Two days ago, I spotted a short commentary[i] in the journal, International Journal of Molecular Sciences, from this past August, which really caught my attention. Here is why: it was written by 3 researchers in the department of neurology at Rutgers University’s medical school who state that, “We will explore the potential for treatment of ASD [autism spectrum disorders] by targeting the microbiome with probiotics….this paper will attempt to provide significance to the aggregation of the research in this area of research.” It really is a great summary of what we now know.
Here are just some of the facts the paper presents:
They conclude this list of findings by stating, “Taken together, all these microbiome alterations may be associated with the increased gastrointestinal disturbances in individuals with ASD.”
More than that, there are other highly significant findings in autism that point to a gut origin. A few examples:
Ok – so let’s summarize. We know that people with autism have GI symptoms markedly more often than people without ASD, and that the severity of those symptoms correlate with the severity of their autism. We know that they have altered gut microbiota, including SIBO, lower levels of beneficial bacteria, lower levels of anti-inflammatory SCFAs, increased frequency of leaky gut/leaky brain. We know that “This ‘leaky gut’ theory would offer a mechanism by which GI disturbances could play a role in neurodevelopment and cognition.”
But wait…there’s more. We know that TREATING these microbiome alterations alleviates the symptoms of autism. Again, just a few of the findings the paper cites.
(Just yesterday, in fact, I read about a study[ii] out of Baylor College of Medicine wherein, researchers tested probiotics in a rodent model of autism. The researchers report that, “…administration of the bacterium Lactobacillus reuteri could lead to specific changes in the brain that reverse social deficits through a mechanism that involves the vagus nerve and the oxytocin-dopamine reward system.” (I have written about L.reuteri and autism before in a post about these researchers’ previous paper on this subject!) When the vagus nerve, which connects the brain to the gut (and many other parts of the body), is activated it releases oxytocin, a hormone that increases social behavior. Lowering the level of the L.reuteri in the guts of pups reduces their social behavior. Increasing the level restores it. If the vagus nerve that connects the gut to the brain is cut, L.reuteri does not restore social behavior, proving that it exerts its effect through the nerve. In mice who were genetically engineered to “…lack oxytocin receptors in the reward neurons or blocked the receptors with specific drugs, L.reuteri also could not restore social behaviors in the ASD mice.” Thus, the scientists were able to determine the exact mechanism by which the probiotic was exerting its effect.)
Back to the commentary, in the concluding paragraphs, the researchers say, “While research into the gut-brain connection in autism still remains in its preliminary phases, there is a convincing body of evidence that suggests a relationship between gastrointestinal distress and autism….”
A week ago, two papers[iii] were published in the eminent journal, Pediatrics, which showed that 1 in 40 children born in the United States (between the ages of 3 and 17) has autism. This is literally a national catastrophe at this point. Obviously, we need way more research into the gut-brain axis in autism. After all, as these scientists write, “…even today, it is becoming evident that the gut, specifically the disturbance of it, plays an important role in certain neurological disorders including ASD.”
[i] Fowlie, G, Cohen, N, Ming, X. The perturbance of microbiome and gut-brain axis in autism spectrum disorders. International Journal of Molecular Sciences. 2018;19(8): pii: E2251. doi: 10.3390/ijms19082251.
Back to leaky gut, briefly…
For those of you unfamiliar with the term epithelial cells, this is a single layer of cells that line the inside of the intestinal tract and provide a selectively permeable barrier. That is, healthy cells are tightly packed together, only allowing digested food through, while protecting the body from pathogens, undigested food, waste products, and so forth.
When an inflammatory reaction compromises the integrity of this barrier, such as seen in inflammatory bowel diseases, for example (thus allowing things out that should be kept in) we refer to this as a leaky gut.
A new technology has been developed that is allowing scientists to better study the epithelial cells, called organ-on-a-chip. These are microchips lined by living human cells. They have been used, apparently, to study various organ functions in a highly controlled environment. Studying epithelial cells has proven a challenge in the past because of the incredible complexity of the gut biome. Researchers at the University of Texas, using this organ-on-chip technology, have created a model of the human intestine, which allowed them to isolate one factor at a time.[i]
The scientists induced inflammation in these cells (which they termed gut inflammation-on-a-chip) by treating them with a chemical called dextran sodium sulfate (DSS) which is known to induce colitis. Exposure to the chemical impaired the function of the epithelial barrier, distorted the size and shape of the intestinal villi, and caused decreased mucus production. They noticed that contact between the dysfunctional epithelial cells and immune cells led to greatly increased oxidative stress and that, in turn, led to an increase in the production of inflammatory cytokines. Healthy epithelial cells, on the other hand, suppressed oxidative stress and the production of these inflammatory cytokines. “These results show that impaired integrity of the intestinal barrier is the trigger to initiate the inflammatory cascade.”[ii]
They tested the effects of probiotics in this model and discovered “Probiotic treatment effectively reduced the oxidative stress, but it failed to ameliorate the epithelial barrier dysfunction and proinflammatory response when the probiotic administration happened after the DSS-induced barrier disruption.” Thus, they conclude, that in order to stop the inflammatory cascade, epithelial barrier function must first be restored and maintained.
If this all actually translates to in vivo experimentation, it would indicate that in order to successfully treat leaky gut, it’s necessary to reduce inflammation first, before taking probiotics: helminths, prebiotics , short-chain fatty acids, improved diet, and so forth are your first line natural treatments. Interestingly, those of us heavily involved in using the Specific Carbohydrate Diet noticed this phenomenon years ago. As a nutritionist, I always recommended several months of the diet and other natural anti-inflammatory treatments BEFORE staring clients on probiotics. When gut inflammation levels were at their highest at the start of the diet, probiotics were often extremely problematic, causing a myriad of side effects.
[i] Shin, W, Kim, HJ. Intestinal barrier dysfunction orchestrates the onset of inflammatory host-microbiome cross-talk in a human gut inflammation-on-a-chip. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(45) E10539-E10547. https://doi.org/10.1073/pnas.1810819115
While I’m on the subject of butyrate…
An article[i] was published in the International Journal of Pharmaceutics that caught my attention. Researchers tested the efficacy of a probiotic (one I had never heard of) called, Symprove . One of the big issues often raised about probiotics: will the bacteria survive stomach acid to reach the intestines? Most brands are not tested so their true efficacy is unknown.
Using a laboratory simulator of the human gut (with microbiota from health human subjects), researchers were able to determine that all the bacteria from this product made it through to the intestines where they immediately colonized. Symprove contains 4 lactate-producing species: L rhamnosus, L. acidophilus, L. plantarum and E. faecium. Lactate is food for species of bacteria that produce short chain fatty acids [SCFA].
Butyrate levels went up significantly and subsequently, “…an immunomodulatory effect of the probiotics was seen; production of anti-inflammatory cytokines (IL-6 and IL-10) was increased and production of inflammatory chemokines…was reduced.”
Apart from the fact that Symprove looks like a pretty good choice in probiotics, there are two other take-away points I want to leave you with today:
“…dysbiosis in ulcerative colitis (UC) patients has been linked to a reduction in butyrate-producing species, reduced levels of propionate-producing species have been linked with asthma in children while broad changes in the gut microbiota have been linked with irritable bowel syndrome (IBS)…It has also been proposed that butyrate produced from a high-fiber diet can improve brain health and function. Ensuring the gut microbiota is optimally balanced and so producing high SCFA, especially butyrate, levels is therefore an important focus in maintaining and improving general health and wellbeing.”
A trial of Symprove is definitely in my future!
[i] Moens F et al. A four-strain probiotic exerts positive immunomodulatory effects by enhancing colonic butyrate production in vitro. International Journal of Pharmaceutics, 2018: https://www.sciencedirect.com/science/article/pii/S037851731830838X?via%3Dihub
Yesterday I devoted several hours to reading a fascinating article on the connection between stress and the microbiome.[i] The conclusion: the lack of exposure to our “old friends” (those commensal organisms with which humans co-evolved) has caused immune dysregulation, leading to a greater susceptibility to the adverse effects of stress…and that stress, in turn, has caused alterations to the biome and immune system.
The paper was extensiveso I will just hit on some of the major highlights. (And even just highlights means this is going to be a loooong post, so brace yourself!)
Unfortunately, these authors – like most scientists these days – limit their definition of Old Friends to the bacterial microbiome. Our Old Friends, though, are far more diverse and include viruses (as I pointed out, for example, here), macrobiotic organisms (like helminths, as I have pointed out many times (for example, here), protozoa (as I talked about here), and so forth. As in any ecosystem, there is much greater complexity than a single class of organisms and all are inexorably intertwined. Limiting scientific research to only the bacterial microbiome is like saying you will research a rain forest but only study the mammals…forgetting that the diversity of the mammalian population in the forest is reliant upon all their co-inhibitors, like the insects, the birds, the reptiles, and so forth.
As always, I will continue to hope that at some point, science starts to think about the bigger picture. The question I constantly ask myself is, can biome restoration really happen if we only attempt it using 1 type of organism?
[i] Langgartner, D, Lowry, CA, Reber, SO. Old Friends, immunoregulation, and stress resilience. European Journal of Physiology. 2018. doi: 10.1007/s00424-018-2228-7
In my last post, I talked about how microbiome depletion results from immigrating to the United States (and subsequent dietary changes), which leads to obesity and metabolic diseases. I promised to tell you more about immigrant studies on biome depletion so today I am addressing a paper from 2 years ago in which researchers describe the effects of macrobiome (helminth) depletion in immigrants to a westernized nation.
In this case, scientists looked at the development of allergy in 126 Ethiopians newly arrived in Israel.[i] They were tested upon arrival and then, 115 of them were retested a year later. The health assessments consisted of allergy testing – and stool and blood sampling, in order to determine the presence of helminths. Anti-helminth medication was offered to all those with helminths but only 46.3% of the people chose to take it.
At baseline (i.e. when the people first arrived): most of them were positive for helminths. Of the 18 who were not, 22.2% (so 4 people) tested positive for allergies. Of the 108 who were helminth-positive, only 7 (so 6.5%) tested allergy positive. Thus, a total of only 11 people (8.7%) tested positive for allergies
Now here’s where it gets really interesting. A year later, after living in a highly-developed nation, “…a significant general increase in allergy…was observed.” 30 people (26.1%) now tested positive for allergies, as opposed the 11 of the previous year. After not only looking at allergic symptoms, but also skin prick testing for reactivity, the scientists concluded that allergic reactivity had increased in all the immigrants.
The research showed that “Helminth infection is significantly associated with low allergy and low SPT [skin prick testing] reactivity.” Even in the helminth-positive population that had chosen to not take the anti-helminth medication, an increase in allergic sensitivity was observed. There are several possible explanations for this, including the fact that lack of exposure to helminths meant they were slowly losing their helminth population as worms died off. Certainly too, other environmental factors – for example, dietary changes leading to microbiome depletion – also played a role. However, the conclusion of the paper is that the loss of helminths was definitely the major factor in the increase in allergic sensitivity.
One last note of interest: I can think of at least 1 paper in the literature that shows that multiple kinds of helminths leads to markedly higher levels of regulatory cytokines (those chemicals that turn off the inflammatory response). That finding was confirmed by this research as well: “Infection with several parasites had even lower allergy than monoinfection compared to the non infected individuals.”
Unfortunately, the research ended there. It would have been great to see what happened to those individuals allergy-wise if helminths were reintroduced. Oh well….
[i] Stein, M, Greenberg, Z, Boaz, M, Handzel, ZT, Meshesha, MK, Bentwich, Z. The role of helminths infection and environment in the development of allergy: a prospective study of newlyl-arrived Ethiopian immigrants in Israel. Plos: Neglected Tropical Diseases. 2016;10(1): e0004208. doi: 10.1371/journal.pntd.0004208.
Last week, a really interesting new study[i] was published in the journal, Cell, detailing how immigrating to the USA negatively impacts the gut bacteria. Researchers looked at people from Southeast Asia and found that there was a significant reduction in the diversity of gut microbes with each subsequent generation, culminating with their microbiota resembling those of Americans of European origin.
You all know that a reduction in microbial diversity is associated with an increase in inflammatory health issues, including obesity. I’ve written about this several times before on this blog. 514 female immigrants to the Minnesota area, provided stool samples and diet diaries for this study. Some had lived in Thailand, some were first, and some second generation Americans. These were compared to the bacterial microbiomes of 36 Americans of European origin.
The dominant species of the recent immigrants was Prevotella but that changed remarkably quickly to Bacteroides. Prevotella is important in the digestion of high fiber foods, which are much more predominant in an Asian diet (as opposed to the “western” diet, which is heavy in sugar, fat and protein). Dan Knights, a co-author of the study, points to the change in diet as a key factor in this loss of diversity which changes within just a few months: “People began to lose their native microbes almost immediately after arriving in the U.S. The loss of diversity was quite pronounced: Just coming to the USA, just living in the USA, was associated with a loss of about 15 percent of microbiome diversity.” The children of these immigrants lost a further 10% of diversity. What’s really scary, and kind of amazing, is that “Even a short period of residence in the United States was sufficient to induce pronounced increases, in some cases over 10-fold, in the ratio of Bacteroides to Prevotella.”[ii]
The change in diet, and the loss of microbial diversity, was clearly associated with an increase in obesity and diabetes.
An important note: in the conclusion of the paper the authors of course point out the limitations of the study. While they looked at the diet/microbiome connection, they did not take into consideration changes in stress levels, exercise, drinking water, antibiotic use, and treatment with anti-helminth drugs. All of these, some more, some less, will also have an impact on the loss of microbial diversity. (In fact, in my next post, I’ll tell you about a different immigrant study from a couple of years ago, this one looking at Ethiopian immigrants to Israel and the health implications arising from the loss of their native helminth populations.)
Wouldn’t it be interesting to look at immigration the other way? What happens to the microbiota of Americans who move to less industrialized countries? Can this loss be reversed? The answer is currently unknown.
[ii] Vangay, P, et. al. US immigration westernizes the human gut microbiome. Cell. 2018;175(4):962-972.
I know you were all missing your Tuesday post from me. 🙂 I was on my way home from Florida, where we saw my son’s autism doctor. So with autism on my mind, I thought I’d share a little article[i] I found today that ties together several topics I’ve covered in the last month or so.
The article covers a talk given by a scientist, Dr. Michael Conlon, at a recent summit on probiotics. He discussed about how polyphenols (remember those from my article on ways to boost Akkermansia?) improve health through boosting levels of good bacteria. Resveratrol, found in grape and berry skins, for example, increases levels of lactobacillus and Bifidobacterium in the gut according to a 2016 study. (I did start the cranberry extract and grape seed extract after writing that post. Over the weekend, completely coincidently, I also spotted a product made by Life Extension (one of my favorite organizations, as you know) called Berry Complete , which I ordered for myself this morning).
Remember too my article about “eating like a queen bee”? Well, studies show that propolis (another polyphenol), produced by honey bees, reduces bacterioides, alleviating colitis and intestinal inflammation. (I did some looking around and found this product that contains both royal jelly, as per that post of mine, and propolis. With cold and flu season coming up here in the northeastern USA, I plan on adding this too to my daily regime.)
Dr. Conlon also talked about new strains of probiotics that will hopefully be available soon, including Akkermansia muciniphila. Akkermansia, as you know from my posts, has many health benefits including protecting against atherosclerosis. And it turns out that low levels are not only associated with Alzheimer’s, as I wrote about a few weeks ago, but also autism. Says Dr. Conlon in his presentation, “Some of you may or may not know that kids with autism actually have significantly more gut problems, so we investigated and one of the initial findings was that there is a decrease in A.muciniphila.” He goes on to say that bacterial metabolites in the children’s urine indicate, leaky gut…which I covered just last week.
I went to PubMed and found Dr. Conlon’s paper[ii], from 2011, which had several interesting findings, two of which really jumped out at me. Firstly, the strain Bifidobacterium longum, which is found to be low in kids on the spectrum, has been shown to improve anxiety in animal studies by stimulating the vagus nerve. (Probiotics, like VSL#3, have this strain.) If there is any one symptom I have seen in children with autism (and, all too often, their typical siblings), it’s high levels of anxiety. Secondly, the aforementioned finding of low levels of Akkermansia in the autism population was new to me: “…our finding of a lower abundance of A. muciniphila in ASD children and their siblings may indicate a thinner GI mucus barrier in ASD children…These results could represent indirect evidence of impaired gut permeability in children with ASD.” As I wrote about last week, leaky gut = leaky brain.
[ii] Wang, Lv, Christophersen, CT, Sorich, MJ, Gerber, JP, Angley, MT, Conlon, MA. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. In feces of children with autism. Applied and Environmental Microbiology. 2011;77(18):6718-6721.
As you all know, one area of particular interest to me is healthy aging. (After all, we are all getting older! ugh) An interesting article appeared on Medical News Today[i] this past Friday that I thought I’d share. It’s about new research, presented at a London conference on the microbiome last week, on how the diseases associated with aging are intricately tied to the bacterial microbiome.
Dr. Marina Ezcurra, of Queen Mary University in London, used the worm C.elegans (which is commonly used in research on human disease) as a model for aging because it lives only 2-3 weeks and as it ages, believe it or not, it develops pathologies not unlike humans. What is totally fascinating is that the aging of the worm is 100% the result of the aging of its gastrointestinal tract. Thus, it is easy to test what manipulation of various gut bacteria does to increase or decrease the worm’s lifespan…and what diseases may be associated with any particular change.
One body of research out of Baylor College of Medicine, presented by Dr. Ezcurra, involved creating 4,000 different mutant strains of E.coli, each with a specific gene deleted. The C.elegans were then fed these different strains to see what happened. Says the senior researcher on this study, “Of the nearly 4,000 bacterial genes we tested, 29, when deleted, increased the worms’ lifespan. Twelve of these bacterial mutants also protected the worms from tumor growth and accumulation of amyloid-beta, a characteristic of Alzheimer’s disease in humans.” One mutant bacterium overproduced an acid which simulates the mitochondria (the powerhouse of cells), measurably increase the worms’ lives.
Dr. Ezcurra also raised the issue of how metformin, which I have written about several times, increases lifespan. Metformin is known to alter the bacterial microbiome, and in fact, studies on C.elegans have shown that metformin does not work to increase the worms’ lives when they are germ-free and lack gut bacteria. That is, it exerts its anti-aging effects through the microbiota. Apparently, what the drug does is affect bacterial folate metabolism which, in turn, regulates aging.
Dr. Ezcurra’s own research has shown that by colonizing the guts of C.elegans with strains of bacteria previously shown to reduce intestinal aging, she can increase the worms’ lifespans. She will soon be doing experiments colonizing the worms with bacterial strains from humans, the idea being, of course, to narrow down what particular strains of bacteria do, to prevent (or cause) aging and disease.
We already know that we lose microbial diversity as we age. As Dr. Ezcurra said, in her talk, “By better understanding the links between nutrition, microbiome, and health, we can understand how the elderly can maintain their microbiome, and also help them directly by using pre- and probiotic strategies. This would help us age in [a] better way, maintaining health and quality of life in old age without drugs or surgery.”
So yet again, I am left with the conclusion that caring for our biome as we age is going to turn out to be an awfully good idea.
If you remember, my last post was a quick update on what we currently know about the microbiome-depression link, and I mention leaky gut with a promise to write more about it this week. Toward that end, on Friday evening, I read an article from the journal Microorganisms entitled, “Leaky Gut, Leaky Brain?,”[i] and was looking forward to sharing some highlights with you this week. More on this in a moment.
A little coincidental tangent: on Saturday, I came across an article on Helio summarizing the “Psych Congress” summit about the microbiome.[ii] This particular piece is about the gut-brain connection in psychiatric illness and I realized it fit in perfectly with today’s leaky gut focus while also being a great segue from talking about depression. “We are not better today at treating depression than we were 70 years ago,” says the presenting doctor. (Well, that is er…depressing.) Depression, he goes on to state, is an inflammatory disease, pointing to those same raised blood markers I mention in my last post. Simply prescribing the usual anti-depressants is simply not good enough for most people. The microbiome needs to be addressed.
This doctor’s presentation included information about things you can do now: an anti-inflammatory low-processed-sugar diet that includes fruit, veggies, whole grains, lean meat, fish, etc. I also liked his suggestions to “tidy up blood-brain barrier leakiness”: curcumin, green tea, garlic and cinnamon, probiotics and prebiotics .
How’s that for timely? And this, from a mainstream physician! As it turns out, the article I am covering today (“Leaky Gut, Leaky Brain?”), starts off with an extremely pertinent quote: “’Leaky gut’ syndrome…has attracted much attention in recent years and for decades, was widely known in complementary/alternative medicine circles.” That is absolutely correct. I remember only too well when the concept of a leaky gut was considered “alternative” and the gut-brain connection was scoffed at by mainstream medicine…and I’m not that old! I keep telling you that times they are a’changing! (Thank goodness. As I always say, just because something is unproven doesn’t mean it’s wrong. And there is something called common sense…)
The blood-brain barrier is a membrane very similar to the epithelial lining of the gut. Both are made up of tightly packed cells that, when healthy, prevent infiltration by anything not meant to get through. We know that inflammation in the gut causes those tight cell junctions to open up in the gut, allowing bacteria, bacterial toxins, undigested food, etc. directly into the blood stream causing immune havoc. Why was it ever a reach to believe that those “invaders” could also cause inflammation in the blood-brain barrier causing central nervous system issues? I really don’t understand why it has taken so long for this concept to become commonly accepted.
Anyway…this paper reviews what we know about “…the possible neurophysiological basis of leaky gut; leaky brain disease; and the microbiota’s contribution to inflammation, gastrointestinal, and blood-brain barrier integrity…” It was actually pretty technical, so I’ll just stick to some of my favorite highlights.
A final quote to share with you. I have added the bold highlights to emphasize to you just how far reaching are the consequences of blood-brain barrier dysfunction:
“A dysfunction of the blood brain barrier leading to a ‘leaky brain’ can be linked to various neurological diseases, including autistic spectrum disorders (ASD), dementia, Alzheimer’s disease, depression, and schizophrenia. A breakdown in the blood brain barrier was observed in patients with major psychiatric illnesses. Moreover, the blood-brain barrier may become ‘leaky’ in select neurological diseases that have an immunologic component, such as multiple sclerosis (MS), Alzheimer’s disease, brain trauma, edema, brain cancers, amyotrophic lateral sclerosis [ALS], meningitis, and systemic diseases such as liver failure. Moreover, co-metabolism within the gut-brain-endocrine interactome play a role in the same neurodegenerative disorders, including Parkinson’s disease (PD)….”
So to sum it all up, it is starting to look like most chronic inflammatory diseases are caused by a dysfunction of the gut barrier. Treating biome dysbiosis and/or depletion may turn out to be the cure for more than we can possibly grasp right now.
[i] Obrenovich, MEM. Leaky gut, leaky brain? Microorganisms. 2018;6(107). doi: 10.3390/microorganisms6040107.