Is There Any Doubt Left that Propionic Acid is a Cause of Autism? Apparently not

I first started to write about autism and propionic acid (PPA) not long after creating this blog, back in the fall of 2016.  In January 2017, I described to you some of the work of Dr. Derrick MacFabe, which as particularly fascinated me for well over a decade.  For many years now, Dr. MacFabe has been publishing research showing that abnormally high levels of this ordinarily beneficial short-chain fatty acid adversely affect the developing brain, resulting in autistic –like behavior (in rodents).  Dr. M has many times injected PPA directly into the blood stream in rats and found that doing so induces cognitive deficits, repetitive behaviors, impaired social interactions, abnormal motor movements, ASD-like neurochemical changes and abnormal levels of inflammation.

Then, just a couple of months ago, I described to you research out of the University of  Central Florida, wherein scientists introduced, in vitro, PPA to human neural stem cells  and found that PPA caused the stem cells to become glial cells (the immune cells of the brain – as opposed to neurons) at a greatly increased rate.[i]  They propose a hypothesis that PPA exposure during fetal gestation – during the earliest stages of brain development – leads to abnormal brain connectivity and increased brain inflammation.

It’s important to remember that propionic acid is commonly used as a food preservative.  Thus, maternal exposure  – between diet and bacterial dysbiosis – has increased over the years, and yes, PPA can pass into both the brain (through the blood-brain barrier) and the placental barrier.

At this point, the evidence that PPA plays a role in the pathogenesis of at least some cases of autism is so overwhelming that it appears to be considered accepted fact…which was news to me.  In a newly published paper, the authors state emphatically:  “…we evaluated the consequences of PPA (one of the factors which provokes autism) on social and anxiety-related behavior…”[ii]   There is no “may provoke” in that sentence.

These authors state that it has been proven that individuals with autism have “…increased levels of toxin-generating enteric bacteria and short-chain fatty acids, produced by these bacteria…Excessive levels of PPA can produce adverse effects, including developmental delay, mitochondrial dysfunction, oxidative stress, and other metabolic and immune reactions.”  Also, it is accepted as fact that “PPA readily crosses the gut-brain barrier, and affects functional brain networks, provoking the changes in neurotransmitter synthesis, neuro-transmission, brain signaling and mitochondrial function.”

Previous research has also shown that in rodents, chronic exposure to high levels of PPA affects social skills, cognitive flexibility (i.e. rigidity) and other alterations observed in autism.

In this study, the scientists were looking to discover whether or not a one-off, acute dose of only a small amount of PPA would be enough to affect the brain and behavior of the rodents and if so, how.  Specifically, re: the brain, they were looking in detail at the effects on the amygdala, which plays a key role in social behavior, social communication, eye gaze, attachment behavior, emotional memory and emotional processing…so obviously important in determining autistic behaviors.  Their findings were remarkable – and depressing:  “Our experiments revealed that not only chronic treatment, but also acute…injection of low dose of PPA is sufficient to provide the decrease of social motivation…”

Even worse, one dose of PPA led to mild neurobehavioral changes plus significant changes to the amygdala, including alterations to the populations of neurons (mildly) and glial cells (greatly).  Postmortem examinations of the brains of those with autism have shown similar changes, including excessive glial cell proliferation and subsequent high levels of proinflammatory cytokines. That is – the immune system of the brain is activated leading to inflammation of that organ.

To sum up, their data supports the findings of other researchers, including Dr. MacFabe, and indicates that “…even acute administration of low dose of PPA produces significant decrease of social motivation.  Behavioral changes are associated with significant modifications in amygdala’s structure/ultrastructure…”

The authors point out that difficulty metabolizing PPA is more common than previously recognized, and many of these people have cognitive impairments, movement disorders, and seizures.

What causes this potentially disastrous rise in PPA?  As I mentioned in my last post on the subject (and earlier in this one), maternal dysbiosis and food intake may play a part.  Early-life microbiome alterations, must be considered: antibiotics?  Lack of breast feeding?  C-sections?  I don’t think we know all the answers as yet.  But certainly, it seems to me that the evidence is solid enough now to confirm, as these authors state, that this is one of the causes of autism.

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[i] Abdelli, LS, Samsam, A, Naser, SA. Propionic acid induces gliosis and neuro-inflammation through  modulation of PTEN/AKT pathway in autism spectrum disorders.  Scientific Reports. 2019. 9(8824).  doi.org/10.1038/s41598-019-45348-z

[ii] Lobzhanidze, G, Lordkipanidze, T, Zhvania, M, Japaridze, N, Pochkidze, N, Gasimov, E. Rzaev, F. Effect of propionic acid on the morphology of the amygdala in adolexcent male rats and their behavior. Micron. 2019;125.

Helminths and Susceptibility to HIV?????????? A Medical Mystery Waiting to be Solved

A couple of times over the last year, I have described early stage research into the potential of helminths to prevent cancer?  File this post under the same heading:  the very beginning of a new area of research.

Sometimes it just hits me how much we don’t know. Today is one of those days.

The idea exists in the medical community that helminth colonization is associated with a greater risk of infection with HIV.  Certainly, the parts of the world where colonization with helminths is still the norm (the non-industrialized world) have much higher rates of HIV/AIDS.  And prior research shows, as just one example, that Schistosoma mansoni (SM), a kind of fluke common in the non-industrialized world, “… has been linked with an increased risk of HIV acquisition in women…. [In women uninfected with HIV] Schistosomiasis treatment induces a profound reduction of HIV entry into cervical and blood CD4+ T cells that is sustained for up to two months.”[i]

Many times over the years I have written about helminths (intestinal worms, which are the major component of the human macrobiome (which we have eradicated in the industrialized world)) so my regular readers are familiar with their remarkable immune modulating capabilities.  For those less familiar:  in order to survive in you, helminths modulate the immune system and inflammatory response. One of their main benefits is that they boost levels of regulatory cytokines, which modulate inflammation. They also modulate the activity of a kind of immune cell called CD4+ which is a kind of T-lymphocyte…which also happens to be the main  immune cell affected by HIV.

So logically, it makes perfect sense that the reduction of inflammation in the body predisposes us toward a greater likelihood of acute infection from viruses (like HIV) and bacteria.  After all, inflammation is our bodies’ natural response to fight infection.

HOWEVER…

“… many areas endemic for S. mansoni infection have high HIV-1 prevalence rates, indicating that co-infection is likely. However, clear epidemiological evidence to date is lacking for the assumption that treating S. mansoni in co-infected individuals would be beneficial for their HIV-1 disease, as studies have reported contradictory findings.”[ii]

And now, research just published in PLOS Pathogens has determined, through in vitro experimentation, that helminths  appear to reduce human susceptibility to HIV infection.[iii]

Researchers from Liverpool and Amsterdam found that an extract from the eggs of this same helminth, S. mansoni, blocked HIV transmission.  They discovered that the mechanism of action involves the binding of a component of the extract to dendritic (immune) cells, which ordinarily promote HIV infection.  In binding to the dendritic cells this way, the extract of the helminth eggs “…reduced the susceptibility of T-cells to HIV-1 infection.”  A second component of the helminth egg extract was also found to modulate HIV infection.

Of course this needs a huge amount of further testing.  There are so many factors that still have to be determined, including what kind of helminth eggs may work (or is it only the eggs of S. mansoni)? Can only the extract prevent or alleviate infection or can the egg from the live worm also work in vivo?  If the latter, what kind of helminth load would be necessary to be efficacious? Is this preparation a potential anti-HIV treatment?  And what about other viruses?  Do helminths or their eggs have anti-viral properties, in general?

In spite of the many questions still to be answered, this is still a pretty astounding finding:  “We provide evidence here that Th cells…are less susceptible to R5 HIV-1 infection, suggesting that helminthic infections may be beneficial when considering HIV-1.”

In 2015, researchers at Duke University’s School of Medicine  and the University of North Carolina at Chapel Hill published a paper that examined the effects on the immune system of lab rats when their macrobiomes were restored. Prior research had demonstrated that “…low levels of ‘natural’ antibodies were found in laboratory rats compared to wild rats. This finding has implications for the progression of cancer in biome depleted environments, since natural antibodies are important for tumor surveillance.”[iv]  Biome enrichment in helminths led to an enhanced immune responsiveness (increased humoral immunity, meaning better production of antibodies) as opposed to a decrease that you might expect:

“These studies suggest that biome depletion [i.e. the loss of the helminths of our macrobiome] may be associated with attenuated humoral immune responses…To the extent that biome depletion affects laboratory animals and humans in Western countries in a similar fashion, the implications of this finding are potentially far-reaching.  For example, attenuated responses to tumor antigens as a result of biome depletion might underlie, at least in part, the proposed connection between increased rates of cancer and biome depletion.”

And of course, decreased humoral immunity, as a result of biome depletion, suggests that we are less able to mount appropriate antibody responses to viral infections.

????????

Where this leaves us – I have no idea.  Science has yet to come up with any kind of definitive answer.  We’re catching this line of research right at the beginning, I think, so we’ll just have to wait and watch.

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[i] Yegorov, S, et. al. Schistosoma mansoni treatment reduces HIV entry into cervical CD4+ T cells and induces IFN-I pathways. Nature Communications. 2019;10(2296). doi: 10.1038/s41467-019-09900-9

[ii] https://medicalxpress.com/news/2019-09-helminthic-infections-beneficial-hiv-.html

[iii] Mouser EE, Pollakis G, Smits HH, Thomas J, Yazdanbakhsh M, de Jong EC, et al. (2019) Schistosoma mansoni soluble egg antigen (SEA) and recombinant Omega-1 modulate induced CD4+ T-lymphocyte responses and HIV-1 infection in vitro. PLoS Pathog 15(9): e1007924. doi.org/10.1371/journal.ppat.1007924

[iv] Pi, C. et. al. Increased biodiversity in the environment improves the humoral response of rats.  PLOS One. 2015;10(4).  doi:10.1371/journal.pone.0120255.

The Two Sides of Bacteroides fragilis

Back in May, 2018, I wrote about Bacteriodes fragilis (B. fragilis), a species of bacteria some strains of which are toxic, some of which are highly beneficial.  The main thrust of that post was about how our immune system, when functioning properly, can recognize a probiotic species…and while antibodies ordinarily mark “invaders” for destruction, the main antibody of our digestive system, IgA, actually binds to B. fragilis to help it colonize the intestine.

One of the researchers involved in that work stated, “It is surprising to find that an immune response actually helps beneficial bacteria to thrive, which in turn helps the host thrive….The study of immunology has mainly been in the context of pathogenic bacteria. But there are trillions of bacteria in the gut, and most of the time none of them are making you sick. Our study shows that there is active immune recognition of these bacteria, but it helps rather than hinders them. This suggests that the immune system is more than just a defense system and antibodies are more than just weapons.”[i]

Fostering the growth of this beneficial species is just that crucial to our health.  Thus, I’ve tried to keep an eye out for anything new on it.

I was happy to read another article[ii] this week about B. fragilis. It is a truly fascinating organism that reminds me of the poem by Henry Wadsworth Longfellow:

There was a little girl,

Who had a little curl,

Right in the middle of her forehead.

When she was good,

She was very good indeed,

But when she was bad she was horrid.

A little about the organism first:  B. fragilis is comprises about 1-2% of fecal bacteria, and colonization with it begins at birth.  Diet, life style, exercise, medicines and so forth all affect levels of the species, with diet being by far the most crucial. Age is also a factor:  levels seem to decrease as we get older.  Exercise, however, boosts levels.  Colonization seems to rely upon a “tolerant host immune system that allows colonization of the gut, and certain host immune molecules (e.g. IgA) have even been shown to stabilize bacterial colonization.”  To sum up, healthy humans seem to host a meaningful number of the non-toxic strains of this organism, which is pretty indispensable for good health, as I will describe.

Non-toxic B. fragilis (NTBF) inhibits inflammation in various organs of the human body, including the digestive tract, obviously, but also the brain, the lungs, etc.  These probiotic strains “…inhibit infection by pathogenic bacteria…” and have actually been found to support cancer treatments.  The main functional molecule secreted by these bacteria is a polysaccharide called PSA, which enhances the production of T-regulatory cells – those which produce anti-inflammatory cytokines and which therefore, modulate the inflammatory response.  (I talk about these all the time in regards to helminths and our missing macrobiome.  You can read more about that many times on my blog, including here.)

NTBF also produces short-chain fatty acids in abundance, further reducing inflammation, improving GI health and the integrity of the gut barrier.

A few high points:

  1. “Studies of mice indicate that PSA released by B. fragilis …has significant effects on the treatment of experimental colitis and may protect against weight loss and inflammation…” In animal models, PSA not only prevents colitis – it actually cures it.
  2. In a rat model, a strain of NTBF alleviates antibiotics-associated diarrhea.
  3. This is pretty amazing:
    • As a powerful anti-inflammatory and immune system regulator (i.e. booster of Treg), NTBF appears to inhibit “…central nervous system demyelinating disease” (ie. multiple sclerosis).
    • In mice, when pregnant mothers have their immune systems stimulated (ie. maternal immune activation( MIA)), pups are born with characteristics of autism, including social impairments as well as leaky gut. “However, oral administration of B. fragilis ameliorated both neurodevelopmental disorders and gastrointestinal abnormalities in these deficient offspring.”
  4. NTBF seems to protect against airway inflammation and asthma.
  5. It also seems protective against pathogenic bacteria, including, interestingly, Bartonella, a tick-borne disease.
  6. As mentioned earlier, it also appears to promote anti-cancer therapies, and an in vivo experiment suggests it may prevent the development of colon cancer.

And now for the horrid:

ETBF (enterotoxigenic B. fragilis) – the strains that comprise the dark side of the species – “…have been implicated in various conditions involving intestinal and extra-intestinal infections, including inflammatory bowel disease (IBD)…systemic inflammation and neurological disorders.”  (Interestingly, healthy adults may harbor ETFB as well, although it is asymptomatic.)  There is a virulent factor, B. fragilis toxin, that can disrupt the integrity of the intestinal mucosa and induce inflammatory bowel disease and colorectal cancer.  In fact, “…a significant association has been detected between the proportion of ETBF and colorectal carcinogenesis.”

Because of the inflammation-induced leaky gut caused by ETFB, it may actually enter the blood stream causing major systemic inflammation.  Toxins from the organism “…may also pass through the blood-brain barrier and gradually promote the development of Alzheimer’s disease…”  In fact, the toxins produced by ETBF may be “…exceptionally potent drivers of pro-inflammatory degenerative neuropathology.”

The species is particularly adept at adapting itself to antibiotics, so resistance is a major problem.

On the bright side, NTBF is now on the short-list of what is being called “next generation probiotics,” along with organisms you are all familiar with, like Akkermansia. The research currently suggests that it may well turn out to be a highly effective means of eliminating other bacterial infections as well as a treatment for leaky gut and more.  I’ll stay on top of this one – hopefully it won’t be too many years before these “new generation probiotics” become available commercially.

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[i] https://www.sciencedaily.com/releases/2018/05/180504133624.htm

[ii] Sun, F, Zhang, Q, Zhao, J, Zhang, H, Shai, Q, Chen, W. A potential species of next-generation probiotics? The dark and light sides of Bacteroides fragilis in health. Food Researcher International. 2019;126.  https://doi.org/10.1016/j.foodres.2019.108590

C.Difficle Infections…A Case of the “omes” Working Together?

As my regular readers know, I am particular interested in science that looks at how the various kingdoms of the human biome interact to promote health or disease.  Another interesting article came out recently that looks at how yeasts and bacteria work together to perpetuate Clostridia difficile infections (CDI).[i]  In this case, researchers have found that various yeast (mycobiome) species flourish in people infected with the pathogen. They believe, in fact, that these yeasts, along with other pathogenic species of bacteria (bacterial microbiome), play a role in perpetuating this life-threatening infection.

To give you some idea of the severity of a CDI:  according to the US CDC, nearly half a million Americans suffer from such an infection every year.  Believe it or not, an infection is so virulent that 29,000 patients die within 30 days of the initial diagnosis of C. difficile.[ii]

These researchers looked at 49 stool samples collected from hospitalized patients, 18 of whom had tested positive for C.difficile infection (CDI).  Initially, they found that 2 fungal species and 9 bacterial were markedly higher in those with the infection. Upon further analysis, they found that other fungal species were also elevated, and that these elevated levels of yeasts were associated with decreased levels of probiotic bacteria:  there were “…negative cooccurring relationships between fungi and commensal gut bacteria. Candida and Byssochlamys were present at relatively high abundances within CDI+ individuals and formed strong negative relationships with several bacterial taxa…”  These fungi may be critical to the perpetuation of the CDI.  Their findings lend “…further support to the concept that the dysbiosis associated with CDI has an important contribution from fungal organisms.”

The presence of pathogenic yeasts and bacteria, especially E.coli and another bacterial species, Pseudomona, led to biofilm production: “…the causal dysbiosis of CDI my self-perpetuate, potentially contributing to treatment failure.”  For those who are unfamiliar with the term biofilm, it’s defined as a mass of organisms that stick together to form a slimy matrix. (Think of plaque on your teeth.)  Organisms are able to hide in the thick biofilm, making them harder to kill.  What these researchers are saying then is that the C.difficile works with yeasts and pathogenic bacteria to perpetuate the state of dysbiosis – and their own survival –by working together to form a biofilm.  If their findings are replicated, it would certainly go a long way toward explaining why treating CDI is so incredibly difficult and why it recurs so often.

By the way, none of this was found in the people without C.difficile infections.

Their next steps are to determine which of these altered species is particularly significant to perpetuating a CDI.  As C.difficile infection is highly associated with antibiotic use, it’s possible that if, for example, a particular yeast is found to help initiate and perpetuate an infection, it would be possible to treat CDI without using antibiotics but instead, perhaps treating with antifungals, which is much safer for the biome: “The researchers believe it’s a research question worth pursuing. C. difficile infection is difficult to control, largely because it affects patients who have already been treated with antibiotics. If researchers pin down a clear cause-and-effect relationship between fungal species and C. difficile infection, they might be able to develop treatments that don’t involve antibiotics.”[iii]

That would be a pretty critical finding.

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[i] David B. Stewart, Justin R. Wright, Maria Fowler, Christopher J. McLimans, Vasily Tokarev, Isabella Amaniera, Owen Baker, Hoi-Tong Wong, Jeff Brabec, Rebecca Drucker, Regina Lamendella. Integrated Meta-omics Reveals a Fungus-Associated Bacteriome and Distinct Functional Pathways in Clostridioides difficile Infection. mSphere, 2019; 4 (4) DOI: 10.1128/mSphere.00454-19

[ii] https://www.cdc.gov/media/releases/2015/p0225-clostridium-difficile.html

[iii] https://www.sciencedaily.com/releases/2019/08/190828140108.htm

The Bacterial Microbiome and Immune Response to Vaccines

I love it when one of my readers contacts me to talk about a post, to show me something new or just wants to introduce him or herself and say hi.  As I’ve pointed out recently on the Biome Buzz Facebook page, we are all here to learn, bearing mind, always, that science does not yet have all the answers.

Now an introductory side note, before I describe the research I read these past couple of days:

As the parent of a young man with autism – who had a horrendous physical and behavior regression in his 2nd year of life – it would be all too easy for me to jump to conclusions regarding the cause.  After all, it feels good to have something to blame. However, I maintain scientific objectivity because that really is the only way to someday uncover the truth.  That there is a massive increase in the rates of autism, as well as allergy, autoimmunity and other immune-mediated diseases in our society is irrefutable.  No one disagrees with that. The WHY of it though, is simply not yet known.  And as I’ve written about before, it’s NOT going to be a simple solution:  undoubtedly, the answer will turn out to be a complex interplay of many factors.

So keeping our scientific objectivity in at the forefront, I am writing today about what we know – and mainly don’t know – about the relationship of the bacterial microbiome to vaccine response.

A couple of days ago, I got a message from a reader who runs a website devoted to increasing awareness of the importance of the bacterial microbiota to health.  One focus of The Gut Club is to forward real scientific research into the connection between adverse vaccine reaction and an altered gut microbiome. He wanted to know if I’d write about the subject, and my first reaction was…no way!  I am not touching that one with a 10-foot pole!  I have enough stress in my life and my blog is supposed to be one of my fun hobbies…not a source of aggravation. But science is science, so I still took the time to see what his site was about, and to read the short paper he recently co-authored with two scientists.[i]

As it turns out, scientists are starting to look at the effects of biome alterations on response to vaccines.  This is not controversial at all.  When you consider that at least 70% of your immune system is in your gut, and the crucial role we now know the gut flora plays in immunity, it makes perfectly logical sense that there may be a connection, especially considering the variability in immune responses to vaccines. Some people require only 1 to achieve a lifetime of immunity while other people need to be re-inoculated multiple times, while still others never gain immunity at all.  Why that is, no one knows, but scientists are starting to suspect that gut bacterial variability is a key factor.  And this is the crux of today’s post.

The short paper Keith co-authored simply asks the question, “Do gut microbiota mediate adverse vaccine reaction?” which is a fair question since, again, there is no argument that some people do react poorly to vaccines. The paper’s central hypothesis is, “…that gut microbiota have a significant effect on host response to vaccination where a reduced or absent population of commensal flora coupled with an overgrowth of pathogenic strains may become a microbial predisposition to adverse vaccine reaction.”  It goes on to give a brief summary of some of the science substantiating that idea.  For example, Dr. Lijuan Yuan, another co-author – who runs a lab at the Virginia-Maryland College of Veterinary Medicine – has developed a pig model that has been used to test the connection between vaccine reaction and biome alterations.  In one study, they found that “…vaccinated UHMG [unhealthy] pigs had higher viral shedding titres and more severe clinical signs compared to HHGM [healthy] pigs after virulent HRV [rotovirus vaccine] challenge.”

The paper is a call for more research: enough evidence currently exists to merit serious scientific inquiry into this connection.

In the interest of time, I selected to read just one of the papers listed in the bibliography, and found that indeed, there is research out there connecting biome alterations to vaccine response. By response, I mean whether or not the vaccine works to confer adequate immunity.  The paper I selected was authored in 2018 by a scientist from a major Australian University and one from Stanford University School of Medicine.[ii] They note from the start that vaccine response (i.e. the generation of antibodies by the individual) is “highly variable,” and that emerging science currently shows that the “…gut microbiome plays a key role in shaping systemic immune responses to both orally and parenterally [elsewhere in the body, besides the digestive tract – so via shot, in chis case] administered vaccines.”

To illustrate the first point, vaccine response variability, they provide several examples including: 1. the response to the yellow fever vaccine “…can vary by more than 10-fold” while, 2. response to the seasonal influenza vaccine “…can vary by more than 100-fold.”  Incredible, right?  A randomized trial of 1709 infants in the USA, vaccinated with the pneumococcal conjugate vaccine (PCV), indicated, “…considerable variation in the response between infants.”

These authors go on to point out that antibiotic exposure profoundly alters the composition of the microbiota and can “…lead to a long-lasting loss of diversity and dysregulation of the microbiome…” Dysbiosis very early in life, as you all know, is already associated with life-long inflammatory illnesses like allergy and obesity, and has profound impact on systemic immunity.  They go to say that, “Several lines of evidence now suggest that antibiotics can modulate vaccine responses.”

These 2 scientists explain that right now, the “…most convincing evidence in mice to date that the microbiota can influence vaccine responses is a study of mice immunized with the seasonal influenza vaccine that showed that germ-free or antibiotic-treated mice had significantly impaired IgG and IgM antibody responses to this vaccine.”

One of the most significant sentences in this paper, to my mind, is in a paragraph discussing the metabolites produced by gut bacteria, including pro-inflammatory LPS (lipopolysaccharides – which are often used in experimentation to induce inflammation in the intestines and which are known to contribute to autoimmunity in humans).  They state that while it is not currently known whether or not LPS can influence vaccine response, it is entirely possible:  “…the immunomodulatory activity of LPS produced by the microbiota may be particularly relevant if vaccines are administered after antibiotics.  Antibiotic exposure is commonly associated with a subsequent overgrowth of specific species of bacteria, such as members of the Enterobacteriacceae, which produce high levels of endotoxin (LPS).”  That is, antibiotics not only alter the gut microbiota, but in doing so, often lead to excessively high levels of proinflammatory LPS toxins, further altering the immune status of the individual.  The response to a vaccine at that point may subsequently be radically altered.  They go on to state:  “Further work is now necessary to determine whether immune responses to vaccines are altered in mice or people who have been recently exposed to antibiotics and have high levels of gut dysbiosis.”

One more key point in this article: a few studies in human “…suggest a potential role of the microbiota in determining optimal vaccine responses in humans.”  They provide a couple of examples:

  1. “The relative abundance of several bacterial species in the stool microbiota of 48 Bangladeshi infants have been associated with vaccine-specific IgG and T cell proliferation responses to the oral polio, BCG [tuberculosis], tetanus toxoid, and HBV vaccines.  Increased abundance of Actinobacteria was positively associated with vaccine responses, whereas higher levels of several other species such as Enterobacter, were negatively associated.”
  2. “The composition of the infant gut microbiome in infants from rural Ghana was also found to be correlated with rotavirus vaccine responses, where a higher abundance of Bacteroidetes was associated with impaired responses.”

Unfortunately, the few studies done have been done have been small in sample size and as yet, there “… is no human study that demonstrates a causal impact of the microbiota on immune responses to vaccination…”

I did some last minute snooping around and came across an article on Science Daily from 2013:  Gut Bacteria Play Key Role in Vaccination.[iii]  It summarizes two studies that had just been published in PLoS One, out of the University of Maryland, that looked at how biome diversity affected oral vaccine response.  To summarize:  “The scientists found that more diversity in the gut microbiota may enable more robust immune responses to the vaccine.”  Again though, this response was not measured in humans…yet.

To reiterate:  at this point, there is no definitive evidence that the microbiota affect human vaccine response, meaning, whether or not the vaccine is effective in providing immunity, let alone whether or not the bacterial microbiome is at fault in causing adverse vaccine reaction.  What we have right now is nothing more than “the question”:  since the human biome is such an integral part of the immune system, do alterations and/or depletion of the biome affect response – both positive (conferring lifelong immunity) and negative (adverse response and/or lack of immunity) – to vaccines?

 I’m very much looking forward to following this line of research in the future.  Thank you, Keith, for bringing it to my attention.

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[i] Yuan, L, Tsai, PCC, Bell, K.  Do gut microbiota mediate adverse vaccine reaction?  Ann Clin Trials Vaccines Res. 2018:2(2);11-12.

[ii] Lynn, DJ and Pulendran, B. The potential of the  microbiota to influence vaccine responses.  Journal of Leukocyte Biology. 2019:103(2);225-231.  doi: 10.1189/jlb.5MR0617-216R

[iii] https://www.sciencedaily.com/releases/2013/06/130605185931.htm

5 Years to a Designer Bacterial Microbiome? My Money’s on Yes

My psychic powers are in overdrive after reading an article on Medical Express yesterday morning about research being presented at the upcoming American Chemical Society’s fall meeting.[i]  I truly believe this is the first step toward custom modeling of the human microbiome.

Obviously, diet will always come first, but facing facts, getting people to change their diets – no matter how dire the situation – is often like trying to move Mount Everest.  So while we stubbornly stick to our unhealthy habits, we, in the industrialized world, continue to slide into inflammatory illnesses at ever increasing rates.

Probiotics and prebiotics may also help, but ultimately, (and I wish I could say I believed differently, but I don’t), I believe we (as a society, I mean) are going to end up needing pharmaceutical options to revamp our altered microbiomes.  People like to just take the pill; everything else is too much work.  And to boot, there are many factors out of our control that also adversely affect our microbiomes, such as stress levels or pollution exposures.  As the lead researcher on this study, Dr. M. Reza Ghadiri, says, “If we all ate a healthy diet, exercised and didn’t age, we wouldn’t have problems with our gut microbiome and many diseases. But, that’s not how all people live.”

At the upcoming conference, Dr. Ghadiri and colleagues from The Scripps Research Institute are presenting work they recently conducted in which they created artificial peptides (short strings of amino acids – so basically little proteins) called self-assembling cyclic D, L-α-peptides.  These artificially created peptides target very specific pathogenic bacteria, and by inhibiting the growth of the organism, allow beneficial bacteria a competitive advantage.

Says Dr. Ghadiri:  “Our hypothesis was that instead of killing bacteria, if we could selectively modulate the growth of certain bacteria species in the gut microbiome using our peptides, more beneficial bacteria would grow to fill the niche, and the gut would be ‘remodeled’ into a healthful gut…”

He goes “Our theory was that process would prevent the onset or progression of certain chronic diseases.”

The scientists first tested their peptides in an in vitro mouse model.  They used a type (LDL receptor knockout mice) that have been bred to do well on low fat diets.  When fed a high fat “Western” diet, they rapidly develop extremely high levels of LDL (bad) cholesterol and within weeks, arterial plaques.  The researchers grew models of these mice microbiomes in their lab, tested several of the new peptides on them, and ended up selecting 2 that seemed the most effective for modulating the microbiomes to look more like those of healthy mice on low fat diets.

Their next step was an in vivo experiment in which they split this same type of mouse into 3 groups:  the first group was fed a low fat diet; a second group was fed a high-fat Western-type diet; and a third group was fed a high-fat diet plus one of the selected peptides. They then analyzed the mice’ microbiomes from fecal samples and also tracked immune markers, inflammation levels and the development of arterial plaques.  The mice on the peptides had a 50% reduction of plasma cholesterol as compared to the mice fed a high-fat diet not on the peptides, and no significant plaques formed in their arteries.  They also had markedly lower levels of inflammation as well as higher levels of regulatory cytokines (which modulate inflammation levels).  “These mice resembled those on a low-fat diet,” says Dr. Ghadiri.

The scientists hypothesize that the shift in gut bacteria affects genes that, in turn, affect bile acids (which digest fats), thus leading to changes in cholesterol levels.  They also believe the biome alterations may affect other genes related to the immune system and inflammatory processes.

By the way, the peptides are not digested and pass right through the animals.

The potential ramifications of this work are vast.  Firstly, if this ends up working in humans – which I can’t believe is far off – we may not only be able to easily sculpt an unhealthy microbiome to resemble those of healthy people (think about all the diseases now associated with altered bacterial microbiomes – from autism to obesity to autoimmune diseases to fibromyalgia/chronic fatigue to depression to Parkinson’s, etc.) but perhaps too, antibiotics may have to be used markedly less…not just in us, but in the food-animal markets.

Here is a link to a great 10 minute talk by Dr. Ghadiri from this past April on this topic.  It’s worth the few minutes of your time.  He actually gave me a serious LOL…so yeah…spend 10 minutes watching this.  (If I had $50 million, I’d lob it his way, believe me.)  He says we all need to hang on for 5 more years.

Believe me, I will be following this very closely.

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[i] https://medicalxpress.com/news/2019-08-remodeling-unhealthful-gut-microbiomes-disease.html

ADHD and the Microbiome…and a Nutritional Supplement

A small pilot study, done by New Zealand researchers, was just published[i] that has me pretty excited.  (I love studies that involve nutrition!) The research involved 17 children (aged 7 to 12), diagnosed with ADHD.  10 of these were given micronutrients supplements for 10 weeks, while the others were given a placebo.  While the supplement did not lead to any changes in the structure or composition of the gut bacteria, it did lead to an increase in diversity (richness), which did not occur in the placebo group.  Perhaps most importantly though, there was a significant drop in Bifidobacterium.  A decrease in Bifido species is already associated, potentially, with an improvement in symptoms of ADHD (I’ll come back to this in a moment), and the authors of this study suggest that a multi micronutrient supplement may prove to be a completely safe way of downregulating Bifidobacterium, should there be a need.

Back to the association between Bifidobacterium and ADHD symptoms:

In 2017, a paper was published by an international team of researchers on the gut microbiome of children with ADHD.[ii]  They discovered, “… that the relative abundance of several bacterial taxa differed between cases and controls…A nominal increase in the Bifidobacterium genus was observed in ADHD cases.”  They hypothesize about the potential mechanism of action:  how might such an increased load of Bifido bacterium cause the symptoms of ADHD?  They theorize that this gut bacterium affects dopamine synthesis in such a way as to reduce the ability to await “reward,” which “…constitutes one of the hallmarks of ADHD.”  That is, essentially, the metabolic pathways influenced by the excess of Bifido increase the need for instant satisfaction.

In prior research, this New Zealand team of scientists looked at children with ADHD who stayed on the supplement long term – a year.[iii]  Of the 84 children who finished the study, 84% were “…identified as ‘much’ or ‘very much’ improved relative to baseline functioning…”  This is remarkable in that, only 50% of the children who switched to psychiatric meditations and 21% of those who discontinued treatment reported improvements.  In fact, a switch to medications was “…associated with deterioration in mood and anxiety.”  No side effects were reported with the supplement.

Of course, the link to high levels of Bifidobacteria is not yet confirmed.  The lead researcher of this paper states:  “More research is needed with larger groups of people with ADHD, and to understand the potential effect of diet, medications, age, ethnicity and gender on the results that have been reported.”  Still, remembering my philosophy, “If it can’t hurt and it could help, do it” – perhaps a trial of a broad-spectrum supplement is in order?

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[i] Aaron J. Stevens et al. Human gut microbiome changes during a 10 week Randomised Control Trial for micronutrient supplementation in children with attention deficit hyperactivity disorder, Scientific Reports (2019). DOI: 10.1038/s41598-019-46146-3.

[ii] Aarts, E., et. al. Gut microbiome in ADHD and its relation to neural reward anticipation.  PLoS One. 2017:12(9).  doi: 10.1371/journal.pone.0183509

[iii] Darling, KA, Eggleston, MJF, Retallick-Brown, H, Rucklidge, JJ.  Mineral-vitamin treatment associated with remission in attention-deficit/hyperactivity disorder symptoms and related problems: 1-year naturalistic outcomes of a 10-week randomized placebo-controlled trial.

Polycystic Ovary Syndrome and the Bacterial Microbiome

I first learned about the concept of fecal microbiota transplant (FMT) a good 20 years ago, from my mentor who is a well-known functional medicine doctor.  I know some people are shocked by the idea but to me, it made sense from the get-go.  (For those unfamiliar, FMT means using stool (which is about made up of about 60% of bacteria from the intestines) to transfer bacterial contents.  Often it’s done via suppository, but nowadays, companies are working on purifying it into a non-noxious oral pill or solution.)

Many times, over the years, I’ve written about research and clinical studies using FMT on this blog.  As just one example, I wrote about a hugely successful study done on children with autism.  At this point (some studies in humans, some in animals), researchers have been able to transfer everything from the aforementioned autism to depression, anxiety, obesity, etc. by transferring the gut microbiome via FMT.

Thus, I was not all that surprised this morning to read about research recently conducted by scientists from China, the US’s National Institute of Health and Penn State University, in which they transferred polycystic ovary syndrome (PCOS) from humans to animals.[i]  For those of you not familiar with PCOS, it is a fairly common endocrine (hormone) disorder that affects women of reproductive age.  According to the Mayo Clinic, “Women with PCOS may have infrequent or prolonged menstrual periods or excess male hormone (androgen) levels. The ovaries may develop numerous small collections of fluid (follicles) and fail to regularly release eggs.”[ii]  It can not only cause incredibly unpleasant side effects for the affected woman (depression, anxiety, excess hair growth on the body, male-pattern balding, painful and prolonged periods, and more), it can also cause serious medical issues, including high blood pressure, gestational diabetes, infertility and miscarriage.  Research shows that this illness affects somewhere between 4% and 12% of women of reproductive age…which is a hell of a lot of women.[iii]

While the ultimate cause is unknown, low grade inflammation is known to be one of the contributing factors, and recently it’s been recognized that alterations in gut microbiome composition and gut barrier integrity (i.e. leaky gut) may play a major role in the development of PCOS.  The researchers involved in this study found that women with the syndrome had less bacterial diversity in their microbiomes, increased levels of the species, Bacteroides vulgatus, and a shift in genes affecting bile salts.[iv]

When they transferred the microbiome from affected humans to mice, the mice developed ovarian dysfunction, insulin resistance (a hallmark of PCOS), alterations in testosterone levels (another hallmark) and also had immunological changes including lowered levels of a cytokine called IL-22.  These bile acid changes and lowered levels of IL-22 are also seen in women with PCOS.  In fact, transferring just Bacteroides vulgatus to mice had the same effect.  The researchers state that this is the first evidence that gut microbiome alterations, and subsequent disruptions in bile acid synthesis, are directly responsible for the development of PCOS.

Giving the mice IL-22 and a bile acid (glycodeoxycholic acid) ameliorated the ovarian dysfunction and infertility, suggesting that this may potentially be a treatment for PCOS:  “This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.”  As there are no treatments right now, hopefully this new research will soon lead to one.  Will FMT end up being the answer for this illness?

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[i] Xinyu Qi, Chuyu Yun, Lulu Sun, et al. Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome. Nat Med. 2019. doi: 10.1038/s41591-019-0509-0.

[ii] https://www.mayoclinic.org/diseases-conditions/pcos/symptoms-causes/syc-20353439

[iii] https://emedicine.medscape.com/article/256806-overview#a5

[iv] https://www.gutmicrobiotaforhealth.com/en/the-gut-microbiota-may-be-involved-in-ovarian-dysfunction-and-insulin-resistance-in-polycystic-ovary-syndrome/

Neurodegnerative and Neuropsychiatric Disorders: Prime Targets for Helminths

Within just a few weeks of each other, two papers have been published looking at the potential of using helminths to treat neurological conditions.  Not surprisingly, both focus on the powerful anti-inflammatory effect of helminths.

(For those of you new to helminths:  these are a kind of macrobiotic organism, intestinal worms, native to all mammals on this planet.  However, in the industrialized world, we have “de-wormed,” completely eradicating our native macrobiomes.  At this point, pinworms are the only one of these organisms that is still around in the westernized world, and when someone gets them, we instantly de-worm them (which is fair enough as they have nasty side effects).  However, there are benign helminths currently being used for “helminthic therapy” – using small, therapeutic doses of these organisms to modulate the inflammatory response.)

The first paper looks at helminths in neurodegenerative disorders like multiple sclerosis and Alzheimer’s disease.[i]  These authors believe that the upregulation (increase) in T regulatory cells (which produce anti-inflammatory cytokines, like IL-10) induced by helminths may play a pivotal role in treating these illnesses.

A few highlights from this paper:

  1. “…until now, helminth infections have not been demonstrated as necessary for proper host immune maturation in either humans or in animal models, and co-evolution over millions of years involves a form of mutualism where both the host and the parasite derive some benefit from their relationship..”
  2. I laughed when I read that sentence.  Isn’t it an oxymoron to say that a parasite is mutualistic?!  Maybe then they should call these therapeutic organisms mutualists, not parasites!
  3. Clinical data, experiments and clinical trials all support the notion that “…helminths not only prevent but also reverse allergy and asthma and autoimmune diseases…”
  4. Neurological inflammation is an important factor in the development of such illnesses as ALS, Parkinson’s, Alzheimer’s and multiple sclerosis. While the molecular mechanisms of brain damage in these diseases (as well as Lewy body dementia and frontotemperal dementia) are different, “the presence of neuroinflammation is a common feature of all these…”
  5. To effectively treat neurodegenerative diseases, anti-inflammatory treatments must be considered, but at the same time, oversuppression of the inflammatory response – which would open the individual up to infection – must be avoided. The authors refer to this as “precise tuning of the immune responses.”  They go on to say, “It seems a promising use for this immunomodulation of the work of our ‘old friends’: gut microbiotic bacteria and parasitic organisms…”

The thrust of the 2nd paper, which focuses on using helminths in the treatment of neuropsychiatric disorders (NPDs), is essentially the same.  They too state that helminths “…have shown to be protective against severe autoimmune and allergic disorders” and have been “…used for modulation of immune disturbances in different autoimmunity illnesses, such as Multiple Sclerosis (MS) and Inflammatory Bowled Disease (IBD).”[ii]

They go on to state that “…’helminthic therapy’ is able to ameliorate neuroinflammation of NPDs (neuropsychiatric disorders) through immunomodulation of inflammatory reactions and alteration of microbiota composition.”

A few high points of this one:

  1. Immune disturbances are well documented in many NPDs. For example, significant elevations of inflammatory cytokines have been found in the blood of children with autism, as well as major depressive disorder and schizophrenia.
  2. The link between autoimmune disease and NPDs is also well established. As just one example, those with inflammatory bowel diseases have nearly 6X the increased risk of anxiety issues.
  3. Treating NPDs with anti-inflammatory agents has been shown to have therapeutic benefit.
  4. Helminths not only directly modulate inflammation, but also, by positively altering the microbiome, have an indirect beneficial effect on the immune system.
  5. The authors point out that there is “…a big opportunity for helminth therapy in NPDs” as few studies have been conducted…but based on what information is in the literature, this looks like an extremely promising treatment.

They summarize all this in their conclusion stating again that inflammation seems to be a driving force behind many neuropsychiatric disorders and helminths are perhaps the most potent natural modulator of the inflammatory response.  Thus, “…helminth therapy may be a promising and new therapeutic option for resolution of neuroinflammation in NPDs.”

Here’s a question for you to contemplate: if neurodegenerative and neuropsychiatric disorders are, at least in large part, caused by out-of-control inflammation…why wait for them the start before working on the unregulated immune system?  As Dr. Jamie Lorimer, of Oxford University says, “Humankind eventually needs to move beyond the idea that helminths are best used as a drug or a therapy. Rather, we need to embrace the view that helminths are a necessary component of the ecosystem of a healthy body, and that helminths should be cultivated for population-wide biota restoration…”[iii]

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[i] Donskow-Lysoniewska, K, Doligalska, M, Gasiorowski, K, Leszek, J. Parasitic worms for the treatment of neurodegeneration. Neuropsychiatry. 2019;9(2):2333-2346.

[ii] Abdoli, A and Ardakani,  HM. Potential application of helminth therapy for resolution of neuroinflammation in neuropsychiatric disorders. Metabolic Brain Disease. 2019. doi: 10.1007/s11011-019-00466-5

[iii] Lorimer, J. Hookworms Make Us Human: the Microbiome, Eco-immunology, and a Probiotic Turn in Western Health Care. Medical Anthropology Quarterly. 2018  Jul 13. doi: 10.1111/maq.12466

Breast Cancer and Metastases: Is Dysbiosis a Factor?

Yesterday, I read an article[i] in the University of Virginia’s online newspaper about the work of a team of their scientists and graduate students that I thought worth sharing with you.  The paper[ii] was just published in the journal, Cancer Research, and while it was conducted in an animal model, the findings are still very interesting and potentially very important.

First a fact:  the most common type of breast cancer, about 2/3rds of cases in fact, is called hormone receptor positive (HR+).  So, using a mouse model of this type:  for two weeks, the experimental group of mice were given non-absorbed antibiotics (that stay in the gut), wiping out much of their gut bacteria, while the control group was given water.  All the mice were then injected with breast cancer tumor cells.

They found that the mice given the antibiotics had “…enhanced tumor cell dissemination to lymph nodes, lungs, and peripheral blood at both early and advanced timepoints after tumor initiation.” That is, the cancer metastasized much more readily than in the control group.  They found too that dysbiosis “…promoted early inflammation within the mammary gland….”

Dr. Melanie Rutkowsi, lead author of the paper, is quoted as saying, “In this inflamed environment, tumor cells were much more able to disseminate from the tissue into the blood and to the lungs, which is a major site for hormone receptor-positive breast cancer to metastasize…”[iii]

To definitively determine that it was the disruption in the gut bacteria causing this phenomenon, the scientists transferred the abnormal gut bacteria to other mice via fecal transplant and sure enough, the receiving mice had the same issue:  aggressive metastasizing of tumor cells.

(By the way, for those of you familiar with breast cancers:  these findings only apply to hormone-positive breast cancer, not triple-negative.)

The authors of the paper point out that this study was not to look at whether or not the gut biome contributes to the initial development of breast cancer, but instead, to look at whether or not it affects the spread of the cancer cells, which ultimately will determine the long term prognosis.

Many chemotherapy drugs cause microbiome disruption and subsequent GI issues, raising several interesting questions.  Does this biome disruption ultimately put patients at risk for metastases?  And does this risk exist before the cancer diagnosis or is it the RESULT of the treatment for the cancer?  Trying to look at the bright side though:  if indeed microbiome alteration/depletion is a risk factor for the spread of breast cancer, then manipulating the microbiota should become a treatment option.  The next step for these researchers is to collect stool samples from women at high risk for metastatic breast cancer, and see if those with greater dysbiosis do indeed have a greater chance for the spread of the cancer.  (If they find some of the women do have high levels of dysbiosis, I sincerely hope they help them treat it!)

Obviously, there are the usual caveats to this research:  it’s early stage, it was done in mice, and so forth.  Whether or not it applies to humans remains to be seen.  However, I find myself concluding yet again, that it makes a hell of a lot of sense to take care of your biome now.  Can’t hurt, could help, as I always say.

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[i] https://www.cavalierdaily.com/article/2019/08/unhealthy-microbiome-found-to-be-linked-to-increased-spread-of-breast-cancer

[ii] Rosean, CB, et. al. Pre-existing commensal dysbiosis is a host-intrinsic regulator of tissue inflammation and tumor cell dissemination in hormone receptor-positive breast cancer. Cancer Research. 2019. DOI: 10.1158/0008-5472.CAN-18-3464

[iii] https://www.forbes.com/sites/victoriaforster/2019/06/11/disrupted-gut-microbiome-promotes-breast-cancer-spread-in-mice/#222a980d30de