Autism and the Microbiome: A Summary of What We Know Now

Two days ago, I spotted a short commentary[i] in the journal, International Journal of Molecular Sciences, from this past August, which really caught my attention. Here is why:  it was written by 3 researchers in the department of neurology at Rutgers University’s medical school who state that, “We will explore the potential for treatment of ASD [autism spectrum disorders] by targeting the microbiome with probiotics….this paper will attempt to provide significance to the aggregation of the research in this area of research.”  It really is a great summary of what we now know.

Here are just some of the facts the paper presents:

  1. “Almost half of children with ASD suffer from at least one GI symptom…with diarrhea and constipation being the most common symptoms reported.”
  2. “Additionally, recent studies show the severity of GI symptoms as being significantly correlated with the severity of autism symptoms.”
  3. “The balance of microorganisms in the intestinal tract of ASD individuals has been found to differ from that of neurotypical individuals.”
  4. “…the presence of autistic symptoms in children has been correlated with a less diverse gut microbiome…”
  5. “The association of ASD and a number of microbial overgrowths, including various species of bacteria and Candida, have been further confirmed by independent studies over time.”
  6. “Small Intestine Bacterial Overgrowth has been correlated with ASD.”

They conclude this list of findings by stating, “Taken together, all these microbiome alterations may be associated with the increased gastrointestinal disturbances in individuals with ASD.”

More than that, there are other highly significant findings in autism that point to a gut origin.  A few examples:

  1. “Stool testing found lower levels of short chain fatty acids [SCFAs] in children with ASD…”
  2. “Another study found increased levels of IgA [antibodies] in stool samples of children with ASD compared to healthy children, suggesting the presence of gut immune abnormalities in ASD.”
  3. “…increased gut permeability or ‘leaky gut’ is implicated in ASD.”
  4. “…both the intestinal barrier and brain barrier may be impaired in ASD, with decreased levels of intestinal tight junction components…”

Ok – so let’s summarize.  We know that people with autism have GI symptoms markedly more often than people without ASD, and that the severity of those symptoms correlate with the severity of their autism.  We know that they have altered gut microbiota, including SIBO, lower levels of beneficial bacteria, lower levels of anti-inflammatory SCFAs, increased frequency of leaky gut/leaky brain.  We know that “This ‘leaky gut’ theory would offer a mechanism by which GI disturbances could play a role in neurodevelopment and cognition.”

But wait…there’s more.  We know that TREATING these microbiome alterations alleviates the symptoms of autism.  Again, just a few of the findings the paper cites.

  1. “Nearly two decades ago, a study found that vancomycin [a non-systemic antibiotic] temporarily improved behavior and communication in ASD.”  (I was actually there when this paper was first revealed at a conference.)
  2. “Parents of children with ASD who received a specific five strain probiotics Delpro  reported a significant improvement in bowel habits and behaviors measured by autism treatment evaluation checklist.” (This surprised me as it’s a very low-potency (10 billion) product.  Might be worth a try!)
  3. “Antifungal treatment also demonstrated some efficacy in vivo.”

(Just yesterday, in fact, I read about a study[ii] out of Baylor College of Medicine wherein, researchers tested probiotics in a rodent model of autism.  The researchers report that, “…administration of the bacterium Lactobacillus reuteri could lead to specific changes in the brain that reverse social deficits through a mechanism that involves the vagus nerve and the oxytocin-dopamine reward system.”  (I have written about L.reuteri and autism before in a post about these researchers’ previous paper on this subject!)  When the vagus nerve, which connects the brain to the gut (and many other parts of the body), is activated it releases oxytocin, a hormone that increases social behavior.  Lowering the level of the L.reuteri in the guts of pups reduces their social behavior.  Increasing the level restores it.  If the vagus nerve that connects the gut to the brain is cut, L.reuteri does not restore social behavior, proving that it exerts its effect through the nerve.  In mice who were genetically engineered to “…lack oxytocin receptors in the reward neurons or blocked the receptors with specific drugs, L.reuteri also could not restore social behaviors in the ASD mice.”  Thus, the scientists were able to determine the exact mechanism by which the probiotic was exerting its effect.)

Back to the commentary, in the concluding paragraphs, the researchers say, “While research into the gut-brain connection in autism still remains in its preliminary phases, there is a convincing body of evidence that suggests a relationship between gastrointestinal distress and autism….”

A week ago, two papers[iii] were published in the eminent journal, Pediatrics, which showed that 1 in 40 children born in the United States (between the ages of 3 and 17) has autism. This is literally a national catastrophe at this point. Obviously, we need way more research into the gut-brain axis in autism.  After all, as these scientists write, “…even today, it is becoming evident that the gut, specifically the disturbance of it, plays an important role in certain neurological disorders including ASD.”

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[i] Fowlie, G, Cohen, N, Ming, X. The perturbance of microbiome and gut-brain axis in autism spectrum disorders.  International Journal of Molecular Sciences. 2018;19(8): pii: E2251. doi: 10.3390/ijms19082251.

[ii] https://medicalxpress.com/news/2018-12-microbial-based-treatment-reverses-autism-spectrum.html

[iii] https://www.spectrumnews.org/news/national-surveys-estimate-u-s-autism-prevalence-1-40/

Senescence, Aging…and the Microbiome: Part 2

As I promised last Thursday, I’ll finish talking about the article[i] on aging, the microbiome,  and senescence today.

A quick summary of my last post:  the evidence currently available points to a depletion of the microbiota as we age (from diet (for example, older people – who may have dental issues – may not eat enough fibrous foods, etc.)), use of antibiotics throughout life, stress associated with aging and so forth:  “…these old-age-related clinical issues could clearly contribute to the increased predisposition to various infections and gut-associated diseases by causing alterations in the microbiota of elderly people.”  Also, the build-up of senescent cells (especially cells of the immune system) may also result from microbiome depletion, as the gut bacteria are crucial for normal immune functioning.  “…however, we still do not have a complete understanding of the mechanisms underlying the aging-mediated changes in the gut microbiome configuration, or whether these microbial changes are the cause of consequence of senescence.”

While we wait (hopefully, not too long) for science to provide us an easy way of “spring cleaning” – lowering our levels of senescent cells (see my last post for more on this) – the article provides us some things we can do now…which, as you know, is my favorite thing to write about.

  1. Levels of  short-chain fatty acids (SCFAs) has been shown to be lower in the elderly, and is correlated with lower fiber intake and antibiotic treatment. These reduced levels are associated with susceptibility to inflammatory bowel diseases, the development of leaky gut (which in turn, of course, causes systemic inflammation to rise), have a negative impact on insulin sensitivity and more.  Thus, “…dietary or relevant therapeutic interventions (e.g. using fiber-rich diets or indigestible-carbohydrates [prebiotics] that promote SCFAs production through fermentation by gut bacteria) that restore/promote the microbiome in a way that the intestinal organic environment is also restored/promoted in terms of beneficial SCFAs might turn out to be effective for ameliorating the aging-related ailments, particularly those originating in the senescent gut.”
  2. Some good news in all this: “…the available evidences on the associations between gut microbiota, nutrition and systemic inflammation suggest that dietary interventions for positively modulating the microbiota composition and diversity could help in promoting the healthier aging and longevity.”
  3. Remember that SCFAs are anti-inflammatory. Thus, boosting levels may be “…particularly important for elderly people, because they are already going through immune-senescence and are at increased risk of developing miscellaneous infections and illnesses.”
  4. Using prebiotics and probiotics to maintain a healthy bacterial microbiome has been shown to aid in the “…prevention of senescence-related diseases such as C.difficile-associated diarrhea, constipation, and common respiratory and gastrointestinal infections.”
  5. Unfortunately, right now (and believe me, no one is sicker of this phrase than me): we simply don’t have enough information to conclude that using probiotics and prebiotics will work in the “…prevention of old-age related illnesses and immune-senescence.”   However, preliminary results do hint at their “…possible potential in improving the gut environment and lowering the incidences of senescent illnesses.”

The article concludes with hope:  “…given the mounting evidence that the gut microbiome plays a fundamental role in numerous aspects of our health and disease, it can be easily envisioned that novel personalized nutritional and therapeutic approaches targeting the intestinal microbiota such as probiotics, prebiotics, nutraceuticals, functional foods, and fecal microbiota transplantation may offer potential  avenues for better health and wellbeing with a particular relevance for our senior comrades.”

Considering that every one of us is getting older by the day, the time to care for you old friends is now.

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[i] Nagpal, R, et. al.  Gut microbiome and aging: physiological and mechanistic insights.  Nutrition and Healthy Aging. 2018;4:267-285.

Senescence, Aging…and the Microbiome: Part 1

Yesterday evening, I read about a study[i] done by scientists at the University of Salford, in Manchester, UK, that fascinated me enough that it sent me into one of my I-can’t-stop-reading jags.

First, a brief explanation:  senescent cells are old cells that have lost the ability to divide.  Once a cell enters senescence, it pumps out hundreds of proteins including chemicals to stop itself from dying. So these cells are not dead – but they are also not quite alive. They do serve several beneficial purposes, which I may go into at a later time, but for the moment, the important thing to know is that these “zombie” cells are known to lead to aging.  By killing off senescent cells, you can stimulate natural repair mechanisms in tissue.  Senescent cells are associated with many aging-associated diseases: cancer, heart disease, obesity, diabetes, infections, bowel diseases, autoimmune diseases,  dementia, and more.

A 2017 article in Scientific America[ii] gives a great summary of current research:  “…dozens of experiments have confirmed that senescent cells accumulate in ageing organs, and that eliminating them can alleviate, or even prevent, certain illnesses…This year alone, clearing the cells in mice has been shown to restore fitness, fur density and kidney function. It has also improved lung disease and even mended damaged cartilage. And in a 2016 study, it seemed to extend the lifespan of normally ageing mice.”

Substances that kill off senescent cells are called senolytics, and the hope is that these will be able to slow down or stop diseases associated with aging.

Several pharmaceutical agents have been shown to be senolytic, as has quercetin, a natural plant flavonoid (found in foods like onions, apples, green tea, for example). This “clearing out” of senescent cells only needs to be done periodically – kind of like a spring cleaning – to prevent disease.  Back to the University of Salford research:  these scientists discovered that ordinary Azithromycin (commonly known as Zithromax, and dispensed frequently as a Z-pack) is an incredibly effective sonolytic.  A single (low) dose of Azithromycin “…was shown to effectively kill and eliminate the senescent cells, with an efficiency of 97 percent.”  Healthy cells remained untouched.

Call me crazy, but I am all for keeping age-related diseases at bay,  and so, I continued to read.  I was pretty sure I’d read the term senescence in relation to the microbiome.  I looked back at  articles I’d read in the last 6 months or so and it turned out that I was right – it was from this past June  in the journal Nutrition and Healthy Aging.[iii]

The article has so much great information in it that it will require a second post.  I’ll cover the “what you can do about it now” information in my next post.  I’ll just conclude today with a general description of the relationship of senescent cells to the human biome.

Firstly, as usual, we don’t know nearly enough.  However, the general theory is that age-related microbiome changes (the decrease of beneficial flora like bifidobaceria and lactobacilli and the increase in opportunistic organisms like C. difficile (and thus, a decrease in anti-inflammatory short-chain fatty acids)) lead to an increase in permeability of the gut barrier (i.e. leaky gut).  This, in turn, leads to systemic inflammation as I’ve discussed in previous posts, which – in the case of aging, is known as inflammaging…which leads to age-related illnesses.  Whether or not these gut biome alterations directly lead to immune-system senescence is unknown.  It is possible that immune-system senescence leads to the biome alterations and inflammation. However, several studies have correlated the loss of microbiome diversity in aging adults (from increased use of drugs as we age, a life-time of antibiotic exposure, dietary modifications, constipation and so forth) with old-age frailty.  I am keeping an open mind but will not be at all surprised if this starts with biome depletion.

After all – given that the biome directly interacts with and affects the nervous system of the gut (the enteric nervous system (ENS)), it is very likely that the gut flora and fauna play a huge role in the functioning of the gut.  And the evidence we now have points to a “…correlation between host aging and senescence-like phenotypic changes to the ENS.”

So to sum up for today, as we age, there are negative changes to biome diversity, with a decrease in good bacteria and an increase in bad.  This leads to a reduction in the production of anti-inflammatory byproducts and these two phenomena then lead to alterations in the permeability of the gut epithelial lining, negative alterations to the enteric nervous system, immune senescence, inflammaging and ultimately, chronic illness and frailty.

More on all this next post!

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[i] https://medicalxpress.com/news/2018-11-antibiotics-senescent-cells-ageing.html

[ii] https://www.scientificamerican.com/article/to-stay-young-kill-zombie-cells/

[iii] Nagpal, R, et. al.  Gut microbiome and aging: physiological and mechanistic insights.  Nutrition and Healthy Aging. 2018;4:267-285.

Treating Leaky Gut: Reduce Inflammation First?

Back to leaky gut, briefly…

For those of you unfamiliar with the term epithelial cells, this is a single layer of cells that line the inside of the intestinal tract and provide a selectively permeable barrier. That is, healthy cells are tightly packed together, only allowing digested food through, while protecting the body from pathogens, undigested food, waste products, and so forth.

When an inflammatory reaction compromises the integrity of this barrier, such as seen in inflammatory bowel diseases, for example (thus allowing things out that should be kept in) we refer to this as a leaky gut.

A new technology has been developed that is allowing scientists to better study the epithelial cells, called organ-on-a-chip. These are microchips lined by living human cells. They have been used, apparently, to study various organ functions in a highly controlled environment. Studying epithelial cells has proven a challenge in the past because of the incredible complexity of the gut biome. Researchers at the University of Texas, using this organ-on-chip technology, have created a model of the human intestine, which allowed them to isolate one factor at a time.[i]

The scientists induced inflammation in these cells (which they termed gut inflammation-on-a-chip) by treating them with a chemical called dextran sodium sulfate (DSS) which is known to induce colitis. Exposure to the chemical impaired the function of the epithelial barrier, distorted the size and shape of the intestinal villi, and caused decreased mucus production. They noticed that contact between the dysfunctional epithelial cells and immune cells led to greatly increased oxidative stress and that, in turn, led to an increase in the production of inflammatory cytokines. Healthy epithelial cells, on the other hand, suppressed oxidative stress and the production of these inflammatory cytokines. “These results show that impaired integrity of the intestinal barrier is the trigger to initiate the inflammatory cascade.”[ii]

They tested the effects of probiotics in this model and discovered “Probiotic treatment effectively reduced the oxidative stress, but it failed to ameliorate the epithelial barrier dysfunction and proinflammatory response when the probiotic administration happened after the DSS-induced barrier disruption.” Thus, they conclude, that in order to stop the inflammatory cascade, epithelial barrier function must first be restored and maintained.

If this all actually translates to in vivo experimentation, it would indicate that in order to successfully treat leaky gut, it’s necessary to reduce inflammation first, before taking probiotics: helminths, prebiotics , short-chain fatty acids, improved diet, and so forth are your first line natural treatments. Interestingly, those of us heavily involved in using the Specific Carbohydrate Diet noticed this phenomenon years ago. As a nutritionist, I always recommended several months of the diet and other natural anti-inflammatory treatments BEFORE staring clients on probiotics. When gut inflammation levels were at their highest at the start of the diet, probiotics were often extremely problematic, causing a myriad of side effects.

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[i] Shin, W, Kim, HJ.  Intestinal barrier dysfunction orchestrates the onset of inflammatory host-microbiome cross-talk in a human gut inflammation-on-a-chip.  Proceedings of the National Academy of Sciences of the United States of America. 2018;115(45) E10539-E10547.  https://doi.org/10.1073/pnas.1810819115

[ii] https://www.medicalnewsbulletin.com/probiotics-gut-barrier-healthy/

 

More on Boosting Levels of Short-Chain Fatty Acids

While I’m on the subject of butyrate…

An article[i] was published in the International Journal of Pharmaceutics that caught my attention.  Researchers tested the efficacy of a probiotic (one I had never heard of) called, Symprove . One of the big issues often raised about probiotics:  will the bacteria survive stomach acid to reach the intestines?  Most brands are not tested so their true efficacy is unknown.

Using a laboratory simulator of the human gut (with microbiota from health human subjects), researchers were able to determine that all the bacteria from this product made it through to the intestines where they immediately colonized.  Symprove contains 4 lactate-producing species: L rhamnosus, L. acidophilus, L. plantarum and E. faecium.   Lactate is food for species of bacteria that produce short chain fatty acids [SCFA].

Butyrate levels went up significantly and subsequently, “…an immunomodulatory effect of the probiotics was seen; production of anti-inflammatory cytokines (IL-6 and IL-10) was increased and production of inflammatory chemokines…was reduced.”

Apart from the fact that Symprove looks like a pretty good choice in probiotics, there are two other take-away points I want to leave you with today:

  1. The scientists determined that it was not actually the probiotic bacteria themselves which conferred the benefit to the gut biome…it was the lactate they produce, that fed SCFA-producing bacteria.  The increased amount of these SCFA-producing bacteria led to a marked increase in anti-inflammatory products, like butyrate:  “The data presented here clearly suggest that in fact integration and colonisation of the probiotic species within the existing microbiota, and the generation of a utilizable nutrient (lactate), stimulates growth of the largely beneficial phyla meaning that it is the rebalancing of bacterial families that confers health benefits to the host.”
  2. The importance of short chain fatty acids cannot be understated. These three sentences really jumped out at me (I’ve added the underlining for emphasis):

“…dysbiosis in ulcerative colitis (UC) patients has been linked to a reduction in butyrate-producing species, reduced levels of propionate-producing species have been linked with asthma in children while broad changes in the gut microbiota have been linked with irritable bowel syndrome (IBS)…It has also been proposed that butyrate produced from a high-fiber diet can improve brain health and function.  Ensuring the gut microbiota is optimally balanced and so producing high SCFA, especially butyrate, levels is therefore an important focus in maintaining and improving general health and wellbeing.”

A trial of Symprove is definitely in my future!

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[i] Moens F et al. A four-strain probiotic exerts positive immunomodulatory effects by enhancing colonic butyrate production in vitro. International Journal of Pharmaceutics, 2018: https://www.sciencedirect.com/science/article/pii/S037851731830838X?via%3Dihub

Staying Young, Healthy and Chock Full of Akkermansia

You know how whenever you learn a new word, for example, suddenly it appears everywhere?  I have been having that experience of late with all kinds of tie-ins to recent posts.  Coincidences or…is it just that the Biome Buzz is so trending that I’m on top of stories before they happen?!

Akkermansia.  Suddenly it is HOT.  I started talking about it in October, if you remember, and on the 18th, even wrote a post about ways to boost levels, as it’s not yet available for purchase.   Akkermansia popped up again in my post of November 7th,  which was about  a recent summit on probiotics, at which a researchers discussed adding polyphenols to the diet (like cranberry extract…which is the second thing to be popping up everywhere) to boost levels of Akkermansia, which is not only associated with a reduced risk of inflammatory diseases like Alzheimer’s, obesity, autism and a host of others.

On November 15th, an article appeared in the journal Science Translational Medicine, describing the anti-aging effects of Akkermansia.[i]  I’ve talked before about how we lose microbiome diversity as we age, which leads to many age-related issues like poor digestion, lowered immunity, and insulin resistance.  By feeding the test animals the short-chain fatty acid, butyrate, they were able to restore levels of Akkermansia while also improving insulin sensitivity (to levels seen in younger animals).  Their results suggest “…that the insulin resistance and other pathologies associated with aging and even frailty can be ameliorated by targeting the cascade of events that flow from the depletion of Akkermansia muciniphila…”[ii]

But wait, there’s more!  So now that I once again have Akkermansia on my mind, I spot a little study, also published last week, on cranberry extract![iii] These researchers wanted to ascertain if the polyphenols found in the concentrate ameliorate the negative effects of a poor quality, animal-product-based (inflammatory) diet.  While there were only 11 individuals in the study, it was a double-blind, placebo controlled, crossover study (so the gold standard of clinical trials).  The control diet contained meat, dairy and simple sugar while the experimental diet was the same plus 30 grams of whole cranberry powder.  The subjects were fed one or the other diet for two 5-day periods of time (so a total of 10 days), then taken off the diet, and then the groups were swapped.   While taking the cranberry extract, the subjects’ microbiomes showed fewer negative microbial changes.

“It appeared that adding cranberries to the control diet reduced the rise in secondary gut bile acids that have been associated with colon and GI cancer. Cranberries also lessened the drop in beneficial SCFA [short chain fatty acids] thought to help maintain healthy GI cells. Overall, the treatment diet suggested that cranberry constituents may help support a healthy gut microbiome.”

Red berries on a dark background. cranberries in a bowl.

(As I just mentioned above, short-chain fatty acid (like butyrate) raise the levels of Akkermansia.)

Out of curiosity, I just did a quick search to see if there is any commercially sold form of butyrate.  For whatever reason, it had never occurred to me to check that until now!  Well, guess what! – yes, there is.  This is not something I have ever tried on either myself or any of my nutrition clients.  Therefore, it’s time to experiment on Judy!  I’m buying it today.  Anyone want to volunteer to be a guinea pig with me?!

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[i] Bodogai, M, et. al. Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells. Science Translational Medicine. 2018;10(467).   DOI: 10.1126/scitranslmed.aat4271

[ii] https://www.orlandosentinel.com/news/space/go-for-launch/la-sci-sn-gut-bacteria-aging-20181115-story.html

[iii] https://www.eurekalert.org/pub_releases/2018-11/pc-fts111218.php

Stress and Our Missing Old Friends

Yesterday I devoted several hours to reading a fascinating article on the connection between stress and the microbiome.[i]  The conclusion:  the lack of exposure to our “old friends” (those commensal organisms with which humans co-evolved) has caused immune dysregulation, leading to a greater susceptibility to the adverse effects of stress…and that stress, in turn, has caused alterations to the biome and immune system.

The paper was extensiveso I will just hit on some of the major highlights.  (And even just highlights means this is going to be a loooong post, so brace yourself!)

  1. Many illnesses, both physical (somatic) and mental, are the result of chronic, low-grade inflammation.  That inflammation, in turn, is the result of a “…compromised regulatory T (Treg) cell compartment, a failure of immunoregulation might be involved in promoting an over-reacting of the inflammatory stress response and, thus, predisposing an individual to the development of certain stress-related somatic and mental disorders.”  The regulatory (T regulatory cells, typically abbreviated as Treg) part of the immune system- that is responsible for turning off inflammation when it’s no longer needed to fight pathogens – is deficient.  Levels of the necessary regulatory cytokines are too low, resulting in a continual (and incredibly destructive) inflammatory process.
  2. Chronic stress is known to be a major risk factor for an enormous array of diseases: cardiovascular disease, fibromyalgia, bronchial asthma, atopic dermatitis (eczema), arthritis, inflammatory bowel diseases (IBD), stomach ulcers, diarrhea and digestive problems, chronic pelvic and abdominal pain, infections, headaches, impaired wound healing, cancers, major depressive disorder, PTSD, and chronic fatigue syndrome…and many more.
  3. The greater the degree of industrialization in a country, the higher the incidence of stress and inflammation related disorders, including autoimmune diseases like multiple sclerosis, IBD and type 1 diabetes, allergy, atopic dermatitis, asthma, etc.
  4. “Mental health” diseases that are known to be associated with increased chronic inflammation include PTSD, generalized anxiety disorder, panic disorder, phobias, depression, burnout, chronic fatigue syndrome. There are likely many more but these are the ones confirmed in the medical literature.
  5. I thought this was a pretty interesting point: “From an evolutionary perspective, it makes sense that activation of the innate, rather unspecific and, therefore, fast-acting immune system has been selected to be an inevitable part of the classical stress response.”  The innate immune system – the part we are born with – can act immediately when faced with a threat.  The adaptive immune system, the part responsible for creating antibodies to fight germs, takes a couple of days to kick in.  When you get bruised, for example, the area swells, as that innate immune system rushes (via the blood stream) to the area to fight the damage and invaders.  “Those individuals showing an activated immune status, even before the actual physical injury and pathogenic invasion happens, elicited by perceiving a certain situation psychologically as threatening or dangerous, had an evolutionary benefit and were selected over the past millions of years.”  That is, those early humans whose innate immune systems rapidly primed, ready to kick into action, when the person simply perceived a threat survived better.
  6. The article describes numerous studies relating stress to physical and mental illnesses. A quick example:  “…individuals with inflammatory diseases are three to four times more likely to experience depression.”  In one experiment, people were given a low-dose of toxins (not enough to cause physical symptoms) from the pathogenic bacteria, Salmonella.  However, the toxins did cause a rise in inflammatory blood markers…and an increase in anxiety levels and depressed mood.  It also caused a measurable negative effect on verbal and non-verbal memory.  The higher the level of inflammation (measured by blood markers), the greater the mental symptoms.  (These results have been replicated in multiple experiments in both people and animals.)
  7. How does all this relate back to the gut microbiome? The bacteria of the gut are responsible for profound manipulation of the immune system. “Microbes in large part mediate their immunomodulatory effects by influencing the activity and maturation of immune cells.”
  8. In experiments, when mice raised germ-free are given commensal bacteria, the regulatory system kicks in, boosting levels of regulatory cytokines including one of the key ones, IL-10 (interleukin 10). Even colonizing with just a single strain of a probiotic has this effect.  “…treatment with the probiotic bacterium Bifidobacterium infantis promotes the proliferation of Treg cells in mice and results in an increased production of IL-10 in humans.”  (Not coincidentally, I mention this particular strain in a recent post on depression and the microbiome! )
  9. Commensal gut bacteria promote the production of immune cells in the gut lining (epithelium), and their metabolites (like the short chain fatty acids for example) boost Treg cells both directly and indirectly.
  10. Gut bacteria are very much responsible for the metabolism of the amino acid tryptophan, the precursor to serotonin. As I’m sure you know, serotonin in the brain positively affects mood, and increasing levels of it is the target of medications like Prozac.  Serotonin too is a huge player in normal immune functioning and actually, most of it is produced in the gut – as the gut comprises about 70% of our immune system.  (Remember that most germs enter through your nose and mouth!)
  11. “…alterations of the gut microbial composition can have detrimental effects on host immunity. Besides factors like diet, age, and pharmaceuticals, one highly potent disruptor of the intestinal bacterial community is chronic stress.” So it swings both ways, as you know:  microbiome alterations cause stress.  Stress causes microbiome alterations.
  12. As I have talked about many times before, the depletion of the gut microbiota results from our westernized lifestyles, that has greatly reduced our potential exposure to a myriad of microorganisms that were present during our evolution and that “play a role in setting up regulatory immune pathways”: sanitation, drinking water treatment, antibiotics, changes in diet, formula feeding, cc-sections, time spent indoors, etc. are all factors.
  13. Treating with anti-inflammatory pharmaceuticals DOES positively affect psychiatric disorders like PTSD. However, because of the complexity of the immune system, it makes more sense to clinically treat by activating “…the body’s own immunoregulatory mechanism, which is able to comprehensively suppress unnecessary inflammation…”  (You’ve heard this sentiment from me many, many times before.  This is why, for example, I talk about using helminths so often.  They are perhaps the most potent stimulator of the Treg system we have!  And our industrialized society has basically removed the possibility of exposure.)
  14. The authors of this paper ran a study on young, healthy men raised (during the first 15 years of life) in either a city or a farm. (By the way, if the city residents had a pet growing up they were disqualified, as pets increase microbial exposure and thus, reduce the risk of inflammatory disorders.)  As the researchers predicted, those raised in an urban environment had an increased systemic immune response when exposed to a stressor than did their rural peers.  More than that, the Treg system of the urbanites was suppressed, “…suggesting immunoregulatory deficits relative to rural participants…”  I’m shocked. NOT
  15. I think 15 highlights is more than enough so the last one. “In addition to the protective effects of various Old Friends against a plethora of inflammatory somatic disorders, Old Friends have been further shown to positively affect mood, stress coping, and fear extinction, as well as to prevent the negative consequences of chronic psychosocial stress in humans…”

Unfortunately, these authors – like most scientists these days – limit their definition of Old Friends to the bacterial microbiome.  Our Old Friends, though, are far more diverse and include viruses (as I pointed out, for example, here), macrobiotic organisms (like helminths, as I have pointed out many times (for example, here), protozoa (as I talked about here), and so forth.  As in any ecosystem, there is much greater complexity than a single class of organisms and all are inexorably intertwined.  Limiting scientific research to only the bacterial microbiome is like saying you will research a rain forest but only study the mammals…forgetting that the diversity of the mammalian population in the forest is reliant upon all their co-inhibitors, like the insects, the birds, the reptiles, and so forth.

As always, I will continue to hope that at some point, science starts to think about the bigger picture.  The question I constantly ask myself is, can biome restoration really happen if we only attempt it using 1 type of organism?

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[i] Langgartner, D, Lowry, CA, Reber, SO. Old Friends, immunoregulation, and stress resilience.  European Journal of Physiology. 2018.  doi: 10.1007/s00424-018-2228-7

Helminths and Allergies: Another Look at an Immigrant Population

In my last post, I talked about how microbiome depletion results from immigrating to the United States (and subsequent dietary changes), which leads to obesity and metabolic diseases.  I promised to tell you more about immigrant studies on biome depletion so today I am addressing a paper from 2 years ago in which researchers describe the effects of macrobiome (helminth) depletion in immigrants to a westernized nation.

In this case, scientists looked at the development of allergy in 126 Ethiopians newly arrived in Israel.[i]  They were tested upon arrival and then, 115 of them were retested a year later.  The health assessments consisted of allergy testing – and stool and blood sampling, in order to determine the presence of helminths.  Anti-helminth medication was offered to all those with helminths but only 46.3% of the people chose to take it.

At baseline (i.e. when the people first arrived):  most of them were positive for helminths.  Of the 18 who were not, 22.2% (so 4 people) tested positive for allergies.  Of the 108 who were helminth-positive, only 7 (so 6.5%) tested allergy positive.  Thus, a total of only 11 people (8.7%) tested positive for allergies

Now here’s where it gets really interesting.  A year later, after living in a highly-developed nation, “…a significant general increase in allergy…was observed.”  30 people (26.1%) now tested positive for allergies, as opposed the 11 of the previous year.  After not only looking at allergic symptoms, but also skin prick testing for reactivity, the scientists concluded that allergic reactivity had increased in all the immigrants.

The research showed that “Helminth infection is significantly associated with low allergy and low SPT [skin prick testing] reactivity.”  Even in the helminth-positive population that had chosen to not take the anti-helminth medication, an increase in allergic sensitivity was observed.  There are several possible explanations for this, including the fact that lack of exposure to helminths meant they were slowly losing their helminth population as worms died off.  Certainly too, other environmental factors – for example, dietary changes leading to microbiome depletion – also played a role.  However, the conclusion of the paper is that the loss of helminths was definitely the major factor in the increase in allergic sensitivity.

One last note of interest:  I can think of at least 1 paper in the literature that shows that multiple kinds of helminths leads to markedly higher levels of regulatory cytokines (those chemicals that turn off the inflammatory response).  That finding was confirmed by this research as well:  “Infection with several parasites had even lower allergy than monoinfection compared to the non infected individuals.”

Unfortunately, the research ended there.  It would have been great to see what happened to those individuals allergy-wise if helminths were reintroduced.  Oh well….

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[i] Stein, M, Greenberg, Z, Boaz, M, Handzel, ZT, Meshesha, MK, Bentwich, Z. The role of helminths infection and environment in the development of allergy: a prospective study of newlyl-arrived Ethiopian immigrants in Israel.  Plos: Neglected Tropical Diseases. 2016;10(1): e0004208. doi: 10.1371/journal.pntd.0004208.

 

The Negative (Biome) Side of Moving to the USA

Last week, a really interesting new study[i] was published in the journal, Cell, detailing how immigrating to the USA negatively impacts the gut bacteria.  Researchers looked at people from Southeast Asia and found that there was a significant reduction in the diversity of gut microbes with each subsequent generation, culminating with their microbiota resembling those of Americans of European origin.

You all know that a reduction in microbial diversity is associated with an increase in inflammatory health issues, including obesity. I’ve written about this several times before on this blog. 514 female immigrants to the Minnesota area, provided stool samples and diet diaries for this study. Some had lived in Thailand, some were first, and some second generation Americans. These were compared to the bacterial microbiomes of 36 Americans of European origin.

The dominant species of the recent immigrants was Prevotella but that changed remarkably quickly to Bacteroides. Prevotella is important in the digestion of high fiber foods, which are much more predominant in an Asian diet (as opposed to the “western” diet, which is heavy in sugar, fat and protein). Dan Knights, a co-author of the study, points to the change in diet as a key factor in this loss of diversity which changes within just a few months: “People began to lose their native microbes almost immediately after arriving in the U.S. The loss of diversity was quite pronounced: Just coming to the USA, just living in the USA, was associated with a loss of about 15 percent of microbiome diversity.” The children of these immigrants lost a further 10% of diversity. What’s really scary, and kind of amazing, is that “Even a short period of residence in the United States was sufficient to induce pronounced increases, in some cases over 10-fold, in the ratio of Bacteroides to Prevotella.”[ii]

The change in diet, and the loss of microbial diversity, was clearly associated with an increase in obesity and diabetes.

An important note: in the conclusion of the paper the authors of course point out the limitations of the study. While they looked at the diet/microbiome connection, they did not take into consideration changes in stress levels, exercise, drinking water, antibiotic use, and treatment with anti-helminth drugs. All of these, some more, some less, will also have an impact on the loss of microbial diversity. (In fact, in my next post, I’ll tell you about a different immigrant study from a couple of years ago, this one looking at Ethiopian immigrants to Israel and the health implications arising from the loss of their native helminth populations.)

Wouldn’t it be interesting to look at immigration the other way? What happens to the microbiota of Americans who move to less industrialized countries? Can this loss be reversed? The answer is currently unknown.

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[i] https://www.news-medical.net/news/20181104/Migration-affects-gut-microbiota-which-in-turn-affects-health-find-researchers.aspx?fbclid=IwAR0UpAWiDnA2dhi1UfvMh6wlfgc7Rdu-U7pGrTYPT3y5tN7jleFpmYIH54k

[ii] Vangay, P, et. al. US immigration westernizes the human gut microbiome. Cell. 2018;175(4):962-972.

Interesting Bits and Pieces About Autism, Akkermansia and More Things You Can Do Now

I know you were all missing your Tuesday post from me. 🙂  I was on my way home from Florida, where we saw my son’s autism doctor. So with autism on my mind, I thought I’d share a little article[i] I found today that ties together several topics I’ve covered in the last month or so.

The article covers a talk given by a scientist, Dr. Michael Conlon, at a recent summit on probiotics. He discussed about how polyphenols (remember those from my article on ways to boost Akkermansia?) improve health through boosting levels of good bacteria. Resveratrol, found in grape and berry skins, for example, increases levels of lactobacillus and Bifidobacterium in the gut according to a 2016 study. (I did start the cranberry extract and grape seed extract after writing that post. Over the weekend, completely coincidently, I also spotted a product made by Life Extension (one of my favorite organizations, as you know) called Berry Complete , which I ordered for myself this morning).

Remember too my article about “eating like a queen bee”? Well, studies show that propolis (another polyphenol), produced by honey bees, reduces bacterioides, alleviating colitis and intestinal inflammation. (I did some looking around and found this product that contains both royal jelly, as per that post of mine, and propolis. With cold and flu season coming up here in the northeastern USA, I plan on adding this too to my daily regime.)

Dr. Conlon also talked about new strains of probiotics that will hopefully be available soon, including Akkermansia muciniphila. Akkermansia, as you know from my posts, has many health benefits including protecting against atherosclerosis.  And it turns out that low levels are not only associated with Alzheimer’s, as I wrote about a few weeks ago, but also autism. Says Dr. Conlon in his presentation, “Some of you may or may not know that kids with autism actually have significantly more gut problems, so we investigated and one of the initial findings was that there is a decrease in A.muciniphila.” He goes on to say that bacterial metabolites in the children’s urine indicate, leaky gut…which I covered just last week.

I went to PubMed and found Dr. Conlon’s paper[ii], from 2011, which had several interesting findings, two of which really jumped out at me. Firstly, the strain Bifidobacterium longum, which is found to be low in kids on the spectrum, has been shown to improve anxiety in animal studies by stimulating the vagus nerve. (Probiotics, like VSL#3, have this strain.) If there is any one symptom I have seen in children with autism (and, all too often, their typical siblings), it’s high levels of anxiety. Secondly, the aforementioned finding of low levels of Akkermansia in the autism population was new to me: “…our finding of a lower abundance of A. muciniphila in ASD children and their siblings may indicate a thinner GI mucus barrier in ASD children…These results could represent indirect evidence of impaired gut permeability in children with ASD.” As I wrote about last week, leaky gut = leaky brain.

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[i] https://www.nutraingredients.com/Article/2018/11/05/Resveratrol-and-propolis-Two-promising-targets-to-boost-gut-microbiota

[ii] Wang, Lv, Christophersen, CT, Sorich, MJ, Gerber, JP, Angley, MT, Conlon, MA. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. In feces of children with autism. Applied and Environmental Microbiology. 2011;77(18):6718-6721.

Improving Health as We Age Through Manipulation of the Gut Microbiota

As you all know, one area of particular interest to me is healthy aging.  (After all, we are all getting older! ugh)  An interesting article appeared on Medical News Today[i] this past Friday that I thought I’d share.  It’s about new research, presented at a London conference on the microbiome last week, on how the diseases associated with aging are intricately tied to the bacterial microbiome.

Dr. Marina Ezcurra, of Queen Mary University in London, used the worm C.elegans (which is commonly used in research on human disease) as a model for aging because it lives only 2-3 weeks and as it ages, believe it or not, it develops pathologies not unlike humans.  What is totally fascinating is that the aging of the worm is 100% the result of the aging of its gastrointestinal tract.  Thus, it is easy to test what manipulation of various gut bacteria does to increase or decrease the worm’s lifespan…and what diseases may be associated with any particular change.

One body of research out of Baylor College of Medicine, presented by Dr. Ezcurra, involved creating 4,000 different mutant strains of E.coli, each with a specific gene deleted.  The C.elegans were then fed these different strains to see what happened.  Says the senior researcher on this study, “Of the nearly 4,000 bacterial genes we tested, 29, when deleted, increased the worms’ lifespan.  Twelve of these bacterial mutants also protected the worms from tumor growth and accumulation of amyloid-beta, a characteristic of Alzheimer’s disease in humans.”  One mutant bacterium overproduced an acid which simulates the mitochondria (the powerhouse of cells), measurably increase the worms’ lives.

Dr. Ezcurra also raised the issue of how metformin, which I have written about several times, increases lifespan.  Metformin is known to alter the bacterial microbiome, and in fact, studies on C.elegans have shown that metformin does not work to increase the worms’ lives when they are germ-free and lack gut bacteria.  That is, it exerts its anti-aging effects through the microbiota.  Apparently, what the drug does is affect bacterial folate metabolism which, in turn, regulates aging.

Dr. Ezcurra’s own research has shown that by colonizing the guts of C.elegans with strains of bacteria previously shown to reduce intestinal aging, she can increase the worms’ lifespans.  She will soon be doing experiments colonizing the worms with bacterial strains from humans, the idea being, of course, to narrow down what particular strains of bacteria do, to prevent (or cause) aging and disease.

We already know that we lose microbial diversity as we age.  As Dr. Ezcurra said, in her talk, “By better understanding the links between nutrition, microbiome, and health, we can understand how the elderly can maintain their microbiome, and also help them directly by using pre- and probiotic strategies. This would help us age in [a] better way, maintaining health and quality of life in old age without drugs or surgery.”

So yet again, I am left with the conclusion that caring for our biome as we age is going to turn out to be an awfully good idea.

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[i] https://www.medicalnewstoday.com/articles/323484.php

Leaky Gut and Leaky Brains…and Disease

If you remember, my last post was a quick update on what we currently know about the microbiome-depression link, and I mention leaky gut with a promise to write more about it this week.  Toward that end, on Friday evening, I read an article from the journal Microorganisms entitled, “Leaky Gut, Leaky Brain?,”[i] and was looking forward to sharing some highlights with you this week.  More on this in a moment.

A little coincidental tangent: on Saturday, I came across an article on Helio summarizing the “Psych Congress” summit about the microbiome.[ii]  This particular piece is about the gut-brain connection in psychiatric illness and I realized it fit in perfectly with today’s leaky gut focus while also being a great segue from talking about depression.  “We are not better today at treating depression than we were 70 years ago,” says the presenting doctor.  (Well, that is er…depressing.)  Depression, he goes on to state, is an inflammatory disease, pointing to those same raised blood markers I mention in my last post.  Simply prescribing the usual anti-depressants is simply not good enough for most people.   The microbiome needs to be addressed.

This doctor’s presentation included information about things you can do now:  an anti-inflammatory low-processed-sugar diet that includes fruit, veggies, whole grains, lean meat, fish, etc. I also liked his suggestions to “tidy up blood-brain barrier leakiness”:  curcumin, green tea, garlic and cinnamon, probiotics and prebiotics .

How’s that for timely?  And this, from a mainstream physician!  As it turns out, the  article I am covering today (“Leaky Gut, Leaky Brain?”), starts off with an extremely pertinent quote:  “’Leaky gut’ syndrome…has attracted much attention in recent years and for decades, was widely known in complementary/alternative medicine circles.” That is absolutely correct.  I remember only too well when the concept of a leaky gut was considered “alternative” and the gut-brain connection was scoffed at by mainstream medicine…and I’m not that old!  I keep telling you that times they are a’changing! (Thank goodness.  As I always say, just because something is unproven doesn’t mean it’s wrong.  And there is something called common sense…)

The blood-brain barrier is a membrane very similar to the epithelial lining of the gut.  Both are made up of tightly packed cells that, when healthy, prevent infiltration by  anything not meant to get through.  We know that inflammation in the gut causes those tight cell junctions to open up in the gut, allowing bacteria, bacterial toxins, undigested food, etc. directly into the blood stream causing immune havoc.  Why was it ever a reach to believe that those “invaders” could also cause inflammation in the blood-brain barrier causing central nervous system issues?  I really don’t understand why it has taken so long for this concept to become commonly accepted.

Anyway…this paper reviews what we know about “…the possible neurophysiological basis of leaky gut; leaky brain disease; and the microbiota’s contribution to inflammation, gastrointestinal, and blood-brain barrier integrity…”  It was actually pretty technical, so I’ll just stick to some of my favorite highlights.

  1. The author points out that it is not only the gut and immune system that evolved in the presence of trillions of microorganisms and their byproducts – it is also the central nervous system: “…dysfunction is as likely to arise from the absence or disruption of normal microbial components as it is from their inappropriate distribution ratios.”  That is, both biome depletion and dysbiosis have negative consequences that reach far beyond just gut health.
  2. In the case of dysbiosis, pathogens have developed mechanisms to target the host barrier integrity so that they can invade other organs and tissues. For example, the bacteria Neisseria meningitides is found in the nasal passages of about 10% of healthy people, but under certain circumstances, has the ability to disrupt the tight cells of the mucosal barrier of the nasal passages to make its way into the blood stream and the brain, causing meningitis.
  3. Celiac, he states, is the “archetypal leaky syndrome” as the inflammation of the gut in the presence of gluten is well-known to lead to involvement of many other organs, including the brain. Symptoms can include not just GI symptoms but also issues with motor function, headaches, cognitive impairment and neuropsychiatric disease.
  4. He points out that there is an emerging body of work that suggests that maternal microbiota directly affects blood-brain barrier development in utero, and thus, the developing brain in infants.
  5. Another crucially important point: “Stress has immunologic consequences as well, and also has a role in these interactions.”   Stress is proinflammatory.
  6. The commensal bacteria of the gut have been shown to preserve gut and brain barrier integrity. Germ-free rodents, for example, have increased permeability and this was improved when normal bacteria of the rodent biome were introduced.
  7. Autism most certainly appears to be an illness of gut-brain barriers dysfunction. A post-mortem study comparing 8 people with autism versus 33 normally-developing people found distinct gut and brain barrier permeability in the autism group.  A second post-mortem study of 9 individuals with ASD versus 12 without showed that 75% of the ASD people had reduced components necessary for normal barrier forming and 66% had increased levels of molecules that lead to intestinal permeability problems. The same issues were found in people with schizophrenia.

A final quote to share with you.  I have added the bold highlights to emphasize to you just how far reaching are the consequences of blood-brain barrier dysfunction:

“A dysfunction of the blood brain barrier leading to a ‘leaky brain’ can be linked to various neurological diseases, including autistic spectrum disorders (ASD), dementia, Alzheimer’s disease, depression, and schizophrenia.  A breakdown in the blood brain barrier was observed in patients with major psychiatric illnesses.  Moreover, the blood-brain barrier may become ‘leaky’ in select neurological diseases that have an immunologic component, such as multiple sclerosis (MS), Alzheimer’s disease, brain trauma, edema, brain cancers, amyotrophic lateral sclerosis [ALS], meningitis, and systemic diseases such as liver failure.  Moreover, co-metabolism within the gut-brain-endocrine interactome play a role in the same neurodegenerative disorders, including Parkinson’s disease (PD)….”

So to sum it all up, it is starting to look like most chronic inflammatory diseases are caused by a dysfunction of the gut barrier. Treating biome dysbiosis and/or depletion may turn out to be the cure for more than we can possibly grasp right now.

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[i] Obrenovich, MEM. Leaky gut, leaky brain?  Microorganisms. 2018;6(107). doi: 10.3390/microorganisms6040107.

[ii] https://www.healio.com/psychiatry/practice-management/news/online/%7Bad397d11-3ba5-447d-98ec-edbc1a1c86a9%7D/microbiome-gut-brain-axis-plays-role-in-evaluating-treating-psychiatric-illness?page=2