THE BIOME BUZZ
BUGS AND WORMS AND OTHER GREAT STUFF
Adding to the Pile of Evidence Linking IBD to the Virome
Yet another study, this one out of Massachusetts General Hospital (one of Harvard’s teaching hospitals) associating inflammatory bowel diseases (IBD) with alteration in the virome. These scientists wanted to move beyond correlation and look for actual causation. Exactly how does the virome affect intestinal tissue?
To figure this out, they used something called “enriched virus-like particles” (VLP) from people with and without IBD, seeing how a part of the human immune system (macrophages) and how intestinal epithelial cells themselves respond to the presence of VLP. Viruses isolated from the colonic tissue of healthy people elicit an anti-inflammatory response and protected the gut cells. Viruses collected from those with IBD provoke an inflammatory response and damage intestinal cells: “IBD-associated enteric viromes promoted inflammation, spontaneously and after DSS-induced colitis, while viruses from non-IBD tissue were protective and also suppressed inflammatory properties of IBD enteric viromes.”[i]
Taking the research a step further, VLP were then introduced into the intestines of healthy mice. The same happened: if the mouse were given viruses from healthy human intestines, they were protected from inflammation as opposed to those given viruses from humans with IBD. They were, therefore, able to conclude that the virome is an autonomous driver of inflammatory bowel diseases: that is, it can cause disease on its own, without even the involvement of other parts of the human biome.
The researchers found a significant elevation of two kinds of viruses in those with IBD: Caudovirales, bacteriophages, and viruses from the Picornavirus family, which are eukaryotic viruses. These latter types of viruses have been associated with the development of diabetes. Thus, they are two potential culprits. But, they also found many, many viruses that are, as yet, unknown and thus, uncategorized. And considering that there are likely at least 100 million species of virus in the human virome, and thus far, about 10,000 of them have been sequenced, it will be awhile before all suspect species have been identified. As one of the lead researchers states, ““[Finding the individual culprits] would be a game-changer in the arena of complex immune and autoimmune diseases.”[ii]
Still, even the knowledge that the virome is a potential leading – or maybe even lead – cause of IBD is an important finding. Before you can come up with a cure, you need to know what you’re curing!
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[i] Adiliaghdam, F, et. al. Human enteric viruses autonomously shape inflammatory bowel disease phenotype through divergent innate immunomodulation. Science Immunology. 2022;7(70). DOI: 10.1126/sciimmunol.abn6660
[ii] https://www.medicalnewstoday.com/articles/gut-microbiome-and-ibd-intestinal-virome-could-be-missing-link#Finding-the-responsible-viruses
How Gut Inflammation Feeds Pathogenic Bacteria in Crohn’s Disease
The results of a multi-year study of the role E. coli plays in Crohn’s Disease is absolutely fascinating. Back in December, 2021, I described to you research that showed that stress can cause flare-ups of Crohn’s by leading to an increase in invasive E.coli (“adherent-invasive E.coli (AIEC for short)). Stress hormones decrease those very immune cells that kill off pathogens. This invasive E.coli has been found in up to 63% of people with Crohn’s.
In a continuing effort to understand exactly why the microbiome changes and how this leads to the intestinal inflammation seen in inflammatory bowel disease, scientists characterized the small intestine microbiome, as well as the chemical environment and genetic predispositions of patients with and without Crohn’s.[i] This same pattern of a drive toward AIEC is seen in not just humans, but dogs, cats and mice as well. The scientists theorized then that AIEC may feed on substances produced by intestinal inflammation, giving them a competitive advantage over other, beneficial, species.
It turns out that their hypothesis was proven correct: they found that the ileal (part of the small intestine) mucosa provides an “extensive menu of chemicals” that promote the growth and virulence of AIEC. These metabolites include phospholipids and amino acids that AIEC can “…selectively use for growth, energy, stress resistance and movement toward the gut lining.”[ii] More than that, they were able to determine that a metabolite called ethanolamine, as well as the amino acid glutamine, increase the aggressiveness of AIEC. The authors write that in an in vitro model, “We link metabolism to virulence, finding that ethanolamine and glutamine enhance AIEC motility, infectivity and pro-inflammatory responses…”
To make matters worse, the AIEC found in people with Crohn’s tends to be resistant to multiple kinds of antibiotics. Thus, the use of antibiotics does nothing except promote the growth of AIEC as its competition gets killed off. Thus, there is no suggestions yet as to how to best treat this. Stress reduction? Diet? Let us hope that some kind of treatment will be found in the not-very-distant future.
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[i] Shiying Zhang, Xochitl C, Morgan, Belgin Dogan, Francois-Pierre Martin, Susan R. Strickler, Akihiko Oka, Jeremy Herzog, Bo Liu, Scot E. Dowd, Curtis Huttenhower, Matthieu Pichaud, Esra I. Dogan, Jack Satsangi, Randy Longman, Rhonda Yantiss, Lukas A. Mueller, Ellen Scherl, R. Balfour Sartor, Kenneth W. Simpson. Mucosal metabolites fuel the growth and virulence of E. coli linked to Crohn’s disease. JCI Insight, 2022; DOI: 10.1172/jci.insight.157013
[ii] https://www.sciencedaily.com/releases/2022/04/220427115747.htm
New Information on the Ever-Growing Parkinson’s Disease/Microbiome Connection
As you know, I’ve been following the developing story of the bacterial microbiomes relationship to the development of Parkinson’s Disease (PD) for years now. This past week, science took another step forward: Brazilian researchers published a paper in Scientific Reports that suggest, yet again, that alterations in gut bacteria may be at the heart of the development of the disease.
The lead author, Dr. Fonseca, points out the specific cells (enteroendocrine cells) in the epithelial lining of the gut have many neuron-like properties and they also express the protein alpha-synuclein (aSyn), abnormalities of which have been implicated in the development of the disease. These cells are connected to the nervous system of the gut (the enteric nervous system). There is already existing research that has demonstrated that it appears aSyn migrates to the brain via the enteric nervous system, eventually causing an immune response in the brain that leads to the destruction of dopamine producing cells in the substantia nigra.I’ve written about this process many times on this blog.
I have also written frequently about the benefits of certain probiotic species, like Akkermansia municiphila – but have also written countless times about how too much of a good thing is equally as bad as too little. Some research has shown that Akkermansia has been found at excessive levels in those with PD. (See here.) Thus, Dr. Fonseca and colleagues wanted to see if these bacteria secrete anything that might trigger the abnormal aggregation of aSyn. They cultured the proteins produced by these bacteria and found that indeed, they did lead to aggregation of aSyn. More than that, they also determined that aSyn can be transferred from enteroendocrine cells to the cells of the enteric nervous system. The paper concludes by stating that, “This represents a major breakthrough in understanding the mechanisms underlying the progression of synucleinopathies by shifting the focus of PD etiology to the peripheral nervous system…”[i]
What does the cascade look like? Proteins excreted by Akkermansia lead to a calcium overload, intracellularly, in the enteroendocrine cells. This in turn, stresses their mitochondria, which are the energy-producing centers of the cell. This leads to the production of reactive oxygen species (i.e. oxidative stress) which damage the intracellular structures and that, finally, leads to abnormalities in, and aggregation of, the protein, aSyn. While no one yet knows for certain all the functions of aSyn, at this time it is believed to have, at least in part, a function in the immune system.
Says Dr. Fonseca, “The cascade of reactions can start in the gut and move up into the brain. People predisposed to sporadic [non-genetic] Parkinson’s usually suffer from recurring constipation many years before they manifest the disease. In our study with animal models, we found a direct correlation between gut dysbiosis and Parkinson’s.”[ii]
So where does this leave us? The recognition that the disease almost certainly starts with alterations of the bacterial microbiome may soon lead to preventative strategies: dietary changes, fecal transplants, and so forth. One big problem though seems to be the contradictory research. I also wrote, in the not-very-distant-past, about research that shows that Akkermansia seems to alleviate symptoms of PD. See here
Of course, it is possible that both scenerios are true. That is – just making up a suppose to illustrate my point – excess Akkermansia is a cause of the development of the disease but after the disease is present, the microbiome shifts (perhaps due to the increased constipation symptoms????) and Akkermansia levels drop. I will, of course, continue to follow this ever-developing story!
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[i] Rodrigues, P.V., de Godoy, J.V.P., Bosque, B.P. et al. Transcellular propagation of fibrillar α-synuclein from enteroendocrine to neuronal cells requires cell-to-cell contact and is Rab35-dependent. Sci Rep 12, 4168 (2022). https://doi.org/10.1038/s41598-022-08076-5.
Treating ALS: A New Link Found Between the Microbiome and the Gut Nervous System
A bit of hopeful news for you today[i]. I don’t know about you all, but lately, I really feel like I need WAY more good news.
Researchers at the University of Illinois, Chicago, have published research which shows that there appears to be a link between intestinal inflammation and the microbiome in both the development of, and the progression of, ALS (amyotrophic lateral sclerosis). Apparently, the lead researcher, Dr. Jun Sun’s, interest in ALS was sparked by the upsetting recognition that many soldiers who suffer from GI issues go on to develop ALS, and subsequent research has shown that veterans have an elevated risk of developing the disease. According to the opening paragraph of their paper, these early GI symptoms (also apparent in other chronic illnesses like Parkinson’s disease, by the way) have been ignored for too long: “Thus, the current evidence indicates that intestinal dysfunction and dysbiosis may actively contribute to ALS pathogenesis.”[ii]
The scientists focused their attention on the interactions between the enteric nervous system (ENS), which is the nervous system of the gut directing its functioning and the microbiome. For their study they used mice which had been genetically engineered to carry the SOD1 gene (mutated superoxide dismutase 1, which is known as a cause of ASL). The mice were given the short-chain fatty acid butyrate, which is known to have a protective effect (as I’ve written about many times: see here and here as just two examples) or antibiotics. They then tracked intestinal motility, microbiome alterations and protein markers of the ENS prior to the onset of ALS. And what did they find?
The mice had significant microbiome alterations, decreased intestinal motility, and loss of physical stamina before the onset of the disease. BUT – in the good news – in the mice that were treated with butyrate or antibiotics, these changes took way longer to appear. SOD mice showed dysbiosis (for example, increased Clostridium sp. ASF502) by 1 month of age, before the dysfunction of the ENS. By 2 months of age, still before the onset of ALS, they had significantly lower intestinal mobility, decreased grip strength, etc.: “These changes correlated with consistent dysbiosis and increased aggregation of mutated SOD1G93A in the colon and small intestine.” ALS had set in by 3 months of age, and by then, showed significant changes in gut motility and an altered microbiome.
The scientist though found, “…that butyrate treatment and antibiotic treatment restored intestinal mucosal function and corrected dysbiosis in the ALS mice. Manipulating the microbiome improves the muscle performance of SOD1G93A mice. Our study provides insights into the fundamentals of intestinal neuromuscular structure/function and the microbiome in ALS.”
The conclusion of the study states that there is a link between early microbiome changes, the ENS (which regulates motility) and the onset of ALS. However, by inducing changes in the microbiome, via antibiotics or the protective short-chain fatty acid, butyrate, they were able to improve neuromuscular function in ALS in the animals, suggesting “…the potential to use microbial biomarkers for the diagnosis and to manipulate the intestinal microbiome for the treatment.”
They are not claiming that this is a cure for ALS but – they already they can make these animals live markedly longer. Dr. Sun states, “One mouse year equals about 30 human years. The treated mice lived an average of 38 days longer, which if you promote that to human life, it will be years of longer lifespan compared to the current drugs available to treat ALS.” And that is some good news at least.
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[i] https://medicalxpress.com/news/2022-03-link-neurons-gut-microbiome-als.html
[ii] Sarah Martin et al, A Gut Feeling in Amyotrophic Lateral Sclerosis: Microbiome of Mice and Men, Frontiers in Cellular and Infection Microbiology (2022). DOI: 10.3389/fcimb.2022.839526
Two Pieces of Research on Specific Bacteria Associated with Disease: Heart Attacks and IBD
Two interesting bits of research for you this week, to make up for missing a post last week. Sorry – just too busy these days to get to write regularly. Both are about research that has isolated specific bacterial microbiome differences in those with different disease (heart attacks and inflammatory bowel diseases (IBD) and those without. The findings are so specific, in fact, that there is hope that treatment for these illnesses, via manipulation of the gut microbiota, is not very far in the future.
The first paper is out of Rabin Medical Center and the Weizmann Institute of Science in Israel. (How many times have I reported on research out of the latter over the years?!) The scientists looked at the gut bacteria of 199 patients who had just had a heart attack. They had a substantial enough number of samples to allow them to spot a trend that had never been seen before. A type of bacteria from the Clostridiaceae family was completely missing from those who’d had heart attacks, but was present in the healthy control group: “ACS patients had distinct serum metabolome and gut microbial signatures as compared with control individuals and were depleted in a previously unknown bacterial species of the Clostridiaceae family.”[i]
Correlation does not, of course, prove causation. So these scientists are conducting further research to try to figure out what the relationship is between this species of Clostridiaceae and heart disease. Their working hypothesis is that it prevents arteriosclerosis (often called hardening of the arteries). They are also attempting to figure out whether or not they can use the presence, or lack, of these bacteria as a screening tool.
Knowing now that when it is absent that the heart is at risk, the researchers are attempting to isolate the bacteria from healthy donors and package it into pills, which – they hope – will prevent heart attacks in those prone. A clinical trial is expected to start in about a year![ii] Cool, right?
Today’s second paper is out of Harvard Medical School. These scientists have been researching the relationship between bile acids, the bacteria that produce those bile acids, and gut inflammation.[iii] Looking at both humans and mice, they discovered three critical bacterial species (and bacterial genes) that regulate bile acid modification: “The studies identify three bile acid metabolites and corresponding bacterial genes that produce molecules that affect the activity of inflammation-regulating immune cells.” [iv]
What’s exciting is that they found that people with inflammatory bowel diseases have markedly lower levels of both these microbes and these bacterial genes that are responsible for the production of the critical bile acids. Says one of the researchers, “All three molecules and the bacterial genes that we discovered that produce these molecules are reduced in patients with IBD…Restoring the presence of either the compounds or the bacteria that make them offers a possible therapeutic avenue to treat a range of inflammatory diseases marked by these deficiencies and affecting millions of people worldwide.”
So more specific probiotics to treat diseases in the future?
[i] Talmor-Barkan, Y., Bar, N., Shaul, A.A. et al. Metabolomic and microbiome profiling reveals personalized risk factors for coronary artery disease. Nat Med 28, 295–302 (2022). https://doi.org/10.1038/s41591-022-01686-6
[ii] https://www.timesofisrael.com/israeli-study-mines-donor-poop-for-bacteria-that-could-avert-heart-attacks/
[iii] Paik, D., Yao, L., Zhang, Y. et al. Human gut bacteria produce ΤΗ17-modulating bile acid metabolites. Nature (2022). https://doi.org/10.1038/s41586-022-04480-z
[iv] https://hms.harvard.edu/news/countering-gut-inflammation
Two interesting bits of research for you this week, to make up for missing a post last week. Sorry – just too busy these days to get to write regularly. Both are about research that has isolated specific bacterial microbiome differences in those with disease (heart attacks and inflammatory bowel diseases (IBD) and those without: so specific, in fact, that there is hope that treatment for these illnesses, via manipulation of the gut microbiota is not very far in the future.
The first paper is out of Rabin Medical Center and the Weizmann Institute of Science in Israel (how many times have I reported on research out of the latter over the years?!) kind of blew my mind. The scientists looked at the gut bacteria of 199 patients who had just had a heart attack. The fact that they had a substantial enough number of samples led them to spotting a trend that had never been seen before. A type of bacteria from the Clostridiaceae family, was completely missing from those who’d had heart attacks, but was present in the healthy control group: “ACS patients had distinct serum metabolome and gut microbial signatures as compared with control individuals and were depleted in a previously unknown bacterial species of the Clostridiaceae family.”[i]
Correlation does not, of course, prove causation. So these scientists are conducting further research to try to figure out what the relationship is between this species of Clostridiaceae and heart disease. Their working hypothesis is that it prevents arteriosclerosis (often called hardening of the arteries). They are also attempting to figure out whether or not they can use the presence, or lack, of these bacteria as a screening tool.
Knowing now that when it is absent, the heart is at risk, the researchers are attempting to isolate the bacteria from healthy donors and package it into pills, which – they hope – will prevent heart attacks in those prone. A clinical trial is expected to start in about a year![ii]
Today’s second paper is out of Harvard Medical School. These scientists have been researching the relationship between bile acids, the bacteria that produce those bile acids, and gut inflammation.[iii] Looking at both humans and mice, they discovered three critical bacterial species (and bacterial genes) that regulate bile acid modification: “The studies identify three bile acid metabolites and corresponding bacterial genes that produce molecules that affect the activity of inflammation-regulating immune cells.” [iv]
What’s exciting is that they found that people with inflammatory bowel diseases have markedly lower levels of both these microbes and these bacterial genes that are responsible for the production of the critical bile acids. Says one of the researchers, “All three molecules and the bacterial genes that we discovered that produce these molecules are reduced in patients with IBD…Restoring the presence of either the compounds or the bacteria that make them offers a possible therapeutic avenue to treat a range of inflammatory diseases marked by these deficiencies and affecting millions of people worldwide.”
Two interesting bits of research for you this week, to make up for missing a post last week. Sorry – just too busy these days to get to write regularly. Both are about research that has isolated specific bacterial microbiome differences in those with disease (heart attacks and inflammatory bowel diseases (IBD) and those without: so specific, in fact, that there is hope that treatment for these illnesses, via manipulation of the gut microbiota is not very far in the future.
The first paper is out of Rabin Medical Center and the Weizmann Institute of Science in Israel (how many times have I reported on research out of the latter over the years?!) kind of blew my mind. The scientists looked at the gut bacteria of 199 patients who had just had a heart attack. The fact that they had a substantial enough number of samples led them to spotting a trend that had never been seen before. A type of bacteria from the Clostridiaceae family, was completely missing from those who’d had heart attacks, but was present in the healthy control group: “ACS patients had distinct serum metabolome and gut microbial signatures as compared with control individuals and were depleted in a previously unknown bacterial species of the Clostridiaceae family.”[i]
Correlation does not, of course, prove causation. So these scientists are conducting further research to try to figure out what the relationship is between this species of Clostridiaceae and heart disease. Their working hypothesis is that it prevents arteriosclerosis (often called hardening of the arteries). They are also attempting to figure out whether or not they can use the presence, or lack, of these bacteria as a screening tool.
Knowing now that when it is absent, the heart is at risk, the researchers are attempting to isolate the bacteria from healthy donors and package it into pills, which – they hope – will prevent heart attacks in those prone. A clinical trial is expected to start in about a year![ii]
Today’s second paper is out of Harvard Medical School. These scientists have been researching the relationship between bile acids, the bacteria that produce those bile acids, and gut inflammation.[iii] Looking at both humans and mice, they discovered three critical bacterial species (and bacterial genes) that regulate bile acid modification: “The studies identify three bile acid metabolites and corresponding bacterial genes that produce molecules that affect the activity of inflammation-regulating immune cells.” [iv]
What’s exciting is that they found that people with inflammatory bowel diseases have markedly lower levels of both these microbes and these bacterial genes that are responsible for the production of the critical bile acids. Says one of the researchers, “All three molecules and the bacterial genes that we discovered that produce these molecules are reduced in patients with IBD…Restoring the presence of either the compounds or the bacteria that make them offers a possible therapeutic avenue to treat a range of inflammatory diseases marked by these deficiencies and affecting millions of people worldwide.”
[i] Talmor-Barkan, Y., Bar, N., Shaul, A.A. et al. Metabolomic and microbiome profiling reveals personalized risk factors for coronary artery disease. Nat Med 28, 295–302 (2022). https://doi.org/10.1038/s41591-022-01686-6
[ii] https://www.timesofisrael.com/israeli-study-mines-donor-poop-for-bacteria-that-could-avert-heart-attacks/
[iii] Paik, D., Yao, L., Zhang, Y. et al. Human gut bacteria produce ΤΗ17-modulating bile acid metabolites. Nature (2022). https://doi.org/10.1038/s41586-022-04480-z
[iv] https://hms.harvard.edu/news/countering-gut-inflammation
[i] Talmor-Barkan, Y., Bar, N., Shaul, A.A. et al. Metabolomic and microbiome profiling reveals personalized risk factors for coronary artery disease. Nat Med 28, 295–302 (2022). https://doi.org/10.1038/s41591-022-01686-6
[ii] https://www.timesofisrael.com/israeli-study-mines-donor-poop-for-bacteria-that-could-avert-heart-attacks/
[iii] Paik, D., Yao, L., Zhang, Y. et al. Human gut bacteria produce ΤΗ17-modulating bile acid metabolites. Nature (2022). https://doi.org/10.1038/s41586-022-04480-z
[iv] https://hms.harvard.edu/news/countering-gut-inflammation
More Fascinating Findings on Phages: Affects on Memory and Cognition
For today, a topic I haven’t had a chance to write about in months: the virome. Published last week in Cell Host & Microbe is an article that shows that a specific bacteriophage has been found to improve executive function and memory in both animals and in humans.[i] Apparently, previous research has shown that the virome, like the bacterial microbiome, changes with age: from the family Cuadovirales, Microviridae goes up and Siphoviridae goes down. (What is kind of extraordinary is that in animals, this also happens when they are fed high fat diets!)
As you know from previous posts on this topic (see here for just one example), bacteriophages (phages for short) are viruses that infect bacteria. If you remember, they are being studied as a means of manipulating the gut bacteria as well as being used in lieu of antibiotics. In this case, the scientists were surprised to find a strong negative association between specific Cuadovirales and multiple aspects of folate metabolism, including the use of vitamins B2 and B6 in the folate cycle, as well as DNA repair mechanisms; however, some bacterial pathways associated with folate metabolism were increased. For example, a gene was upregulated tha,t in humans, is known to affect neuroplasticity, neurological development and memory retention.[ii]
The researchers tested this all in a cohort of 115 humans. They found that those with increased levels of specific Cuadovirale and Siphoviridae in their gut microbiomes had better performance in executive processes and verbal memory. Those with increased levels of Microviridae, which as noted above, are known to increase with age, had greater impairment in executive abilities. Some differences in responses were noted between men and woman. The scientists repeated the study using a cohort of almost 1000 people (942). The results were even more pronounced in men, interestingly: Cuadovirales were noticeably associated with improvements in executive functioning, short-term and long-term memory and information processing speeds.
Transplanting microbiota from human donor with higher levels of specific Caudovirales led to improved memory test scores in mice. They also tested this in flies (they use aversive tastes) and believe it or not, and found the same type of results.
The paper points out that in multiple cohorts, they found a positive association between Cuadovirales and various species of probiotic bacteria, including various strains of Lactobacillus and streptococcus. Both are associated with fermented dairy products (i.e. yogurt, etc.) as well as with human milk. The paper states that, “Consistently, we found positive associations between specific Caudovirales levels and dairy product consumption and medium-chain fatty acids which are naturally occurring in dairy fat, as well as between specific Caudovirales-linked lactic acid bacteria and dairy products. On the contrary, the Microviridae family had negative associations with medium-chain fatty acids. Interestingly, supplementation with medium-chain fatty acids has shown to improve synaptic plasticity and cognitive function in mice and humans.”
The upshot is that in the not-very-distant future, direct supplementation of certain phages may well be used to improve our health, and to treat diseases of aging: “All these findings may have implications in the design of dietary interventions targeted at improving cognitive and memory dysfunction.”
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[i] Mayneris-Perxachs, J, et. al. Caudovirales bacteriophages are associated with improved executive function and memory in flies, mice, and humans. Cell Host & Microbe. 2022. https://doi.org/10.1016/j.chom.2022.01.013.
[ii] https://www.lifespan.io/news/gut-viruses-found-to-improve-cognition-in-humans/
FMT Reduces Sensitivity to Peanuts Even in the Highly Allergic
A quick note this week to tell you about a very exciting clinical study that was just reported this weekend, out of Boston Children’s Hospital. The trial was a phase one, and thus small – only 15 participants, aged 18-33, who have severe peanut allergy: that is, they had to demonstrate allergic reactions to 100 milligrams of peanut, which is about a half a peanut, or less.[i] The study was to determine the safety and potential efficacy of using fecal microbiota transplant (FMT) to alleviate the severe allergy symptoms. The FMT was delivered in a non-invasive form using pills provided by OpenBiome (a Boston-based nonprofit which provides approved donations for FMT around the country), from rigorously screened donors who were peanut-allergy free.
The subjects received FMT, swallowing 36 capsules over the course of three hours. In one arm of the study, 10 participants received a single dose of FMT alone. Believe it or not, 3 of the 10 were able to tolerate larger amounts of peanut — one as much as four peanuts — when challenged both one and four months after FMT! That is amazing! The second arm of the study involved the other 5 subjects. They were first given antibiotics to wipe out much of their existing gut bacteria, and then given the FMT. In this case, 3 of the 5 became more peanut-tolerant.
It gets even more interesting, because the researchers also tested the participants’ immune systems before and after the FMT. Those patients who responded to FMT had increases in the regulatory T cells associated with immune tolerance, and reductions in the T helper cells associated with allergy. The scientists took samples of their microbiomes, and transplanted these into a strain of allergy-prone mice. The mice showed similar immune changes and were protected from anaphylaxis when challenged with food allergens. However, when the non-responders’ microbiomes were transplanted, the allergic mice were not protected. This, of course, provided proof that the protection from severe allergy is microbiome-related.
By the way, prior to this study, these researchers had already done proof-of-concept studies in mice. In 2019, they published a study in which the microbiota of infants with allergy were transplanted into mice. Sure enough, the mice would suffer anaphylaxis when given allergic foods; control mice, given FMT from non-allergic babies, did not.
While improving tolerance from half a peanut or less to eating more than 2 peanuts before reacting may not sound like a dramatic improvement, in actuality, it may be life saving. That amount may be enough to eliminate concern about traces of peanuts in foods, which presently, can hospitalize or kill those with severe enough allergy. The researchers are planning a phase II trial in children 12-17 years old. Those children will be given the antibiotics first – because that does appear to improve efficacy – and then a purified FMT preparation.
The more these kinds of studies appear with positive results, the more hopeful I become that at some point in the not-very-distant future, these kinds of non-invasive FMT products will become available for a wide variety of biome related illnesses.
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[i] https://www.eurekalert.org/news-releases/944014
A Bacterial-Derived Metabolite and Anxiety in Autism and Schizophrenia
Readers with (or who have family members with) anxiety issues, autism, or schizophrenia, please pay special attention to today’s post. I have feeling that this is a really significant finding.
Researchers at Cal Tech (along with colleagues at Stanford and other major California Universities) have discovered that a small gut-bacterial-derived metabolite seems to be very much an activator of anxiety behaviors.[i] They started, of course, looking at a rodent model. Several years back, researchers in their lab had noted that a metabolite of the bacterial microbiome called 4-ethylphenyl sulfate, or 4EPS, which is readily absorbed into the blood stream in both humans and mice, was at much higher levels in mice with altered neurological development – especially in mice that presented with rodent models of autism and schizophrenia. While other metabolites also differed in the animal guts, 4EPS was by far the most altered. And when they looked at humans, in a study of 231 people, 4EPS was found to bey 7X higher in children with autism than non-autistic controls!
In this most recent work, published last week in the eminent journal, Nature, the scientists compared two groups of mice, one of which was colonized with 2 kinds of bacteria that were engineered to produce 4EPS. The control mice were also colonized with the same 2 bacterial species, but normal ones, not engineered to produce 4EPS. The mice were then introduced to a novel environment to see what would happen. The former set, the 4EPS ones, did not normally explore their new environments and spent much of their time hiding, as compared to the controls. Brain scans of the 4EPS mice showed that the regions of the brain associated with fear and anxiety were more activated, and to boot, there were changes in brain activity and functional connectivity. Cells in the altered regions, called oligodendrocytes, which produce myelin (the protective coating – like insulation – around neurons and nerve fibers) were different. The oligodendrocytes were less mature and produced less myelin, leading to thinner myelin sheathes around nerves: “Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS.”
Now for the good news, which you may have just spotted: when the 4EPS mic were treated with a drug known to increase myelin production in oligodendrocytes, the mice regained normal production of myelin and returned to normal behavior![iii] I do not as yet have the name of that medication – I’m waiting for the full text of the paper to arrive and will fill you in on that when it does.
But Jude, you’re thinking, this was in mice! How does this apply to us humans?! Wait for it….
A second study, also performed by one of the lead authors of the above paper (this one published last week as well, in Nature Medicine) showed that giving mice an oral medication called Kremezin, which is an FDA approved drug for the treatment of chronic renal failure, is highly effective in treating this issue as well.[ii] It was so effective on rodents, and is so safe, that the scientists were immediately permitted to try it in a small pilot study on humans – 30 individuals with autism. I did a lot of snooping around, and found that Kremezin seems to be basically a high-powered form of activated charcoal: it is capable of absorbing even small molecules, including bacterial-derived metabolites, including 4EPS, in the gut before they have a chance to make their way into the blood.
In both mice and humans, 8 weeks of Kremezin (given 3x per day) led to reduced levels of 4EPS in both the blood and urine, and decreased both anxiety and irritability: ”AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints [in mice], most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment [in both mice and humans].”
Kremezin is available from Japanese pharmacies, if anyone is interested in trying it.
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[i] Needham, B.D., Funabashi, M., Adame, M.D. et al. A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature (2022). https://doi.org/10.1038/s41586-022-04396-8
[ii] Stewart Campbell, A., Needham, B.D., Meyer, C.R. et al. Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial. Nat Med (2022). https://doi.org/10.1038/s41591-022-01683-9
[iii] https://www.sciencedaily.com/releases/2022/02/220214121254.htm
A Step Forward in Figuring Out the Microbiome/Weight Gain Connection
Today, for your reading pleasure, a quick summary of a super interesting article I spotted in the journal, Nature Metabolism, over this past weekend. As you know from my (many) past posts on the topic of obesity, it is NOT a simple question of how much you eat = how much fat is on your body. What you eat probably matters as much as how much you eat, and more than that, there are an incredible number of co-factors that complicate the question. (After all, how many of us know people who eat like they have a bottomless pit inside instead of a stomach, yet remain skinny?) Those co-factors involve everything from stress levels to genetics to activity levels to the composition of your microbiome. As the authors of today’s paper succinctly state in the opening sentence of their paper, “Obesity and obesity-related metabolic disorders are linked to the intestinal microbiome.”[i]
This latter factor, in fact, has actually led scientists to believe that in a way, the tendency toward fatness is “catching.” That is, since people living in the same households tend to share gut bugs, those that predispose a body toward storing fat can be passed around. Interestingly, a summary article of this study that I found on the website, Science Alert, states, “Recent studies have even suggested that leanness or weight gain could be contagious, through the spread of different microbes.”[ii]
A little biology before I launch into my explanation of today’s paper. Carnitine is derived from amino acids, and is found in animal products, as well as being produced by the human body. It is used by our bodies to transport fat molecules into the mitochondria of cells. Mitochondria are where energy for the cells of the body is produced. These scientists found, in mice exposed to microbes, a gut bacterial metabolite circulating in the blood called delta-valerobetain and oddly, they did not find it in germ-free mice. They then discovered that this metabolite led to decreased levels of carnitine, which, in turn meant that the mice were unable to make efficient use of fat in their diets for energy. Thus, mice fed high fat diets similar to “western diets,” stored that extra dietary fat as adipose tissue: the mice gained weight, as well as accumulated fat in their livers.
They have not as yet completely proven this same effect in humas but the data look promising. In a study of 214 humans, the blood levels of the bacterial metabolite delta-valerobetaine and carnitine – as well as body fat – match up. That is, the average blood level of delta-valerobetaine was 40% higher in people with a BMI over 30 (defining obesity) as those with lower BMIs. The scientists hypothesize that certain kinds of gut bacteria produce more delta-valerobetaine than others, and levels of those bacteria are likely determined mainly by what is being eaten, but also, cofactors such as those mentioned above: who we live with, what medications we take, and so forth.
Delta-valerobetaine is also present in commonly eaten foods, by the way, including meat and milk, and actually has benefits as well: it seems to reduce cancer cell viability. The belief is that, from an evolutionary perspective, it makes sense that our gut bugs produce it, in order to protect us from starvation when food is scarce: it makes us efficient at storing fat on our bodies. Unfortunately, in societies like ours, where food is abundant, that efficiency has an adverse effect.
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[i] Liu, K.H., Owens, J.A., Saeedi, B. et al. Microbial metabolite delta-valerobetaine is a diet-dependent obesogen. Nat Metab 3, 1694–1705 (2021). https://doi.org/10.1038/s42255-021-00502-8
[ii] https://www.sciencealert.com/scientists-discover-how-some-gut-microbiomes-could-be-promoting-obesity
Probiotics and Mental Health: A Review of Human Studies
As regular readers of this blog know, one of my particular areas of interest is the relationship of the gut biome to mental health, including memory and cognition. Very early on, if you remember, I told you the story of losing my grandmother to dementia, which was truly hell on earth. So today, another interesting review study for you, just published. Researchers at the University of Reading, in the UK, combed through the medical literature to determine what we actually know to date about the relationship of probiotics to cognitive functioning.[i] They looked at studies done on humans that involved at least one probiotic strain and that measured at least one cognitive outcome in memory, attention or executive functioning. With these parameters, they were able to isolate 30 appropriate studies and using the data provided from them, grouped participants into 3 age categories: infants and children; young and middle aged adults; older adults.
Their results were interesting. Firstly, they followed the health of premature infants who received probiotics in the neo-natal intensive care units until they were discharged from the hospital for 18 months up to 5 years, and found that probiotics had no significant impact on their development. Two studies on full term babies also found the same: probiotics seemed to have no significant effects. They conclude though that these findings are not as significant as they might have been because no information was available in the data sets on whether or not the babies were breast fed. Breast milk contains prebiotics which help good bacteria establish in the gut, so knowing what the infants were fed is pretty crucial in knowing how probiotics might affect infants and children in the future. Also, we already know that giving antibiotics early in life often has last repercussions, but this doesn’t seem to have been taken into account when analyzing this data: that is, for infants and young children given antibiotics, do probiotics make a difference? Remember: the probiotics were only given while in the neo-natal unit – not after (as far as these researchers know). So to sum up: no real conclusions could be drawn.
The results in the studies performed on young through middle aged adults were more significant. Four studies were done on people with cirrhosis of the liver, which can lead to brain inflammation that manifests as impaired memory and intellectual functioning. 3 of the 4 studies failed to show, after 8-12 weeks of supplementation, that probiotics were in any way helpful. One though found that in those with this kind of encephalopathy that probiotic supplementation caused significant improvement in cognitive scores after only 30 days. In those with HIV, 6 months of probiotics led to significant improvements in standardized tests of memory, verbal fluency and working memory. Similar results were found in those with fibromyalgia and chronic fatigue syndrome and/or major depression disorder. Interestingly, in 1 study on those with chronic fatigue, four weeks of a probiotic along with an antibiotic (erythromycin) demonstrated improved attention, processing speed, memory, verbal fluency and cognitive flexibility.
In healthy adults though, results were mixed. That is, some studies found that probiotics did absolutely nothing for cognitive tasks while others have shown some improvements in different measurements including, interestingly, stress-related processing.
In older adults, with mild cognitive impairment, one study showed that 24 weeks of probiotics led to improvements in standardized tests and another showed significant improvements in 3 tasks related to memory and attention in those with mild cognitive issues after only 12 weeks of probiotic supplementation. Three studies done on those with confirmed Alzheimer’s Disease showed mixed results. Two found improvements in test scores after 12 weeks of probiotics, but another did not. Results have also been mixed on studies on healthy aging adults: one found significant improvement in tasks involving executive functioning but a second found no differences between test subjects and controls.
So, how to sum up the results? Overall, there is definitely enough evidence at this point to state that there is indeed a relationship between probiotic use and improved cognitive functioning in adults: “The evidence suggests there may be potential for probiotics to enhance cognitive function or attenuate cognitive decline, particularly in clinically relevant adult populations for whom cognitive dysfunction may be present.” Of course, some of the results also show though that this may be more important in those with inflammatory-type illnesses than those who are healthy. On the other hand, because these studies didn’t examine lifestyles and other co-founding factors (after all, studies can only test so much!), the results need to be understood with their limitations. For example, in the studies done on healthy adults: were the studies long enough? What probiotics were people taking and how much? What did their diets look like? Did they smoke? Were they overweight? Did they exercise? The list of things that can affect the biome is endless, really.
One doctor, who was not involved in the research, is quote as saying, “This seems to be a safe approach in middle-aged and older adults. […] I don’t think anyone is saying that probiotics will cure cognitive dysfunction in and of themselves, but they may provide a significant piece of the puzzle and may be significant, in terms of their contribution to improving these kinds of symptoms.”[ii] He goes on to state, “This gives us something that we can do to stem the rising tide of […] dementia. Hopefully, [it] can be a key target of something that we can affect, either through lifestyle changes — what we eat and what we don’t eat — or through supplementation with different prebiotics, probiotics, and synbiotics.”
And that is, I think, is the take-away point for today!
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[i] Eastwood, J, Walton, G, Van Hemert, S, Williams, C, Lamport, D. The effect of probiotics on cognitive function across the human lifespan: A systematic review, Neuroscience & Biobehavioral Reviews, Volume 128, 2021,
Pages 311-327, https://doi.org/10.1016/j.neubiorev.2021.06.032.
[ii] https://www.medicalnewstoday.com/articles/could-probiotic-supplementation-improve-cognitive-function
