Another really interesting paper was just published on the subject of the gut biome’s relationship to schizophrenia.[i] I first wrote about this subject back in 2017, and have kept a pretty close on in it since. Firstly, schizophrenia is very closely related to autism, so of course it peaks my interest. Secondly though, if you remember, my after-college roommate had a brother afflicted with the illness, and I’ve never forgotten his (and the whole family’s) suffering.
In this study, 63 patients with schizophrenia had their stool samples analyzed and compared to 69 healthy controls. Significant differences were found.
Firstly, those with the disease had less microbial diversity, with higher levels of several kinds of bacteria (including Veillonellaceae, Prevotellaceae, Bacteroidaceae, and Coribacteriaceae). They also had much lower levels of a variety of other species (including Lachnospiraceae, Ruminococcaceae, Norank, and Enterobacteriaceae).
The scientists then compared the microbiome profile of those with schizophrenia to those with major depressive disorder and found a distinct microbiota fingerprint that was unique to those with schizophrenia.
Now for the best part. The researchers took the fecal samples from the humans with schizophrenia and transplanted them into germ-free mice. They then ran a series of tests on the animals and discovered that, “Collectively, these behavioral tests showed that mice transplanted with SCZ [schizophrenia] microbiota displayed locomotor hyperactivity, decreased anxiety- and depressive-like behaviors, and increased startle responses, suggesting that the disturbed microbial composition of SCZ microbiota recipient mice was associated with several endophenotypes characteristic of mouse models of SCZ…” That is, the mice developed those behaviors associated with the known animal model of schizophrenia. They also found that there were disruptions in glutamate signaling which is generally thought to be relevant to the mental illness. (Glutamate abnormalities are also associated with autism and seizure disorders, among others.)
Of course, an animal model of schizophrenia is not a perfect parallel. But considering that by using fecal transplant, scientists have now been able to transfer (from humans) symptoms of depression, autism, obesity, etc. to mice, the evidence is mounting for microbiota alterations being, at the very least, a major factor in so many human illnesses.
How these microbiota alterations first develop is unknown, but in their discussion the scientists write, “In the context of these findings, several events shown to influence composition of the gut microbiome, especially during the microbiome’s establishment/dynamic period in infancy—e.g., cesarean versus vaginal birth, breast versus formula feeding, or early life antibiotic treatment—have all been associated, to some degree, with risk or onset of SCZ.” So once again, early life events and biome depletion likely play a central role in increasing the risk of developing the disease.
[i]Peng Zheng et al. The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice, Science Advances (2019). DOI: 10.1126/sciadv.aau8317
Yesterday, I read a cool little pilot study[i] out of the University of California, testing the tolerability and efficacy of a probiotic and bovine colostrum on a small group of children with autism. And while the results on this population were interesting, as I’ll describe, there are actually many generalized items of interest to be found in the paper as well, which I’ll also point out.
Firstly, a few facts:
Over half of all children with autism spectrum disorders (ASD) have gastrointestinal issues including diarrhea, constipation, abdominal pain, and symptoms of irritable bowel. (I’d bet money that number is a gross underestimation, since many parents don’t realize that constipation is a major medical issue). The severity of these symptoms has been correlated with the degree of dysbiosis. The trial, on 8 children (11 actually started in the trial, but 3 were discounted for various reasons (i.e. missing a stool sample)), was small, but was double blind and crossover. (There was no control group, however). It was also, sadly, quite short in duration: one group started with both the colostrum and the probiotic, the other with the colostrum only, which they took for 5 weeks. After a 2 week washout (i.e. on neither treatment), the groups were switched.
For those interested in what was used and how much:
A reminder of some significant findings in the autism population:
2. Children on the spectrum have been shown to have epithelial damage (damage to the lining of the intestines, associated with “impaired gut barrier integrity” (i.e. leaky gut)), increased pro-inflammatory cytokines and low levels of regulatory cytokines, which turn off the inflammatory response.
3. Children on the autism spectrum have been found to have higher levels of allergy, both environmental and food.
Of course, many of these findings also apply to other inflammatory illnesses (i.e. allergic and autoimmune diseases, and so forth).
In spite of the study’s limitations, including the small sample size, the short duration, the lack of controls, and so forth, the results were still meaningful. As a parent of a young man with autism, I was happy to read that at the end of the study, most of the children’s parents asked for help in finding commercially available substitutes for the treatments involved. To me, that speaks volumes.
Even with all the limitations of the study (I’ve only presented some in this post), the findings were significant, especially since many of the children’s GI issues had been resistant to previous treatment. There were no significant side effects beyond mild gassiness really (which is common when starting any prebiotic). A larger study (or several studies) is, of course, called for to replicate the results. Still, at least this gives people some ideas for potential treatments while we wait.
[i] Sanctuary MR. et al. (2019) Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms. PLoS ONE 14(1): e0210064.
So many studies have come out recently that are of interest that I had a hard time choosing the winner for today’s post. I finally settled on an article[i] from the journal, Medical Sciences, on the potential use of microbiome manipulation in treating neuropsychiatric disorders, as so many of us, friends and family, are now affected by “mental” illnesses ranging from depression to anxiety disorders to autism.
There was so much in this paper that it’s an almost overwhelming task to select the highlights for this post. I’ll do my best!
First though, I have to tell you what stunned me right off the bat. Did you know that the first paper ever published (in the British Journal of Psychiatry) on the use of “psychobiotics” (probiotic bacteria that have a beneficial effect on psychiatric illness) dates back to 1910?! That is astounding! Over 100 years ago, scientists already recognized the potential, and tested the efficacy, of Lactobacilli in treating depression: “Melancholia…lends itself at once to a dietetic form of treatment.”[ii]
We haven’t made a hell of a lot of progress in the last 109 years, have we?
Ok – back to highlights:
In their conclusion the authors state that we are undergoing a “significant paradigm shift” in the treatment of neuropsychiatric disorders.
Well, of course, the Biome Buzz is on top of every biome news story and following this paradigm shift closely, but on occasion, my timing even astounded me. This morning, the biome headlines are screaming about a new, large scale study looking at microbiota differences between those with and without depression. Uncanny coincidence, right?! Microbiologists in Belgium analyzed the microbiota of 1074 Belgians, 173 of which were diagnosed with depression, and found:
“Two kinds of microbes, Coprococcus and Dialister, were missing from the microbiomes of the depressed subjects, but not from those with a high quality of life. The finding held up when the researchers allowed for factors such as age, sex, or antidepressant use, all of which influence the microbiome…They also found the depressed people had an increase in bacteria implicated in Crohn disease, suggesting inflammation may be at fault.”[iii]
Because microbiota vary from population to population, they also looked at a population of 1064 Dutch people and found those exact same two species missing in the those with depression.
They then tried to figure out what it is about these species that could be causative of depression and compiled a list of 56 substances that gut bacteria produce or breakdown which could affect the nervous system. They found, for example, “…that Coprococcus seems to have a pathway related to dopamine, a key brain signal involved in depression, although they have no evidence how this might protect against depression. The same microbe also makes an anti-inflammatory substance called butyrate, and increased inflammation is implicated in depression.”
While this is not yet proof that the missing species are the cause of the depression, this is still a major step forward toward creating a psychobiotic to treat the illness. And by the way, according to this article from Science Magazine, a clinical trial using fecal microbiota transplant to treat depression is planned at the University of Basel in Switzerland! I have high hopes.
[i] Evrensel, A, Onen Unsalver, B, Ceylan, ME. Therapeutic potential of the microbiome in the treatment of neuropsychiatric disorders. Medical Sciences. 2019:7, 21.
[ii] Phillips, J. The treatment of melancholia by the lactic acid bacillus. J. Mental. Sci. 1910, 56, 422–430.
We’ve known for quite some time that gut flora development from birth through the 3rd year of life has a tremendous impact on health throughout the lifetime. However, not much research has been done on the continuing development of the microbiota in school aged children. Researchers from Denmark and China worked together, analyzing the microbiomes and blood markers of 281 Danish children between the ages of 6 and 9 years, looking at factors like the type of delivery, breast feeding, preschool diet, body mass index and waist size, etc. to see if there were any patterns.[i]
I was not at all surprised by their results, and I imagine you won’t be either. The three main factors that determined the type of gut bacteria found in the children were breastfeeding duration, diet (intake of plant-based proteins and dietary fiber), and the moms’ education levels (which, of course, might have a huge bearing on their children’s diets). That is, diet once again is found to be the most important factor for determining the makeup and health of the gut flora.
A few highlights from the paper:
A short description of the paper appeared earlier this week on Gut Microbiota for Health, which concludes with the take-away point from today’s post: “…gut microbiota maturation is not complete by the end of the first three years of life and early-life factors have a relevant influence on gut microbiota in school-age children.”[iii]
[i] Zhong, H, et. al. Impact of early events and lifestyle on the gut microbiota and metabolic phenotypes in young school-age children. Microbiome. 2019:7(1):2. 10.1186/s40168-018-0608-z.
[ii] James, SJ, Cutler, P, Melnyk, S, Jernigan, S, Janak, L, Gaylor, DW, Neubrander, JA. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. American Journal of Clinical Nutrition. 2004:80(6):1611-7.
I was introduced to a new probiotic species this morning that sound like it holds a lot of promise: Roseburia intestinalis. I came across an article[i] on Gut Microbiota for Health describing research into the beneficial effects of butyrate-producing bacteria on atherosclerotic plaques and type 2 diabetes. Butyrate, if you remember, is a short-chain fatty acid, a metabolite of beneficial gut bacteria, that is highly anti-inflammatory.
The research, out of the University of Wisconsin-Madison, was an attempt to figure out exactly how butyrate-producing bacteria produced their beneficial effects. Using mice, the scientists tested out 8 different human gut bacteria, with or without R.intestinalis. They found that the R.intestinalis, which was already known to be a butyrate-producing species, “…showed the strongest negative correlation with atherosclerotic lesion size.”
This is where it gets super interesting. When the mice were fed a diet high in plant polysaccharides (beneficial prebiotics), along with R.intestinalis and other bacteria that were poor butyrate producers, they still had a 4-fold increase in butyrate levels and reduced atherosclerotic plaques. HOWEVER: when mice were given the same bacterial species (including R.intestinalis) but a diet low in plant polysaccharides, this beneficial effect was not seen! “These results show that diet is crucial to the athero-protective effects of R. intestinalis…”
This is a possible explanation as to why – even with the best gut bacteria in the world – a diet high in plant fiber is preventative: “…butyrate-producing gut microbes might be relevant mediators involved in explaining the benefits of dietary fiber for better cardiometabolic health. It should be kept in mind that butyrate protective effects are dictated by diet, which highlights the fact that commensal gut microbes are neither good nor bad per se, and that context (diet and epigenetic changes in this study) also matters.”
But wait, there’s more! The researchers discovered too that butyrate production via R.intestinalis is also associated with an improvement in gut barrier function (i.e. tightening of the cell junctions), so good for leaky gut.
Now my interest was really peaked so I did some snooping around and learned that R.intestinalis is known to be decreased in patients with inflammatory bowel disease. Research published this past year[ii] showed that this species lowered pro-inflammatory cytokines and raised regulatory cytokines (those which turn off the inflammatory response). The data was so strong from this study, in fact, that the researchers state flat out that R.intestinalis may be of potential use in the treatment of IBD.
Well, this is all really promising. Unfortunately, the species is not available yet in a commercial probiotic form. So I looked around to see if there are any specific dietary interventions that are known to increase levels.
A November 2018 human (randomized, open-label, cross-over, 8 week long) trial, published in the eminent journal, Gut,[iii] showed that omega 3 fatty acids are associated with an increase in Bifidobacterium, Roseburia and Lactobacillus. (You do have to wonder if some of the anti-inflammatory effects of omega 3s is not actually due to beneficial microbiome alterations. ???)
These results were completely in line with a study[iv] completed the year before on rats, wherein the animals were fed one of two diets, one with walnuts (which are high in omega 3s) and one with a replacement that contained the same amount of fat, fiber and protein in walnuts, but which lacked the omega 3 component: “Walnuts enriched the microbiota for probiotic-type bacteria including Lactobacillus, Runinococcaceae, and Rosburia…Walnut consumption altered the gut microbial community suggesting a new mechanism by which walnuts may confer their beneficial health effects.”
So, for the moment, we are reliant upon adding plenty of plant fibers, omega 3s and walnuts to our diets….which should come as no surprise to my regular readers ‘cause how many times do I have say, “I told you so”?! 🙂 I will certainly continue to look for more research on this as it becomes available.
[ii] Zhu, C, et. al. Roseburia intestinalis inhibits interleukin-17 excretion and promotes regulatory T cells differentiation in colitis. Molecular Medicine Reports. 2018:17(6):7567-7574. 10.3892/mmr.2018.8833
[iii] Watson, H, et. al. A randomized trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota. Gut. 2018:67(11):1974-1983. doi: 10.1136/gutjnl-2017-314968
[iv] Byerley, LO, et. al. Changes in the gut microbial communities following addition of walnuts to the diet. The Journal of Nutritional Biochemistry. 2017:48:94-102. https://doi.org/10.1016/j.jnutbio.2017.07.001
A couple of articles about helminths have appeared recently in the lay press that struck me for various reasons. While it’s always great to see helminth therapy getting good press, unfortunately, there tends to be misinformation printed that can often do more harm than good.
The first[i] appeared on the e-zine, Goop, a month or two ago. It was nice to see a positive interview with a healthcare practitioner (the interviewee is a chiropractor) who actively uses helminths in his practice. He gets a some things right: for example, he does give a good summary of the biome depletion paradigm. Unfortunately, he also gets a several things incorrect, the main error being this statement: “The goal is to get to a place where the patient’s immune system is regulated well enough that it is not flaring up and overreacting. Then the patient can discontinue the therapy.”
This is simply wrong. Helminths will only exert their inflammation-modulating effect when they are living in you. When you stop taking them, your body will no longer be receiving the stimulation that causes regulatory cytokine levels to go up. In a pretty short period of time, your body will revert to where it was before you took the helminths. This is why I liken helminths to omega 3s. Ensuring you have enough of this essential fatty acid helps prevent excess inflammation. You don’t take them for 3 months though and expect their benefit to then last the rest of your life!
The second article[ii] came out this month in a New Zealand based e-zine called Noted. This one actually made an interesting point that I have not read about in the past: helminths have their own microbiomes, which also may exert an influence upon our immune systems. I never really thought about that before. Another reason though simply taking one excretory product produced by a helminth to make a pharmaceutical product is unlikely to reap the same kind of benefits as simply using the living organisms. The host-helminth interaction is simply too complex to replicate artificially. The researcher interviewed for this one, Kara Filbey, seems to focus on the immunology of helminths: “…Filbey’s results suggest that living with a ‘friendly parasite’ could protect humans against infection as well as autoimmune diseases.”
Says Dr. Filbey: “Worms are amazing. They are big, multicellular organisms with their own microbiome and they have immune systems themselves, so they must be having a big effect on us.”
I took a quick look through her published work and thought this was a super interesting finding. In a 2010 paper[iii] (which, by the way, has one of my favorite helminth researchers, Dr. Rick Maizels of the University of Glasgow, as lead researcher), Dr. Filbey and her fellow scientists found that when they transferred specific regulatory B (immune) cells from mice hosting a native-to-rodents helminth (Heligmosomoides polygyus) to mice without, they also conferred protection from allergic asthma and “…autoimmune-mediated inflammatory events in the CNS [central nervous system]…” Obviously, this is an animal model, and whether or not this transfers to humans is, as yet, unknown. But I found it fascinating, nonetheless. It is yet again another confirmation of the importance of a macrobiome in immune tolerance and inflammatory regulation.
[iii] Wilson, MS, Taylor, MD, O’Gorman, MT, Balic, A, Barr, TA, Filbey, K, Anderton, SM, Maizels, RM. Helminth-induced CD19+CD23hiBcells modulate experimental allergic and autoimmune inflammation. European Journal of Immunology. 2010:40(6):1682-1696. doi: 10.1002/eji.200939721
Last week, I posted a story on the Biome Buzz’ Facebook page about how a metabolite from pomegranates and berries has been found to reduce inflammatory bowel disease.[i] Researchers at the University of Louisville discovered that the metabolite, urolithin A (UroA) and a synthetic form they have devised, increases the proteins that tighten the junctions at the epithelial border, stopping leaky gut. This, in turn, keeps toxins, undigested food, bacterial metabolites, etc. from getting into the blood stream and causing a major systemic inflammatory response. As of now, there are no pharmaceutical treatments for leaky gut, so this is potentially a huge step forward.
“In pre-clinical studies conducted by the researchers, oral administration of either UroA or its potent version synthetic analog has clearly shown the beneficial effect in reducing the colonic inflammation, in acute and chronic colitis. A series of in vitro and in vivo experiments revealed that these small molecules reduce gut permeability by restoring the epithelial barrier by overexpressing the junctional proteins.”
It is really a very exciting finding, especially as UroA has been shown to not only treat existing colitis but also, to prophylactic in preventing it in the first place. Giving the metabolite to mice who have fully developed IBD has reversed the disease; but also, giving the mice UroA and then provoking gut inflammation with chemicals that cause colitis prevented the mice from developing IBD.
This story gets even more interesting in that, it is the gut bacterium, Bifidobacterium pseudocatenulatum that is responsible for generating UroA from these fruit. Thus, some people produce less UroA from their diets because they have lower levels of this bacterium. In fact, some people may not have it at all! Says the lead researcher, “Our study shows that direct consumption of urolithin A or its analog can compensate for a lack of the specific bacteria responsible for production of urolithin A and continuous consumption of pomegranates and berries.”[ii]
Unfortunately, there are no commercial probiotics that can as yet rectify the depletion of Bifidobacterium pseudocatenulatum. A 2016 article though states that a new company, Amazentis, has created a urolithin A product and started clinical trials.[iii] In 2017, the company issued a press release stating that their product successfully passed through phase 1A/1B double-blind, randomized, placebo-controlled trials in elderly people. Why, you ask, did they test the product first in the elderly? Because, as it turns out, UroA is not only effective in tightening the gut epithelium. It also improves the functioning of mitochondria, the powerhouse of every cell in the body.[iv] We all recycle mitochondria in a process called mitophagy. As we age though, this process does not work efficiently: “If worn-out mitochondria are not recycled, they and their decomposing components build up inside cells, eventually causing problems in many tissues, including muscle, which gradually becomes weaker.” There is evidence, that this build-up of faulty mitochondria may play a role in the loss of muscle and subsequent frailty in the elderly and too, may be somewhat responsible for the development of Parkinson’s and other diseases associated with aging.
UroA is, thus far, the only known molecule that can restore normal mitophagy. In their initial experiment, done on the worm C.elegans, scientists found the organisms lived, on average, 45% longer when given UroA. Experiments on rodents showed similar results, and this then lead to this first human trial.
So…at this point, this is a waiting game for all of us. We have no way that I have found yet of increasing levels of Bifidobacterium pseudocatenulatum, and, many of us may have lost the species altogether. I’ll follow this research, obviously. Considering the health implications for so many of us, I hope it won’t be too long before Amazentis’ product becomes available or, a perhaps a probiotic to replace what we have lost.
A pretty interesting, and telling, piece of research[i] came out just yesterday. In previous work, scientists have shown that babies who are allergic to cow’s milk have different gut bacteria than non-allergic infants. The question asked by these University of Chicago researchers is: can the microbiota be protective against developing milk allergy?
Gut microbes from healthy human babies and from babies allergic to milk were transplanted into mice which had been raised in a sterile environment and already sensitized (producing antibodies) to milk proteins. They then exposed the rodents to milk. The microbiota from the healthy babies did indeed protect the rodents from developing an allergy. Those rodents given either no microbes, or the microbiota of allergic babies, developed anaphylaxis when given milk.
The scientists also analyzed the bacterial microbiota from the babies and found many differences between the allergic and non-allergic babies. The non-allergic bacteria included a species already known to be protective against the development of food allergy: Anaerostipes caccae. When transplanted alone into mice, it protected against the development of milk allergy. “Our findings demonstrate that intestinal bacteria are critical for regulating allergic responses to dietary antigens and suggest that interventions that modulate bacterial communities may be therapeutically relevant for food allergy.”[ii]
What I can’t figure out why some babies have the species while others do not. Do the mothers of the allergic babies also have milk allergy? Are they (the moms) lacking this bacterial species? Have the allergic babies been introduced to antibiotics early in life? Where the allergic babies born via c-section?
Anaerostipes caccae is a normal part of human gut flora but not available as a probiotic. I wonder if it will be sold commercially soon. Is treatment of deadly allergy with probiotics or fecal microbiota transplant in our near-term future?
[ii] Taylor Feehley, Catherine H. Plunkett, Riyue Bao, Sung Min Choi Hong, Elliot Culleen, Pedro Belda-Ferre, Evelyn Campbell, Rosita Aitoro, Rita Nocerino, Lorella Paparo, Jorge Andrade, Dionysios A. Antonopoulos, Roberto Berni Canani, Cathryn R. Nagler. Healthy infants harbor intestinal bacteria that protect against food allergy. Nature Medicine, 2019; DOI: 10.1038/s41591-018-0324-z
Tuesday evening I printed out a bunch of new articles to read that looked potentially interesting. I’ve so far made it through 2, and one of those did not disappoint.
A brief seque: I’ve probably mentioned this before, but because of my autism longevity (with Alex now being 24 years old), one of the questions I have been asked the most by parents I’ve worked with is “what treatments seemed to work the best for the most kids on the spectrum?” My answer has not changed for the past 12 years or so: nothing has come close to the Specific Carbohydrate Diet and helminths – which, in my experience help most kids most of the time – but there are a few other things that work often, just not the majority of the time. Of those, high dose fish oil and anti-fungal medicines rank highest.
Thus, I had high hopes for an article[i] just published this past November looking at the levels of anti-Candida antibodies in the autism population, and as I said, I was not disappointed. By the way, I’ve written about the mycobiome in schizophrenia (which is very closely related to autism (and in fact, is sometimes called “adult onset autism”)) several times. In May, 2017, I discussed research showing high levels of anti-Sacchromyces cerevisiae (a yeast which is also a marker for gut inflammation) antibodies in that population and then, this past September, I wrote about a study testing a probiotic to treat those high yeast levels.
Based on these kinds of studies, and my own experience of seeing anti-fungal medications make a huge difference in many children, I was not surprised by the results presented in the paper, especially as previously published science showed high levels of Candida in individuals with autism based upon cultures and stool studies. In this case, the scientists were looking for blood antibodies which would imply that yeast was making its way out of the leaky gut and into the blood stream, leading to an inflammatory response.
The study included 80 children between the ages of 3 and 13, 52 with autism, and 28 typically developing controls. 36.5% of the children with autism tested positive for Candida antibodies, as opposed to only 14.4% of the controls.
A few points made in the discussion section that are worth sharing with you:
I believe this is going to turn out to be a very important area of research in chronic “mental” illnesses going forward. I will, of course, keep my eye out to bring you the latest.
[i] Hughes, HK, Ashwood, P. Anti-candida albicans IgG antibodies in children with autism spectrum disorders. Frontiers in Psychiatry. 2018:9(627).