Over the weekend, I read a great little article about the potential applications of fecal microbiota transplant (FMT) in treating a huge variety of diseases.[i] Of course, we are sorely lacking in clinical trials for almost all but still, there is hope to be had in this treatment for illnesses for which there is precious little now. So, it’s still worth writing about where the science is at present.
Before I tell you about all these potentials though, I just want to share a sentence in the introduction that really struck me and I think will resonate with you too. It sums up what we currently know about the role the gut bacteria play in the human body: “In addition to breaking down foods and synthesizing nutrients, microbiota play an important role in the immune system, provide colonization resistance [to pathogens], protects against epithelial [the intestinal wall] injury, promotes both angiogenesis [development of new blood vessels] and fat storage, modulates human bone mass density, modifies the nervous system, and metabolizes therapeutic agents into active compounds.” Reading that list, it really hit home: there is truly astounding just how much our gut bacteria do for us! (And we probably only know the half of it right now.)
So, back to the treatment potential of FMT, I’ll write this in the form of a list to make it easy for you to scan. I’m not going to go into detail for some of these as there’s apparently not a huge amount of data right now – only common sense and science suggesting that more research should be done because of the known relationship of the bacterial microbiome to that disease. But I’ll list everything, nonetheless, as it’s still exciting to contemplate just how much FMT may help in the future with “incurable” illnesses.
To conclude then, we need WAY more clinical trials, and these trials need to be better standardized in terms of the screening of donors, the preparations of the donations, frequency of dosing, delivery methods of doses, and so on. The great news though is that, “…increasing studies have shown that FMT also presents potential and promising clinical indications for the treatment of many other disorders related to gut microbial dysbiosis.” And actually, if you think about it, there are probably many, many more illnesses that could be added to this list. Fibromyalgia, perhaps? Spondyloarthritis? Post-traumatic stress disorder? ALS? Celiac?…and the possibilities list goes on and on and on.
Considering the total lack of effective treatment for pretty much everything on the above list, this is at least a spot of light at the end of a very long and dark tunnel.
[i] Zhou, Y, et. al. Are there potential applications of fecal microbiota transplantation beyond intestinal disorders? Biomed Research International. 2019. Article ID 3469754. https://doi.org/10.1155/2019/3469754
As regular readers know, I’m always on the lookout for “things you can do now.” I’m especially happy then when actual clinical trials happen as we can get some idea of the effectiveness of treatments. About 18 months ago, a paper was published reviewing studies that looked at the use of probiotics in fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS). [i] I’ve written before (here and here, for example) about bacterial microbiome changes that have been noted in both illnesses, but have not had much opportunity to write about what can be done about it. Unfortunately, as it turns out, there’s a reason for that.
First a quick review for those unfamiliar: fibromyalgia is a chronic pain disorder of unknown origin. The primary symptoms are body wide muscle pain, morning stiffness, fatigue, sleeping issues and it is more often than not, accompanied by both gastrointestinal symptoms (about 81% of patients report issues) and all too often, depression and anxiety. In fact, a large percentage of those with FMS fit the diagnostic criteria for irritable bowel syndrome. There is tremendous overlap with chronic fatigue, which is also a chronic condition of unknown origin characterized by persistent fatigue, which is the predominant symptom, as opposed to the pain of FMS. That said, both illnesses involve pain and fatigue, and like FMS, CFS is also, more often than not, accompanied by GI symptoms (92% fit the criteria for IBS). CFS too often produces affective issues, including depression and anxiety, and in both illnesses, nervousness, memory loss, confusion are not uncommon.
Some research has shown that those with CFS have intestinal overgrowth of d-lactic acid producing bacteria which, if you remember (from this post of mine awhile back ), often produces cognitive dysfunction and neurological issues. Research published in 2004 showed that small intestinal bacterial overgrowth (SIBO) occurs 100% of the time in those with FMS, compared to 84% of the time in those with IBS and 20% of the time in healthy controls. SIBO is, as you know (from this post), difficult to diagnose accurately and may or may not result in symptoms, as shown yet again by the fact that 20% of healthy controls in this study are asymptomatic. However, this does give a good picture of the relationship of biome alterations to the disease, FMS. It makes sense then that probiotics might help those suffering from these illnesses.
The researchers in this review study looked for randomized controlled clinical trials and pilot studies using probiotics in humans with FMS or CFS performed in the previous 10 years, so between 2006 and 2016. While originally coming up with 537 articles on CFS and FMS using their search terms, they ended up with a whopping 2 that actually met the necessary criteria to be included. These were both 8 week long studies on adults, randomized and double-blinded. Neither study looked at FMS at all, only CFS. One had 35 participants, the other 48.
The first study found that Lactobacillus casei (Shirota strain, such as is found in Yakult) had beneficial effect on anxiety but not depression) in those with CFS. This, by the way, completely coincides with the research I wrote about in the past, on stress and anxiety and probiotics. The second study used B. infantis, and the scientists found that treatment led to decreased inflammatory markers, including C-reactive protein (CRP), tumor necrosis factor alpha and interleukin-6. (I’ve also written in the past about B. infantis and its ability to reduce inflammation resulting from stress.)
The researchers conclude the obvious: “The available research concerning the potential usefulness of probiotic treatment for FMS or CFS is limited.” (Ya think?) “Nevertheless, it seems, from the results of the two studies review here…that some probiotic strains might improve the symptoms of anxiety and inflammation in these populations.” They go on to point out that neither study actually focused on fatigue…the core symptom of CFS. Other studies, not included in their review because they did not meet the necessary criteria, have also not demonstrated improvements in fatigue. For example, one trial tested several Lactobacillus and Bifido species on 15 CFS patients, and while improvements in short-term memory and concentration were noted, there were no significant benefits in health. Another study done on those with spondyloarthritis (Ankylosing, psoriatic, etc.) with a combination of B.lactis, L.acidophilus and a strain of Streptococcus, also showed no improvement in fatigue.
Toward the end of the paper, the researchers note that new clinical trials may help further research into this area, including “…the one that Roman and colleagues are performing from 2017.”
So, I had a look and indeed, found this trial which is now published.[ii] This was an 8 week long double-blind, placebo-controlled, randomized trial of a multi-species probiotic on 40 patients with FMS (although only 31 ended up finishing). The scientists looked at cognition, emotional symptoms, quality of life, anxiety and depression: “Our results indicated that probiotics improved impulsivity and decision-making in these patients.” There were no statistical differences between the placebo and the treatment group in self-reported symptoms of FMS, including physical function, depression and anxiety: “Expectation of symptom improvement could be the primary factor underlying this ‘placebo effect.'” The only statistically significant improvement in the treatment group was in cognitive performance.
There was, by the way, a major drawback in this study, as I see it. Diet was not accounted for, meaning that probiotic containing foods like yogurt were not prohibited in the control group. That surprised me as it really could potentially explain the lack of statistical significance in results from the treatment and placebo groups – which these authors acknowledge. Seems to me that this is poor study design…but what do I know.
For those interested, this is the probiotic used in the study, which seems to be low potency (only 6 million units) containing the following strains, Lactobacillus rhamnosus GG ATCC 53103, Lactobacillus paracasei LMG P-21380, Lactobacillus acidophilus DSM 21717, Bifidobacterium bifidum DSM 22892. The subjects took 2 pills at least 30 minutes before breakfast and 2 pills at least 30 minutes before dinner. I do not know why they selected this particular probiotic, and not one including the strains in the 2 studies mentioned above.
So to conclude: we know basically nothing about how probiotics may or may not be used to treat either CFS or FMS. For the moment, we are on our own.
[i] Roman, P, Carrillo-Trabalon, F, Sanchez-Labraca, N, Canadas, F, Estevez, AF, Cardona, D. Are probiotic treatments useful on fibromyalgia syndrome or chronic fatigue syndrome patients? A systematic review. Beneficial Microbes. 2018:9(4);603-611. doi: 10.3920/BM2017.0125
[ii] Roman, P, Estevez, A, Miras, A, Sanchez-Labraca, N, Canadas, F, Vivas, AB, Cardona, D. A pilot randomized controlled trial to explore cognitive and emotional effects of probiotics in fibromyalgia. Scientific Reports. 2018;8(1). DOI: 10.1038/s41598-018-29388-5
I regularly receive FB messages and emails from people asking me what probiotic or prebiotic they should be taking. If I knew the answer, I’d be rich. The answer is…no one knows. We are so at the tip of the iceberg on all this, it’s mind boggling.
Over the weekend, I read a paper that took an in-depth met-analysis look at the differences in bacterial content between control and autistic children’s guts. These scientists reviewed 9 studies, with a total of 254 patients, and found “…that children with ASD had lower percentages of Akkermansia, Bacteroides, Bifidobacterium, and Parabacteroides and a higher percentage of Faecalibacterium in the total detected microflora compared to controls. In contrast, children with ASD had lower abundance of Enterococcus, Escherichia coli, Bacteroides, and Bifidobacterium and higher abundance of Lactobacillus.”[i] The differences were highly statistically significant.
How many illnesses now have been shown to have bacterial microbiome differences? On this blog alone I’ve talked at length about not just autism, but everything from obesity to chronic fatigue syndrome to depression, etc. etc. etc. The list feels endless somedays. And this is just the bacterial microbiome. Don’t forget that differences have also been found in the mycobiome (yeasts)…and the virome (viruses)…and in the metabolome (the secretions from all these various organisms)…and I still haven’t even touched on the parts played by the macrobiome, protozoa, and so on.
As though this is not all complex enough, as it turns out, even prebiotic fiber is unbelievably complex.
So back to the question: what probiotic and/or prebiotic should I take? Well…obviously, that is ultimately going to come down to what is already in your gut. I’ve already written, more than once, about how some day in the not-terribly-distant-future, we will know enough to individualize treatments using diet, probiotics, prebiotics, and so forth that are tailored to the exact needs of each person. I think we took one step closer to that, in research just out Washington University in St. Louis, wherein scientists began the laborious process of figuring out just which prebiotic fiber (and individual components of a prebiotic fibers) affect which bacterial species, and how.[ii]
These scientists took sterile rats, without microbiomes, and colonized them with 20 strains of the common gut bacterial strain, Bacteroides. They had the rats eat a “westernized” diet for 4 weeks, with high saturated fat and low fiber (fruit and vegetables) content, but to this they added one of 34 different kinds of prebiotic fiber, including pea protein, citrus peel, pectin, apple fiber, oat hull fiber, chia seeds, and many more. In total, they tested 144 different diet combinations as to how they affected those 20 bacterial strains. 21 of those 144 combinations had significant effect: citrus pectin and pea fiber enormously increased B. thetaiotaomicron while B. ovatus levels increased dramatically from barley bran. Some kinds of inulin, resistant maltodextrin and psyllium also had significant effects on certain strains.
As I mentioned previously, they also analyzed what it was in the fiber’s carbohydrate content that had the bioactive properties. Pea fiber, for example has a polysaccharide called arabinan that seems to affect bacteria, whereas in citrus pectin, it was something called homogalacturonan that led to the increase in specific bacterial strains.
Says Dr. Gordon, the lead researcher on this study, “…fiber is actually a very complicated mixture of many different components. Moreover, fibers from different plant sources that are processed in different ways during food manufacturing have different constituents…Unfortunately, we lack detailed knowledge of these differences and their biological significance.”[iii]
They also found that there were interactions between species as they fed on the fiber, leading to a distinct hierarchy of bacteria. Some species were stronger competitors than others, in their fight for the nutrients: “…it’s important to understand how the presence of a particular organism affects the dining behavior of other organisms — in this case, with regard to different fibers. If we are going to develop microbiota-directed foods aimed at providing benefits to human health, it’s important to find ways to determine which food staples will be the best source of nutrients and how the microbiota will respond.”[iv]
While obviously we’re not there yet, you can imagine how someday soon, we may be able to easily analyze the bacterial content of each person’s gut, and then have a tailor-made prebiotic that address their specific needs. I’m looking forward to the day I won’t have to respond with “I don’t know” again.
[i] Xu, M, Xuefeng, X, Li, J, Li, F. Association between gut microbiota and autism spectrum disorder: a systematic review and meta-analysis. Frontiers in Psychiatry. 2019. doi: 10.3389/fpsyt.2019.00473
[ii] Michael L. Patnode, Zachary W. Beller, Nathan D. Han, Jiye Cheng, Samantha L. Peters, Nicolas Terrapon, Bernard Henrissat, Sophie Le Gall, Luc Saulnier, David K. Hayashi, Alexandra Meynier, Sophie Vinoy, Richard J. Giannone, Robert L. Hettich, Jeffrey I. Gordon. Interspecies Competition Impacts Targeted Manipulation of Human Gut Bacteria by Fiber-Derived Glycans. Cell, 2019; 179 (1): 59 DOI: 10.1016/j.cell.2019.08.011
As promised on Tuesday, today is the last post in my continuing propionic acid series as we wrap up not-celebrating the Biome Buzz’ official First Annual Propionic Acid week. Today’s post is about just how suspect it is for all our health.
A study published this year by Harvard scientists in the journal, Science Translational Medicine, showed that the propionic acid (PPA) adversely affects metabolism by raising blood sugar levels.[i]
The scientists looked at both animal and humans, and the latter were involved in a double-blind trial with 14 healthy volunteers. The researchers discovered that PPA stimulates the liver to produce more glucose by increasing levels of the hormones, glucagon and fatty acid-binding protein 4, which signal the liver to release sugar into the blood. PPA seems to not directly cause this increase but instead, has an effect on the sympathetic nervous system which, in turn, signals to the body that a raise in blood sugar is needed. Says one of the study’s authors, “…the most interesting thing we determined in these experiments is that a single dose of propionate can increase the hormones in the body that are designed to stimulate glucose production from the liver…There are times when that’s needed, like when you’re starving or have dangerously low blood sugar. But here, it was almost tricking the body into thinking that it needs to produce glucose when it doesn’t.”[ii] The study in mice did demonstrate that chronic exposure to PPA thereby led to weight gain.
In the humans in the study, this continued release of unneeded blood sugar led to insulin resistance: their bodies no longer responded optimally to insulin, which lowers blood sugar levels. Insulin resistance, over time, leads to metabolic disorders like obesity and type 2 diabetes.
While of course this research has the usual caveats – it needs to be replicated in larger cohorts and so forth – it really does get you thinking. PPA is a common food preservative found regularly in cheeses and baked goods (and artificial flavors). It is also produced by various gut bacteria…and alterations to our bacterial microbiome are almost ubiquitous in the industrialized world. Over the past few decades, we have watched rates of not just autism rise (as I talked about in my last 2 posts – bearing in mind, PPA can cross both the blood-brain barrier and through the placenta), but also rates of obesity and type 2 diabetes. Is PPA a major factor?
[i] Tirosh, A, et. al. The short-chain fatty acid propionate increases glucagon and FABP4 prdocution, impairing insulin action in mice and humans. Science Translational Medicine. 2019:11(489). DOI: 10.1126/scitranslmed.aav0120
I am officially declaring this Biome Buzz’ first annual Propionic Acid Week! (Unfortunately, this is not a cause for celebration.)
If you remember, propionic acid (PPA) is a short-chain fatty acid produced by gut bacteria. Ordinarily, PPA , like the other SCFAs, is great for you: it is highly anti-inflammatory, beneficial for the gut flora, and so forth. However, to disprove the old adage, “you can’t have enough of a good thing,” excess amounts are linked to severe neurological issues, including autism.
As a follow up to last week’s post about PPA and autism – really out of sheer curiosity – I took a look to see if there were any known treatments to alleviate the effects of excess PPA in autism and was absolutely floored. Just published, in July of this year, there was an article about using a medication called pioglitazone (brand name, Actos) to do just this.[i]
Why was a floored? Well, therein lies a tale:
Back in the early-ish 2000’s, back when my son, Alex, was really, really sick, we were working with a whole team of doctors. Our immunologist was Dr. Marvin Boris, a wonderful man who – completely coincidentally – had been my pediatrician when I was a child, and who I adored even back then. Also in that practice was my friend, his physician assistant, Alan Goldblatt. Brilliant men, both of them. They were looking at immune issues in the autism population and hypothesized that using pioglitazone would be highly beneficial to deal with the major inflammatory problems in this population that were already accepted by the scientific community, even back then. I’m going to make a long story short here: they did a clinical study on 25 children for a few months, which was published in 2007, measuring behavioral symptoms (hyperactivity, inappropriate speech, irritability, lethargy, and stereotypy), and found “…apparent clinical improvement without adverse events…behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity).”[ii]
(We were among the first to try it and yes, Alex responded very favorably to pioglitazone. In fact, it was one of the few things that helped him, prior to me finding the Specific Carbohydrate Diet, when he was at his sickest.)
These findings have now been replicated several times. Just a couple of examples:
The point is, we’ve known for over 12 years now that pioglitazone has a very beneficial effect on those with autism and we’ve also known, for at least that long, that excess PPA is common in the population has has extremely adverse effects, both on the immune system and neurologically.
Back now to the findings of this propionic acid/ pioglitazone study:
As I mentioned last week, PPA can easily cross the blood-brain barrier and get into the central nervous system causing brain inflammation. In fact, patients with elevated PPA levels in stool and blood show similar symptoms to those with autism.
These scientists took rats that would be equivalent of 3-4 years old humans and gave them PPA for 3 consecutive days. They then broke them up into a total of 8 groups, testing the potential effects of different substances. Yet again, PPA caused marked decreases in sociability, exploratory behaviors, hyperactivity, and worsening anxiety, etc. The rats also had much lower levels of the antioxidant, glutathione (which is also one of the major detoxification molecules in our bodies), and “significant elevation” in inflammatory cytokines as well as a dramatic decrease in the regulatory cytokine, IL-10, which modulates inflammation: “This indicates the neuroinflammation in PPA treated rats as compared with control rats.” However, those treated with pioglitazone showed significantly lowered levels of those inflammatory cytokines and increased IL-10 in the brain.
However (and this is upsetting but not unexpected): “…pioglitazone significantly ameliorated PPA induced changes but this is only partial and not complete as results of pioglitazone treatments in rats are still significantly different from control rats.”
In other words – in rats at least – the changes induced by abnormally high levels of PPA were not entirely reversible. The damage had been done.
They conclude that their results are in line with everything we already know. PPA is a significant factor in causing autism; pioglitazone appears to be way to reduce the subsequent neuroinflammation.
On the bright side then, perhaps pioglitazone is a way to at least ameliorate the effects of excess PPA at an early point in life, when perhaps we can make the most difference in the future of children. On the not so bright side, none of this explains the reasons for the excess PPA issue in the first place. Antibiotics? C-sections? Formula feeding? Maternal diet? We just don’t know yet.
In my next post, to continue not-celebrating PPA week, I will describe to you other new study into adverse effects of PPA on humans.
[i] Mirza, R, Sharma, B. A selective peroxisome proliferator-activated receptor- γ agonist benefited propionic acid induced autism-like behavioral phenotypes in rats by attenuation of neuroinflammation and oxidative stress. Chemico-Biological Interactions. 2019; 311:108758. doi: 10.1016/j.cbi.2019.108758.
[ii] Boris, M, Kaiser, CC, Goldblatt, A, Elice, MW, Edelson, SM, Adams, JB, Feinstein, DL. Effect of pioglitazone treatment on behavioral symptoms in autistic children. Journal of Neuroinflammation. 2007;4(3). doi: 10.1186/1742-2094-4-3
[iii] Ghaleiha, A, Rasa, SM, Nikoo, M, Farokhnia, M, Mohammadi, MR, Akhondzadeh, S. A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: effects on aberrant behavior in children with autism. Psychiatry Research. 2015;229(1-2):181-7. doi: 10.1016/j.psychres.2015.07.043.
[iv] Capano, L, Dupuis, A, Brian, J, Mankad, D, Genore, L, Hastie Adams, R, Smile, S, Lui, T, Odrobina, D, Foster, JA, Anagnostou, E. A pilot dose finding study of pioglitazone in autistic children. Molecular Autism. 2018;9(59). doi: 10.1186/s13229-018-0241-5
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.
[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.
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.
“… 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.
[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.
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:
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.
[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
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.
[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
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:
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.
[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