microbiome 8, 140 (2020).

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The Biggest Microbiome Breakthroughs of 2019

Microbiome research continues to grow at a rapid pace, and in 2019 some amazing advances were made.

The contributions of specific species of bacteria to dysbiosis are being unraveled, prebiotics targeting specific types of bacteria are being developed, and postbiotics are moving to the forefront of research.

Here are some of the top discoveries of 2019:

Specific bacteria linked to depression

One of the most exciting and least understood areas of gut microbiome research is the link between gut bacteria and mental health with a growing body of evidence revealing how the bacteria in the gut can influence the brain through the gut-brain axis.

A large-scale analysis of the association between fecal microbiome data and diagnosed clinical depression in 1,054 individuals enrolled in the ongoing Flemish Gut Flora Project revealed that two species of gut bacteria, Coprococcus and Dialister, are consistently absent or seen at lower levels than normal in study participants suffering from depression, regardless of antidepressant treatment.

Although solidifying the depression-microbiome connection will take many more studies, these new findings are a notable signal to the clinical community that microbiome profiling should be considered for mental health patients. 

Gut bacteria protect against food allergies

There has been a startling rise in potentially life-threatening food allergies, which has been linked to a range of potential culprits, including the misuse of antibiotics and changes in dietary habits.

Differences in gut microbiome populations have been observed between infants allergic to cow’s milk and infants without allergies, and taking Lactobacilli and Bifidobacterium supplements during pregnancy has been shown to prevent atopic sensitization to food allergens among infants predisposed to food allergies.

In a particularly interesting study, scientists from the University of Chicago discovered that a particular bacterium, called Anaerostipes caccae, seems to prevent allergic reactions to food. Interestingly, this bacterium has also been shown to protect against nut allergies. 

The gut microbiome plays a protective role during aging

Studies of the links between the gut microbiome and aging have provided some surprising insights.

One study revealed that a metabolite produced by gut microbes can increase neuron production in the brain, improve intestinal function, and ultimately slow the aging process. Across several compelling mouse experiments, researchers found the negative effects of aging could be counteracted by enhanced microbial production of the short chain fatty acid butyrate. Furthermore, the administration of butyrate alone had protective effects similar to those of butyrate-producing bacteria.

Another study revealed that the decline in gut microbiome diversity that occurs as we age is associated with cardiovascular disease. The reason for the link seems to be the production of the microbial metabolite trimethylamine N-oxide (TMAO), which is produced at increased levels by the elderly microbiome.

Prebiotics and postbiotics

Finally, gut microbiome research has also been accompanied by an increased interest in the use of prebiotics and postbiotics to modulate the gut microbiota and host health.

Prebiotics and probiotics have been shown to improve the immune response of healthy volunteers receiving the influenza vaccine and postbiotics, such as butyrate, have been shown to enhance sleep and protect against neurodegeneration.

Given the notable microbiome breakthroughs of 2019, we’re sure that 2020 will bring even more exciting developments. Be sure to stick with us as we continue to cover how the microbiome influences health and disease and develop research-backed nutritional supplements for microbiome health.

We wish you all a happy 2020!

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Gut Bacteria and Alzheimer’s Disease: Bad Bacteria Could Speed Up the Progression

The gut microbiome influences the brain and immune system, possibly playing a role in the development and progression of Alzheimer’s disease.

  The community of bacteria living in our gastrointestinal tracts  - the gut microbiome – plays a fundamental role in the development of our immune system and helps protect the body against invading pathogens. Consequently, these bacteria can influence a wide range of diseases, even in distant organs such as the brain. 

 Recently, disturbances in the gut microbiome community have been linked to diseases including cancer, diabetes and Parkinson’s.

 Now, in a study published in the Journal of Experimental Disease, scientists have begun to uncover how the gut microbiome affects the development and progression of Alzheimer’s disease.

 Dementia affects 50 million people worldwide and Alzheimer’s disease is one of the most common forms of dementia; it is characterized by memory loss, confusion and additional cognitive symptoms that gradually progress into almost complete dependence and immobility.

 Unfortunately, there is no cure. Drugs can relieve some of the symptoms but not stop the progression of the disease.

 We don’t understand exactly how Alzheimer’s causes these neurological symptoms. The disease is partially characterized by a buildup of protein clumps in the brain, called amyloid-beta plaques, which appear alongside the cognitive decline. Although amyloid beta accumulation characterizes the disease, much remains unknown about where these plaques come from and how they wreak so much havoc in the brain.

 The Gut Microbiome Could Speed Up the Progression of Alzheimer’s Disease

The microbes in the gastrointestinal tract influence the immune system and the brain, possibly playing a role in the development of Alzheimer’s

 Dementia affects 50 million people worldwide. Alzheimer’s disease is one of the most common forms of dementia; it is characterized by memory loss, confusion and other cognitive symptoms that gradually progress into near-total dependence and immobility. About one-third of people that live until age 90 will develop a form of dementia. There is no cure. Drugs can ameliorate some symptoms but cannot stop the progression of the disease.

 For unknown reasons, women are more likely to develop Alzheimer’s disease than men.

 Although we don’t understand exactly how Alzheimer’s causes these symptoms, the disease is partially characterized by a buildup of protein clumps in the brain, called amyloid-beta plaques, which appear along with cognitive decline. Though amyloid beta accumulation characterizes the disease, much remains unknown about how these plaques wreak so much havoc in the brain.

 Normally, the immune system removes amyloid-beta plaques, but scientists think the immune system may also accelerate Alzheimer’s progression. 

 When the immune cells in the brain (called microglia) encounter amyloid-beta plaques, they become proinflammatory and release inflammatory chemicals that at high concentrations, may actually make Alzheimer’s worse.

 Thus, Dodiya and colleagues sought to understand the role of the microbiome in the development of Alzheimer’s and why women are more likely to develop the disease than men.

 The research team tested the effects of the gut microbiome on amyloid beta and microglia in the brain using a line of transgenic mice that produce extra amyloid precursor proteins.

 First, the researchers treated the mice with antibiotics to alter their gut microbial communities. 

 When they looked at brain tissue from the mice, they found that their microglia were behaving properly and the mice had fewer amyloid beta plaques than non-antibiotic-treated mice. 

 To confirm that the change in microbial communities contributes to these effects, the researchers then reintroduced microbes by transplanting fecal matter from healthy mice back into another mice that had been treated with antibiotics. 

 Reintroducing the microbes partially restored the amyloid beta plaques and increased the expression of markers for inflammation-causing microglia. 

 Notably, although the researchers tested both male and female mice, they only found these changes in male mice.

 This is not the first study comparing how the microbiome has different effects in different sexes, but it highlights the importance of considering sex when thinking about treatments for Alzheimer’s and other diseases.

 The finding that antibiotics reduce Alzheimer’s symptoms in male mice can now be used to better understand the timing and influence of gut bacteria on Alzheimer’s disease.  Hopefully, further studies will help to extend these finding to humans.

 Reference

Dodiya et al. (2019). Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes. JEM. DOI: 10.1084/jem.20182386

[thinkbiome]

Butyrate Enhances Sleep

The short chain fatty acid butyrate promotes sleep, according to a new study.

A growing body of research is illuminating the fundamental role that the microbiome plays in our lives. The gut microbiome plays a fundamental role in the development of a healthy immune system, and microbiome dysbiosis has been linked to a plethora of diseases including IBD, metabolic disease, heart disease and rheumatoid arthritis.

The components of bacterial cells, such as lipopolysaccharide (LPS; a component of the bacterial cell wall), and the metabolites made by bacteria are primarily responsible for exerting these effects.

In a new study published in the journal Scientific Reports, scientists report that a key short chain fatty acid (butyrate) produced by bacteria induces sleep in mice and rats.

Sleep is impacted by a variety of signals such as satiety (feeling full), hormones, and proinflammatory signals. Importantly, gut bacteria can affect our behavior and signaling to the brain through the gut-brain axis

The brain sleep mechanisms and the gut flora are linked through a dynamic bidirectional relationship. Depleting gut bacteria has been shown to reduce sleep, while disruption of the normal sleep cycle (i.e., from jet lag) causes intestinal dysbiosis.

These links prompted scientists to ask whether the metabolites made by good bacteria (from the breakdown of fiber) affect sleep.

To test this, the researchers investigated the effects of oral administration and injection of sodium butyrate and tributyrin, a butyrate-yielding prodrug, in mice and rats.

The scientists found that oral administration of butyrate (as sodium butyrate or tributyrin) robustly induced sleep in the animals. However, injecting butyrate directly into the blood had no effect on sleep. The scientists think that this happens because the butyrate acts on the liver on its way out of the gut, which then induces sleep.

Sleep responses to systemic bacterial infection are linked to inflammation. Butyrate is produced by bacteria in the intestines, and it has potent anti-inflammatory properties. Butyrate suppresses inflammation in the colon and liver and the production of proinflammatory molecules in response to LPS. Therefore, it seems that system-wide proinflammatory signals related to bacterial infections negatively affect sleep, whereas bacterial-derived anti-inflammatory signals from the intestinal tract have the potential to positively influence sleep.

Reference

Szentirmai É., et al. Scientific Reports. 2019 May 7;9(1):7035. doi: 10.1038/s41598-019-43502-1.

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Aging Microbiome Linked to Cardiovascular Disease

The aging microbiome may be somewhat responsible for the deterioration often seen in heart health as we age according to a new study from the University of Colorado Boulder.

The risk of cardiovascular disease increases significantly as we age and is associated with stress-mediated arterial dysfunction.

Almost three-quarters of Americans aged 60-79 suffer from some form of heart disease.

A growing body of research suggests that the gut microbiome plays a pivotal role in heart health. Inspired by this, scientists at the University of Colorado Boulder wanted to know whether there was a direct link between alterations in the gut microbiome and arterial dysfunction.To address this question, the scientists treated old and young mice with broad-spectrum antibiotics to kill off their resident bacteria.

After a few weeks of antibiotic treatment, the young mice showed no changes in the health of their arteries; however, the old mice showed significant improvements in several vascular health measures.

In a nutshell, the arteries of the elderly mice were restored to that of the young mice.

This remarkable finding suggests that there is something about the aged microbiome that has a negative impact on heart health.

It is well known that as we age, the diversity of bacteria in our microbiome diminishes. This lack of diversity results in an imbalance called dysbiosis, which could be contributing to the arterial damage.

To identify specific factors that could be driving cardiovascular disease, the scientists carefully studied the microbiomes of the old and young mice.

They found that the microbiomes of the elderly mice had increased numbers of bacteria that are pro-inflammatory and have previously been associated with disease.

Notably, one particular metabolite – TMAO – was present at much higher levels in the microbiomes of the old mice.

TMAO (trimethylamine N-oxide) has previously been linked to atherosclerosis and stroke.

While it’s still too early to draw firm conclusions, increasing evidence suggests that as we age the gut microbiome deteriorate and begins producing toxic molecules, including TMAO, which get into the bloodstream, cause inflammation and oxidative stress and damage tissue.

The researchers are currently focusing on the effects of different diets on gut health and cardiovascular disease in humans. Notably, a compound called dimethyl butanol, which is found in red wine and olive oil, has been found to block the production of TMAO and could be part of the reason that the Mediterranean diet is good for heart health.

Reference:

Brunt, V. E. et al. (2019). Suppression of the gut microbiome ameliorates age‐related arterial dysfunction and oxidative stress in mice. The Journal of physiology.

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New Research Links Specific Gut Bacteria to Depression

A new study examining more than 1,000 people has identified two specific types of bacteria that are strongly linked to mood and depression.

One of the most exciting and least understood areas of gut microbiome research is the link between gut bacteria and mental health.

A growing body of evidence is uncovering how the bacteria in the gut can influence the brain (known as the gut-brain axis), from PTSD to brain inflammation.

Now, researchers have linked two specific types of bacteria in the gut microbiome to depression.

The team analyzed the association between fecal microbiome data and diagnosed clinical depression in 1,054 individuals enrolled in the ongoing Flemish Gut Flora Project.

They focused in on specific groups of bacteria that were positively (increased) or negatively correlated (decreased) with depression. The researchers found two species of gut bacteria, Coprococcus and Dialister, were consistently absent or seen at lower levels than normal in study participants suffering from depression, regardless if antidepressant treatment.

The results were then validated in a different cohort of 1,063 individuals from the Dutch LifeLinesDEEP cohort and in a cohort of clinically depressed patients at the University Hospitals Leuven, Belgium.

Interestingly, a group of bacteria (known as an enterotype) called Bacteroides2 that has previously been linked to Crohn’s disease was found to be more prevalent in patients with depression.

Finally, the authors created a computational technique allowing them to identify gut bacteria that could potentially interact with the human nervous system, the idea being to create a catalog of neuroactive bacteria in the human gut. They found certain types of gut bacteria that could make a wide range of chemicals that interact with the brain.

The researchers hope that this catalog will help other researchers identify specific types of bacteria involved in mental health and the specific ways in which they affect the host. One example the team found is that the ability of gut bacteria to produce DOPAC, a metabolite of the human neurotransmitter dopamine, was associated with better mental quality of life.

While no one is claiming a direct causal link between these bacteria and depression (yet), the findings add more evidence to link gut microbiome dysbiosis and intestinal inflammation with mental health.

Reference:

Valles-Colomer, Mireia, et al. "The neuroactive potential of the human gut microbiota in quality of life and depression." Nature microbiology (2019): 1.

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Gut Bacteria Protect Against A Common Food Allergy

The gut microbiome plays a crucial role in protecting against food allergies, according to a new study.

There has been a startling rise in potentially life-threatening food allergies over the last 50 years. This rise has been linked to a range of potential culprits, including the misuse of antibiotics and changes in dietary habits.

Now, scientists have more concrete evidence that the gut microbiome plays a fundamental role in the development of food allergies and could be modified to prevent their development.

The study has recently been published in the journal Nature Medicine.

Scientists previously found that infants allergic to cow’s milk had different types of gut bacteria to infants without allergies.

Research also showed that some bacteria are associated with lower risk of food allergy – leading scientists to ask whether gut microbes in children without allergies might be protective.

To investigate this hypothesis, scientists at the University of Chicago took fecal samples containing gut microbes from eight human babies. Four of the infants had cow's milk allergy, while the other four did not.

The researchers then transplanted gut bacteria from each of eight infants into groups of mice raised in a germ-free environment and sensitized to milk protein—meaning the animals’ immune systems created allergic antibodies to milk.

The scientists then gave milk to the mice.

Mice that received no bacteria or bacteria from allergic children experienced anaphylaxis, which is a potentially life-threatening allergic reaction.

Mice receiving gut bacteria from non-allergic infants had no reactions.

The investigators then compared the gut bacteria of the allergic germ-free mice with those that showed no allergic reaction.

The comparison revealed the presence of a particular bacterium, called Anaerostipes caccae, which seems to prevent allergic reactions to food.

Anaerostipes caccae belongs to a family of bacteria called Clostridia, and previous work has shown that the presence of these bacteria in the gut protects against nut allergy.

So, it seems that this protection extends to other types of food allergy.

Anaerostipes caccae produces a short-chain fatty acid called butyrate. This nutrient helps the gut to establish a bacterial composition that promotes health.

The researchers were surprised by big of an impact this one species of bacteria can have on the body’s reaction to food. And the race is now on to figure out how to use this information to prevent children from developing food allergies.

Reference:

Feehley, T., Plunkett, C. H., Bao, R., Hong, S. M. C., Culleen, E., Belda-Ferre, P., ... & Andrade, J. (2019). Healthy infants harbor intestinal bacteria that protect against food allergy. Nature Medicine, 1.

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Probiotic Provides Long-Term Protection Against Childhood Eczema

A new study shows that giving a probiotic supplement to pregnant mothers and their children significantly reduces the likelihood of the child developing eczema in the first 11 years.

When given to mothers from week 35 in pregnancy, through breastfeeding, and to the babies from birth until age two years, the probiotic Lactobacillus rhamnosus (strain HN001) cut the children's rate of developing eczema in half.

The probiotic also provided children some protection against developing asthma, hay fever, and allergies.

The research has been published in the scientific journal, Pediatric Allergy and Immunology.

The results come from a project that started in 2004 and involved 474 pregnant women in Wellington and Auckland. The participants were randomly assigned to one of three groups, receiving Lactobacillus rhamnosus (HN001) (six billion colony-forming units [cfu] daily), Bifidobacterium lactis (HN019) (nine billion CFU daily) or a placebo.

The children were followed up at ages two, four, six and now 11 years.

By age two, children taking Lactobacillus rhamnosus (HN001) had a 50% reduction in eczema compared to the placebo.

Interestingly, Bifidobacterium lactis (HN019) had no effect compared to the placebo.

Furthermore, at ages two, four, six, and 11 years, the children who received HN001 experienced less wheezing, less asthma, less hay fever, and less allergy to a skin prick test of common allergens.

The research team doesn’t yet know exactly why the Lactobacillus rhamnosus (HN001) protects against eczema and allergies, but suspect that the bacteria influence the developing immune system and/or modify genes that influence the skin's barrier function.

Understanding the mechanism behind the protection is an important next step.

Reference:

Kristin Wickens et al. Effects of Lactobacillus rhamnosus HN001 in early life on the cumulative prevalence of allergic disease to 11 years, Pediatric Allergy and Immunology (2018). DOI: 10.1111/pai.12982

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Appendix Linked to Parkinson’s Disease

People who have had their appendix removed have lower risk of developing Parkinson’s disease, according to a new study.

Accumulation of misfolded alpha-synuclein protein in the brain is a hallmark of Parkinson’s disease. The reason for this is believed to originate in the gut and changes in the gut microbiome are known to play a key role in the onset of Parkinson’s disease.

Now, a team of scientists at the Van Andel Research Institute (VARI) in the US have discovered that removal of the appendix reduces the risk of developing Parkinson’s disease.

The team analyzed data from more than 1.6 million individuals. They found that removal of the appendix decades before Parkinson’s disease onset was associated with a lower risk for Parkinson’s, particularly for individuals living in rural areas, and delayed the age of onset.

Furthermore, they found that the healthy human appendix contained a build-up of alpha-synuclein and Parkinson’s-associated toxic alpha-synuclein products that are known to accumulate in Lewy bodies (a characteristic of Parkinson’s disease).

Lewy bodies are present in the brains of everyone with Parkinson's but evidence suggests that they may originate in other areas of the body and travel to the brain. Lewy bodies have also been found in the gut and vagus nerve.

This is intriguing because the data suggest that removal of the appendix may interrupt the gut-vagus nerve connection, which is at the center of the gut-brain axis. Severing this nerve may prevent alpha-synuclein from spreading to the brain, reducing the risk of developing Parkinson's.

Although generally thought to be redundant, the appendix actually plays a significant role in our immune system and in regulating the makeup of our gut bacteria.

This study, therefore, provides the first biological link between the gut microbiome and Parkinson’s disease.

Now, the question that remains is why does Parkinson’s develop only in some people with abnormal alpha-synuclein aggregation in the gut, and why others are seemingly resistant?

Reference:

Killinger, et al. The vermiform appendix impacts the risk of developing Parkinson’s disease. Science translational medicine 10.465 (2018): eaar5280.

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The Gut Microbiome May Protect Bone Marrow Recipients

Having a healthy gut microbiome before a bone marrow transplant is associated with increased post-transplant survival, according to a new study.

Blood stem cell and bone marrow transplants (BMTs) are used to treat many types of blood cancer. One of the most serious complications of this therapy, however, is graft-versus-host disease, wherein the donor’s immune cells attack the vital organs of the transplant recipient.

It can be lethal.

Recently, researchers have discovered that a transplant recipient’s gut microbiome plays an important role in their survival after a BMT.

Now, for the first time, investigators have found an association between the health of the gut microbiome before a transplant and a recipient’s survival afterward. The findings were presented at the annual meeting of the American Society of Hematology (December 2nd, 2018).

The researchers found that BMT patients who went into the transplant with a disrupted gut microbiome had a higher risk of death after the transplant.

The researchers studied 1,922 stool samples from 991 people receiving BMTs and evaluated them for a range of bacteria types, including commensals and those known to cause disease.

On average, the investigators found patients about to receive a BMT had reduced bacterial diversity in their microbiomes. They also found that different strains were dominant when compared to healthy volunteers.

Only 10-30% of patients had what researchers considered a balanced gut microbiome before their transplant

This is not surprising considering that most people with blood cancer who need transplants go through long periods of treatment with chemotherapy and antibiotics that throw off the normal, healthy microbiome balance.

Before a patient receives a BMT to treat their cancer, doctors run many tests (to verify heart health, lung and kidney function etc.) to make sure they are otherwise healthy.

This study suggests that doctors should also screen the microbiome. If they find dysbiosis (unhealthy gut microbiome), they may have to do something to repair it before the patient can receive the transplant.

Notably, scientists at Memorial Sloan Kettering are already testing the effectiveness of fecal microbiome transplants (FMT) prior to a bone marrow transplant. A recent study led by Eric Pamer and Ying Taur found that fecal transplants are effective in restoring the balance of healthy microbes that is lost during a BMT.

FMTs could become commonplace prior to bone marrow transplants.

Reference:

Taur Y et al. Science Translational Medicine, 26 Sep 2018: Vol. 10, Issue 460, eaap9489 DOI: 10.1126/scitranslmed.aap9489

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Microbiome Linked to Multiple Sclerosis

Multiple sclerosis affects millions of people worldwide, but the underlying cause and triggering factors remain unknown. Now scientists are looking to the gut microbiome for answers.

In multiple sclerosis (MS), the immune system attacks the myelin coating that surrounds the axons connecting nerve cells. The resulting damage leads to symptoms, such as muscle weakness, fatigue, and vision problems.

While the cause of MS is unknown, researchers have hypothesized that gut bacteria might play a crucial role.

Emerging evidence shows that the gut microbiome is an important factor underlying a variety of conditions including heart disease, cancer, metabolic disease, and mental health.

The gut-brain link goes beyond mood disorders, however, and research has linked gut microbiome dysbiosis to Parkinson’s disease and, more recently, the development of MS.

A new study published in the journal Science Translational Medicine now suggests that the gut may trigger the harmful immune response that causes the myelin damage (called demyelination) in MS.

The study’s authors previously looked at how specialized immune cells (T and B cells) communicate with each other to set off demyelination.

In the current study, the researchers identified other T-cell activation pathways. They found that a protein called GDP-L-fucose synthase is produced by certain gut bacteria in the intestines of people with MS and can activate T cells.

In one particular group of people with MS who have the HLA-DRB3* genetic variant, the gut microbiome appeared to play a much greater role in triggering demyelination than previously suspected.

The scientists hope that this new information can be used to develop better MS treatments.

Current therapies target the whole immune system, which means that, while helping counteract the harmful damage that causes MS, it also weakens helpful immune responses.

The research team hopes to be able to use GDP-L-fucose synthase to target harmful MS-specific T cells, while leaving the rest of the helpful immune response intact.

Reference:

Planas, R., et al. (2018). GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3* 02: 02 patients with multiple sclerosis. Science translational medicine, 10(462), eaat4301.

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Cancer Cells Grow by Altering the Gut Microbiome

Leukemia reduces the numbers of blood glucose-regulating gut bacteria in order to grow, according to a compelling new study.

Cancer incidence rates have long been associated with obesity and diabetes. Although there is no convincing evidence connecting an increased risk of cancer directly to sugar consumption, a growing body of research suggests it is likely.

Glucose, a type of sugar, is an important source of energy for the cells in our body (especially the brain), and cancer cells need a consistent source of glucose to grow. For to tumors to grow aggressively, they must divert glucose away from other (normal) cells and stimulate the body to make more.

Now, using a mouse model, researchers at the University of Colorado Cancer Center have identified two new ways that leukemia alters the body's metabolism to help it grow.

The cancer causes a diabetes-like condition, which diverts glucose from normal cells and makes it available to the tumor.

In the first mechanism, cancer cells stimulate fat cells to overproduce a protein called IGFBP1. This makes the fat cells more sensitive to insulin, meaning they use less and leave more available for the tumor.

The second mechanism serves to keep the body’s insulin production low to stop it from responding to the shortages triggered by the first strategy.

The researchers discovered this by studying the gut microbiome, identifying differences in microbiome composition between healthy mice and animals with leukemia.

The main change they saw in the gut microbiomes of mice with leukemia was a reduction in bacteria that produce short-chain fatty acids, which are essential for gut health.

Another change involves the inactivation of hormones called incretins. These hormones are released by the gut and reduce the level of blood glucose in our system after we eat.

Together, these mechanisms favor the cancer by altering how the body uses energy.

Interestingly, the researchers found that they could extend the lives of the leukemic mice by rebalancing the glucose regulation and slowing the tumor’s growth.

This research doesn’t suggest that removing sugar from a diet will have an effect on cancer growth but does illuminate how cancer steals energy resources. Hopefully, scientists can use this information to develop new strategies (potential through the microbiome) to prevent cancers from obtaining the energy they need to grow.

Reference:

Ye, Haobin, et al. "Subversion of Systemic Glucose Metabolism as a Mechanism to Support the Growth of Leukemia Cells." Cancer Cell (2018). doi: https://doi.org/10.1016/j.ccell.2018.08.016

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Are Baby-Poop Probiotics the Future?

Consuming probiotic bacteria isolated from baby feces could help with conditions ranging from obesity and diabetes to cancer, according to new research.

 The role of the microbiome in human health is firmly established.

The gut bacteria producing metabolites like short chain fatty acids (e.g., acetate, propionate, and butyrate) are often lacking in patients with diabetes, obesity, autoimmune disorders, and cancers.

As a result, scientists think that altering the gut microbiome (e.g., with probiotics) could be beneficial in maintaining or restoring normal gut microbiome composition and human health.

This led researchers to search for human probiotic bacteria from a healthy gut microbiome source – baby poop!

The researchers collected fecal matter from the diapers of 34 healthy babies, and extracted strains of lactobacillus and enterococcus bacteria.

Their goal was to improve short chain fatty acid production in mice.

First, the researchers validated the safety of the probiotic bacteria they had isolated (334 strains).

To test whether the bacteria could change the gut microbiome and increase short chain fatty acids, the researchers next fed mice a probiotic cocktail containing 10 strains of bacteria. They also exposed human feces to the cocktail.

The probiotic cocktail was found to change the makeup of the gut microbiome and boost short chain fatty acid production in mice and human feces.

The researchers hope that this work will lead the way for the development of human-derived probiotics to treat disease.

 Reference:

Nagpal, R., et al. (2018). Human-origin probiotic cocktail increases short-chain fatty acid production via modulation of mice and human gut microbiome. Scientific Reports, 8(1), 12649.

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Autism Risk Determined by Mother’s Microbiome

The risk of developing autism-spectrum disorders is determined by the mother’s microbiome during pregnancy, according to a new study.

Recent studies suggest that autism-spectrum disorders are often associated with dysregulated immune responses and microbiome dysbiosis. But, no one knows how interactions between the gut microbiome and immune system contribute to the development of such neurodevelopmental disorders. 

To get a better understanding, scientists at the University of Virginia School of Medicine analyzed pregnant women’s microbiomes to determine the child’s risk of developing autism. Then, asked if this finding could be used to stop the development of neurodevelopmental disorders in mice.

The researchers found that the risk of developing autism-spectrum disorders is determined by the mother’s microbiome during pregnancy.  And blocking the inflammatory immune molecule Interleukin-17a (IL-17a) could prevent autism-like neurodevelopmental disorders developing in mice.

The work raises the very exciting possibility that preventing forms of autism could be as simple as an expectant mother modifying her diet or taking custom probiotics.

In fact, targeting or modifying the microbiome is a much safer strategy than trying to block IL-17a because it’s an important factor in helping the body to fight off infection.

The study reveals how important the microbiome is in calibrating how a child’s immune system will respond to infection, injury or stress; showing how an unhealthy maternal gut microbiome can cause problems such as making her unborn offspring susceptible to neurodevelopmental disorders.

The next step for the team is to figure out how specific microbiome features in pregnant mothers correlate with autism risk and how other facets of the immune system contribute.

 Reference:

Lammert CR, et al. Cutting Edge: Critical Roles for Microbiota-Mediated Regulation of the Immune System in a Prenatal Immune Activation Model of Autism. The Journal of Immunology. 2018 Jul 2:ji1701755.

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Prebiotic Fiber Prevents Autoimmune Neurological Disease

Incorporating non-fermentable (prebiotic) fiber during early life can help prevent the onset of autoimmune diseases such as multiple sclerosis (MS), according to a new study.

 The rise of the low-fiber, high-fat diet in recent decades (the “Western diet”) has paralleled a rise in autoimmune diseases including multiple sclerosis.

Growing evidence suggests that the “Western diet” negatively affects gut microbiome composition and function, resulting in the development of autoimmune diseases.

While there are numerous efforts to develop new treatments, a better approach might be to identify preventive strategies.

Dietary fibers include complex carbohydrates that can be either soluble (e.g., pectin) or insoluble (e.g., cellulose) and are crucial for human health.

Growing evidence shows that the end products of fiber fermentation (by gut bacteria), short-chain fatty acids (SCFAs), shape the immune system in the gut and help protect against many autoimmune and allergic diseases.

Most insoluble fibers (e.g., cellulose) make up the bulk of plant tissues, including vegetables and fruits, and are poorly digested by the gut microbiome. Although non-fermentable fiber can modulate microbiome composition, their role in autoimmune disease development is still poorly understood.

So, researchers set out to investigate the effects of non-fermentable dietary fiber on the development of central nervous system (CNS) autoimmune disease.

The research team used a genetically engineered spontaneous experimental autoimmune encephalomyelitis mouse model (an MS-like mouse model) to investigate the effects of fiber.

Interestingly, they found that consumption of non-fermentable dietary fiber (a diet rich in cellulose) helped protect mice from developing spontaneous CNS-directed autoimmunity. The protection went away when the mice were switched to a low-fiber diet early in life.

The protective effects were related to changes in the gut microbiome and consequent recruitment of anti-inflammatory immune cells to the intestine.

Overall, the research suggests that a plant-rich diet in early life offers a simple way to prevent CNS autoimmunity, but nutritional studies in humans are now needed.  

Reference:

Berer, K., et al. (2018). Dietary non-fermentable fiber prevents autoimmune neurological disease by changing gut metabolic and immune status. Scientific reports, 8(1), 10431.

[thinkbiome]

Skin Microbiome Protects Against Cancer

The common human skin bacterium Staphylococcus epidermidis produces a substance that protects against cancer and could lead to new preventative treatments.

 We mostly think about the human microbiome in terms of gut bacteria. However, microbes are found everywhere in the body, especially on the skin, which is in constant contact with the surrounding environment.

Bacterial communities vary significantly by their location on the body, and the health benefits they provide are likely to be specific to the area they are found on.  

While studying how certain healthy skin bacteria fight off harmful pathogens, researchers at the University of California, San Diego stumbled upon a strain of Staphylococcus epidermidis that makes an interesting-looking substance.

The chemical made by the bacteria looks a lot like a key component of DNA, called adenine (one of the four DNA “building blocks”).

The researchers found that the chemical, called 6-N-hydroxyaminopurine (6-HAP) inhibited the production of DNA. When tested in cell cultures, 6-HAP prevented several types of tumor cells from growing and multiplying. Furthermore, the team found that 6-HAP was not toxic when injected into mice.

Amazingly, when melanoma cells were introduced to mice, animals that had received 6-HAP intravenously ended up with tumors more than 60% smaller than the mice that did not get 6-HAP.

The team also found that applying 6-HAP to the skin of mice (like sunscreen) protected them against UV radiation.

Staphylococcus epidermidis is commonly found on human skin, but researchers say that only about 20% of the healthy population is likely to have a strain that produces 6-HAP. Therefore, 6-HAP could be developed into a type of sunscreen to protect the wider population from the damaging effects of ultraviolet light.

 Reference:

Nakatsuji, T et al. A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Science Advances, 4.2 (2018): eaao4502.

[thinkbiome]

Scientist Finally Know How A Ketogenic Diet Protects Against Epilepsy

 The answer lies within the gut microbiome.

 A low-carbohydrate, high-fat ketogenic diet can help to treat refractory epilepsy in patients who are non-responsive to anticonvulsive medications.

Studies have shown that more than half of children who switch to the diet see at least a 50% reduction in the number of seizures they experience. Furthermore, a subset (10-15%) becomes seizure-free!

The diet is also being used to manage a growing list of conditions including autism spectrum disorder, Alzheimer’s disease, metabolic syndrome, and cancer.

What scientists haven’t known is why the diet works…

 Until now.

 A team at the University of California, Los Angeles (UCLA), has now found that the gut microbiome plays a pivotal role in mediating the protective effects of a ketogenic diet on refractory epilepsy.

Given the growing understanding of the gut-brain axis, (linking the gut microbiome to dietary responses, neuronal activity, and behavior), the researchers hypothesized that the gut microbiome may also play a role in the antiseizure effects of a ketogenic diet.

They tested the ketogenic diet in two mouse epilepsy models, one that undergoes electrically induced seizures and another that spontaneously develops tonic-clonic seizures. 

 Analyzing the microbiomes of the mice revealed some interesting insights:

The gut microbiomes of the mice changed within a few days of starting the ketogenic diet.

While the diversity of their gut microbiomes was reduced, populations of others, including Akkermansia muciniphila and Parabacteroides species, were significantly increased.

In the electrically stimulated seizures mouse model, the ketogenic diet provided protection against seizures.

 The scientists found that the microbiome had to be present for the protection to occur; the diet had no beneficial effect on germ-free or antibiotic-treated mice.

However, the protective effects could be restored in antibiotic-treated mice by giving them Akkermansia muciniphila and Parabacteroides orally.

Surprisingly, both bacterial species had to be present for the seizure protection to be restored. If the researchers only gave the antibiotic-treated mice one of the two strains, they saw no significant increase in protection.

If scientists restored the microbiomes of mice on the ketogenic diet to “normal,” the protection went away. This suggests that persistent interactions between the ketogenic diet microbiome, diet, and neuronal activity must be maintained.

The team then carried out the same tests in a mouse model of temporal lobe epilepsy that spontaneously develops tonic-clonic seizures. They again found that Akkermansia muciniphila and Parabacteroides could protect the mice from seizures.

Taken together, the findings show that the gut microbiome mediates the anti-seizure effects of the ketogenic diet in various seizure types.   

Finally, the researchers analyzed the animals' gut, blood, and brains. They found that the ketogenic diet bacteria increased brain levels of GABA (a neurotransmitter that silences neurons) relative to brain levels of glutamate, a neurotransmitter that activates neurons to fire.

The increased GABA/glutamate ratio is what protects the mice against seizures.

The data from the mouse study aligns well with human studies showing that antibiotic treatment increases the risk of seizures in epilepsy patients. These findings now need to be verified in humans.

 Reference:

Olson, Christine A., et al. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell (2018). DOI: 10.1016/j.cell.2018.04.027