Today, a little bit of good news. Two late-stage treatments for recurring Clostridioides difficile (C.diff) infections have shown very promising results.[i] The even better news is that these treatments involve using natural gut bacteria to combat the pathogen.
The first (RBX2660) is somewhat more invasive, as it is delivered by enema. The manufacturer, a unit of Ferring called Rebiotix, has not yet given much information about what bacteria they are using. At an online Digestive Disease Week meeting, the Rebiotix representative stated that their product is similar to, but better than, ordinarily fecal microbiota transplantation. The representative stated that because FMT is obtained from human donors and thus, varies from specimen to specimen, they are striving to create a pharmaceutical-grade product with consistent results.
RBX2660’s main phase III clinical trial involved 320 patients who were randomized (in a 2:1 ratio) to either single doses of the product or a saline solution. Patients who had a recurrence of C.diff within 8 weeks were considered failures, and were reassigned to either open-label use of this product or else, were recommended to a different treatment. 270 of the patients, who had no short-term recurrence, were followed for 6 months in total. 70.4% were treated successfully versus 58.1% of those who were given the placebo. This means that there is a 98.6% chance that the product is superior to the placebo.
A second open-label trial of this product was also reported and in this study, those with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) were also permitted to enroll. 125 patients (out of a hopeful 500 people over time) have thus far taken part and the efficacy appears similar to the double-blind study. 74% had no recurrence of C.diff in the following 6 months.
The second treatment, produced by Seres Therapeutics, is less invasive in that it is taken orally: it is a mixture of Firmicutes bacterial spores and is currently known as SER-109. The trials of this showed similar results to RBX2660. 182 patients started the trial: after 8 weeks, 40% of those who got the placebo had had a recurrent infection, compared to only 13% of those who received SER-109. Over 24 weeks of the trial, 47% of those who received the placebo relapsed; only 21% of those who received the real product did so.
When these products will become available to the public is not clear. Considering that upwards of 3 million people a year are infected in the USA alone (with 14,000 of those people dying)[ii], better treatments are pretty desperately needed.
I wasn’t surprised to see this research out of Harvard University: it was inevitable. Scientists at Harvard and the Joslin Diabetes Center have analyzed the genetic makeup of bacterial microbiomes and linked these DNA signatures directly to specific diseases.[i] As more and more research has been done looking at the specifics of microbiome species in diseases like Parkinson’s, autism, depression, Alzheimer’s, ALS and so many more, there was going to come a time when we had enough information to start computing this kind of relational information: microbiome pattern = X disease.
You know how I am always pointing out the insane complexity of the human biome? Well, in previous work, these Harvard researchers have found that there may be more genes in the human biome than there are stars in the observable universe. In a prior research study, for example, they found 46 million genes in just 3500 human microbiome samples. So instead of trying to settle on one type of bacteria that may be problematic, these scientists instead analyzed what they call “microbiome architecture,” meaning the structure and composition of groups of bacteria that might more easily be associated with disease.[ii]
The scientists collected microbiome data from 13 groups of patients – more than 2500 samples – and analyzed the links between these 7 illnesses and the bacterial genes found in the samples. They computed 67 million different statistical samples and found distinct clusters and were able to relate specific microbial DNA patterns to coronary artery disease (CAD), cirrhosis of the liver, inflammatory bowel disease (IBD), colon cancer and type 2 diabetes. Three of these (CAD, IBD and cirrhosis) share many of the same bacteria: those who have this pattern have a measurably increased risk of having one of these diseases: “We find coronary artery disease, inflammatory bowel diseases, and liver cirrhosis to share gene-level signatures ascribed to the Streptococcus genus.” Type 2 diabetes has a very different and distinct microbiome signature. It is the cluster of bacteria, rather than a single member, that were linked to the specific disease: “Type 2 diabetes, by comparison, has a distinct metagenomic signature not linked to any one specific species or genus”
The hope is that in the near-term future, a single stool sample will be able to predict the risk of developing one of these diseases. But considering the unbelievable complexity of the bacterial microbiome, defining such tests may take quite some time! However, as one of the researchers involved states, they’ve taken us one step closer to that dream: “We’ve identified genetic markers that we think could eventually lead to tests, or just one test, to identify associations with a number of medical conditions.”[iii]
[i] Tierney, B.T., Tan, Y., Kostic, A.D. et al. Gene-level metagenomic architectures across diseases yield high-resolution microbiome diagnostic indicators. Nat Commun 12, 2907 (2021). https://doi.org/10.1038/s41467-021-23029-8
Loads of times, I have talked about how our microbiomes are the earliest instructors for our immune systems, teaching how to distinguish good from bad, and self from non-self. Many diseases are associated with lessons poorly learned: autoimmune disease results from the immune system mistaking its own body for pathogens. And we know that colitis is the result of the immune system mistaking commensal bacteria for invaders. Equally dangerous is an under-reactive immune system that doesn’t recognize pathogens as they attack. There is a fine balance here.
How does this process happen though? How is it that our bodies learn that probiotic bacteria should not be attacked as invaders? Researchers at the University of Utah set out to find answers to these questions.[i]
The scientists focused on the thymus gland, which is in the upper chest and makes immune T cells (thus, the “T” cell designation). It also helps educate cells to recognize good/bad, self/nonself. The cells that are flawed and designed to attack self are culled while the good “not self recognizing” cells are sent off into the blood stream to do their jobs. Using mice, they looked at what happens to immune T cells that are specific to one kind of bacteria, when mice are exposed to common gut bacteria. They thought that either the bacteria would be eliminated by the T cells or that the mice would develop anti-inflammatory T cells to protect them from inflammation, as the microbe-specific T-cells attack the commensal bacteria. They were wrong.
So what did happen? “Instead of seeing the development of regulatory T cells that calm immune reactions or loss of microbe-specific T cells, we saw an expansion of them…” explains the lead researcher.[ii] That is, the thymus created more microbe-specific T cells. How did the bacteria in the gut contact the thymus to tell it to create and send more such immune cells? They actually found bacterial DNA in the thymus gland which demonstrates that the organ is communicating somehow with the gut. Further experimentation showed that bacterial DNA is carried to the thymus by other immune (dendritic) cells, whose job ordinarily is to carry suspicious material to the lymph nodes to be carried out of the body. No one knew that dendritic cells also brought material to the thymus, but in their experiments, that is exactly what the researchers found: “Here we show that intestinal colonization in early life leads to the trafficking of microbial antigens from the intestine to the thymus by intestinal dendritic cells, which then induce the expansion of microbiota-specific T cells. Once in the periphery, microbiota-specific T cells have pathogenic potential or can protect against related pathogens. In this way, the developing microbiota shapes and expands the thymic and peripheral T cell repertoire, allowing for enhanced recognition of intestinal microorganisms and pathogens.”
As we age, the thymus gland actually becomes less important, but it is particularly critical when we are young. The gland is considered to be a part of the lymph system, and also, a part of the endocrine system. In infants it’s fairly large and continues to grow until puberty, after which it begins to shrink and is replaced by fat.[iii] Thus, it kind of makes perfect sense that the dendritic cells only make the journey from the gut to the gland in very young animals. The lead authors states that, “”What we think is happening is a kind of templating on the immune system…In that timeframe, the mouse immune system is very underdeveloped and the most relevant thing for it to recognize is microbes. So, it brings gut antigens to the thymus to educate the T cells about these and related dangers.” Once the immune system is “trained,” the gland’s main job is done.
How this all relates to some people’s immune system going wild and attacking themselves or their commensal bacteria is still unknown (i.e. does this learning process go on for too long? Not long enough? etc.) – but these scientists plan on further exploring this question to get more answers. The answers may go a long way toward explaining how our immune systems recognized good from bad and why some people develop allergies and autoimmune diseases while others do not – and perhaps give clues as to how to retrain it.
[i] Daniel F. Zegarra-Ruiz, Dasom V. Kim, Kendra Norwood, Myunghoo Kim, Wan-Jung H. Wu, Fatima B. Saldana-Morales, Andrea A. Hill, Shubhabrata Majumdar, Stephanie Orozco, Rickesha Bell, June L. Round, Randy S. Longman, Takeshi Egawa, Matthew L. Bettini, Gretchen E. Diehl. Thymic development of gut-microbiota-specific T cells. Nature, 2021; DOI: 10.1038/s41586-021-03531-1
My regular readers know that there is a (rapidly) growing body of evidence linking alterations in the bacterial microbiome to neurodegenerative diseases like Parkinson’s, (PD), Alzheimer’s and ALS. (I have provided you links to just 3 of many previous posts on these topics.) No one knows as yet what particular species of bacteria may be the culprits, but Researchers at the University of Florida are attempting to figure it out.[i]
Neurodegenerative diseases are linked to the production of abnormal (“folded”) proteins in the body. When these proteins are misfolded, they can accumulate in tissues (including the brain) and these aggregates interfere with normal cell communications and functioning. What causes misfolded proteins though remains a mystery. We know that those with neurodegenerative diseases have abnormal bacterial microbiomes, including low levels of good bacteria (for example, in PD, we know there is low levels of bacteria which produce the anti-inflammatory short-chain fatty acid, butyrate). So the question becomes – are these linked? If so, what “bad” bacteria may induce the misfolding of proteins? And do any gut bacteria ameliorate this issue?
Using the tiny worm, Caenorhabditis elegans (C.elegans are commonly used in this kind of research, and are particularly useful because they are simple organisms and thus, can provide clarity on complex questions), the scientists introduced specific pathogenic species of bacteria (ones frequently found in humans) to see if they would cause protein aggregation. Short answer: yes, they did indeed. The misfolded protein aggregates could be seen throughout the worms, not just in the intestines. Not only that, but the worms also lost mobility, which is a common symptom of these diseases: “We found that colonization of the C. elegans gut with enteric bacterial pathogens disrupted proteostasis in the intestine, muscle, neurons, and the gonad, while the presence of bacteria that conditionally synthesize butyrate, a molecule previously shown to be beneficial in neurodegenerative disease models, suppressed aggregation and the associated proteotoxicity.” In other words, probiotic bacteria that produce butyrate prevented aggregates from forming. Prevotella species were among the best performers in terms of preventing aggregation, with P. corporis almost completely doing so. (I have written several times, including here, about the relationship of butyrate to PD.)
So what bacteria were the biggest culprits in causing protein misfolding? Many species were tested: “Escherichia, Klebsiella, Proteus, Citrobacter, Shigella, and Salmonella, as well as additional pathogenic bacteria that are associated with gut microbiota; these include gram-negative Pseudomonas and Acinetobacter.” The winners in terms of causing issues included Klebsiella pneumoniae and Pseudomonas aeruginosa and research has already linked these species to diseases like Parkinson’s. The scientists also noted that these two species are also known to be particularly antibiotic resistant, leading them to hypothesize that antibiotic treatments may actually encourage the growth of these pathogenic and resistant species, while decreasing the abundance of good (butyrate producing) bacteria. In fact, a recent meta-analysis found that a history of antibiotic therapy is associated with an increased risk of Parkinson’s disease.[ii]
What really rocked the scientists’ world is that increased protein aggregation was also seen in the offspring of these worms, even though the babies had not been exposed to the bacteria. The lead researcher of the study says that, “This is very interesting because it suggests that these bacteria generate some sort of a signal that can be passed along to the next generation…”[iii]
The authors state in their discussion that, “Our results demonstrate that butyrate, a common metabolite produced by commensal microbiota, can suppress aggregation and the associated toxicity when supplied exogenously or produced by intestinal bacteria.” Thus, butyrate should be considered as a therapeutic treatment for these diseases and clinical trials should be conducted.
Interesting, right? I bet we see clinical trials in the not-terribly-distant future.
[i] Walker AC, Bhargava R, Vaziriyan-Sani AS, Pourciau C, Donahue ET, et al. (2021) Colonization of the Caenorhabditis elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate. PLOS Pathogens 17(5): e1009510. https://doi.org/10.1371/journal.ppat.1009510
For today, the results of a small (but highly significant) human clinical trial using bacteriophages to treat drug-resistant bacterial infection. I came across it while reading a summary article in an online publication from Johns Hopkins University, describing the work of one of their alums who now conducts research at the University of California, San Diego.[i] I was so excited I immediately pulled up the full article that was published by the Infectious Disease Society of America.[ii]
You’ll remember from my previous posts on this subject (for 2 of many examples, look here and here), that bacteriophages are viruses that infect and kill specific bacteria. We are chock full of them: it’s a checks-and-balances system for our guts inhabitants. Back in April, 2020, I wrote about the history of phage research: they were first discovered in the early part of the 20th century and for a time, before the advent of antibiotics, were successfully used to treat numerous infections including dysentery and E.coli. Unfortunately, as is so often the case, the new-fangled antibiotics erased the medical profession’s memory of phages, and they were all but forgotten…until antibiotic resistance became a devastating problem in the world. As the Johns Hopkins article points out, “Common infections, such as pneumonia, staph, gonorrhea, and tuberculosis, are becoming resistant and very hard to treat.” The article points out that antibiotic resistance is, according to the World Health Organization, “…one of the biggest threats to global healthy, food security and development today.” The article goes on to say that according to the CDC, “…at least 2.8 million Americans become infected annually with antibiotic resistant organisms, resulting in more than 35,000 deaths…”
Here is the most depressing part of this paper: in almost 2 years, the researchers reviewed 785 requests for bacteriophage therapy (BT). The requests were matched with labs that are working on various phage therapies for specific types of infection, which narrowed the field down to 119 individuals. And then, the researchers were only permitted to use the treatment for those who were down to their last possible treatment under the “compassionate care act”: “As phage therapy remains experimental, each case required approval from the FDA under a single-use IND.” Thus, some of those 119 patients were not approved as they had infections for which there are not yet phage therapies developed – but also, many died before the phages could be administered. Because of FDA bureaucracy, there was a long period of time between the request and the actual administration of the phages (ranging from 28 days to 386 days, with a median of 170.5 days): “The process from identification of a potential patient to actual clinical phage administration under compassionate use indications is detailed in Figure 2 and, as noted earlier, involves a significant time lag.”
There are just no words…
The paper describes the responses of the first 10 patients treated (with a combination of antibiotics and BT). For the most part, patients were treated with IV BT. 7 of the 10 patients were successfully treated, 2 failed, and 1 had “uninterpretable” results. A couple of notes of interest:
Patient 2 had bacterial pneumonia. He was treated with IV BT alone for 8 weeks and was taken off antibiotics. He had no recurrence of the infection while on BT and was still in the clear 3 months later. The two failures were both cases of bacterial pneumonia, and the patients had “…chronic (>1 year) biofilm-based infections. We hypothesize that treatment failure may be related to poor biofilm penetration of the phages…” (For those not familiar with the term biofilm, it is a thin, slimy film of bacteria (and potentially other microbes) that adhere to a surface, like the plaque on teeth. Biofilms are hard to penetrate and treat, and thus, all kinds of pathogens can grow in them.)
The authors conclude by noting that many clinical trials are upcoming all over the world, and that ““…our experience with BT highlights the promise of BT for multiple clinical indications.” I have long told you that my psychic powers are telling me that phage therapy will someday soon become the new-old thing. Stay tuned on this one: I think we’ll see many more clinical trials in the near future.
[ii] Aslam S, Lampley E, Wooten D, Karris M, Benson C, Strathdee S, Schooley RT. Lessons Learned From the First 10 Consecutive Cases of Intravenous Bacteriophage Therapy to Treat Multidrug-Resistant Bacterial Infections at a Single Center in the United States. Open Forum Infect Dis. 2020 Aug 27;7(9):ofaa389. doi: 10.1093/ofid/ofaa389. PMID: 33005701; PMCID: PMC7519779.
I have talked about impaired tight junctions in the intestinal epithelial lining (i.e. leaky gut) many times on this blog. (Look here and here, for just two examples.) We know this is a factor in diseases ranging from Parkinson’s to autism to Celiac disease to inflammatory bowel diseases, and many more. Leaky gut is both the cause and the result of intestinal inflammation. Protein complexes (i.e. tight junctions (TJ)) are supposed to bind adjacent cells together to prevent toxins, microorganisms, undigested food, and so forth from getting out of the intestine into the blood stream. When inflammation is present, these tight junctions open, compromising the health of the organism and leading to further inflammation.
Currently there is no accepted treatment for leaky gut, but research has begun to focus on finding probiotic species that can reduce intestinal wall inflammation, and tighten those junctions. A study has come out of Penn State College of medicine on this very topic: “The major aim of the present study was to identify probiotic bacteria able to produce a rapid and marked enhancement of intestinal TJ barrier function that can treat intestinal inflammation by targeting the TJ barrier.”[i] These researchers screened more than 20 different bacterial species to find one that could tighten up junctions between epithelial cells, testing this in vitro. Their results: only 1 strain (LA1) of Lactobacillus acidophilus clearly did so. Says the lead researcher, “Our data indicate that LA1 is able to prevent colonic inflammation formation and promote colitis healing…”[ii]
The bacteria appear to work by activating a protein in the cellular membrane called toll-like receptors, which are a part of the immune system. This activation caused the cells to tighten their junctions. Unlike the research out of Wake Forest University which I talked about in this post, this activation required live bacterial/epithelial cell interaction: i.e. heat-killed bacteria, for example, had no effect. The researchers then tested this strain in mice, and it rapidly improved epithelial barrier integrity and protected the mice against chemically-induced colitis. The strain also promoted healing in mice with colitis: “…our studies indicate that LA1 causes a strain-specific, rapid enhancement of intestinal epithelial TJ barrier function. The LA1 enhancement and maintenance of the intestinal epithelial barrier were required for the prevention of DSS-induced colitis and for accelerated healing of the colitis.” The researchers hope to conduct human trials in the near future.
I can’t figure out if this particular strain, LA1, is available commercially. In looking for it though, I stumbled across an article from 1997 which tested this particular Lactobacillus strain, in vitro, in fighting against a variety of pathogens, including Staph, Klebsiella, Listeria, etc.: “We present evidence that the spent culture supernatant of strain LA1 (LA1-SCS) contained antibacterial components.”[iii] I’d love to figure out if it’s in any currently available probiotics! If anyone does find it commercially available, let the rest of us know!
[i] Al-Sadi, R, Nighot, P, Nighot, M, Haque, M, Rawat, M, Ma, TY. Lactobacillus acidophilus induces a strain-specific and toll-like receptor 2-dependent enhancement of intestinal epithelial tight junction barrier and protection against intestinal inflammation. The American Journal of pathology. 2021. DOI:https://doi.org/10.1016/j.ajpath.2021.02.003
[iii] Bernet-Camard MF, Liévin V, Brassart D, Neeser JR, Servin AL, Hudault S. The human Lactobacillus acidophilus strain LA1 secretes a nonbacteriocin antibacterial substance(s) active in vitro and in vivo. Appl Environ Microbiol. 1997;63(7):2747-2753. doi:10.1128/AEM.63.7.2747-2753.1997.
Some good news to start off this May: a new study was just published which shows that several supplements, including probiotics, may lessen the risk of contracting COVID-19 in women.[i] (Sorry guys!) A large population study was just published in the British Medical Journal, Prevention and Health, that found that specifically, multivitamins, omega 3s, vitamin D or probiotics. Surprisingly, some supplements that we associate with benefits in the fight against viruses, were not found to be helpful: zinc, vitamin C or garlic.
In order to conduct this study, an app was launched in the UK, the USA and Sweden in March of 2020 to capture a variety of data as the pandemic began shutting down the world. For this study, the scientists used information supplied by over 370,000 UK subscribers during the 3 month period of May, June and July, 2020. About 2/3rds of these app users were women, and (scarily) over half of the users were overweight.
The researchers found that taking probiotics was associated with the greatest reduction in risk for catching COVID – a 14% decrease. Omega 3s led to a 12% reduction, multivitamins a 13% and vitamin D a 8% reduction. Strangely, this reduction of risk was only seen in women, and that, regardless of their weights: “In women, we observed a modest but significant association between use of probiotics, omega-3 fatty acid, multivitamin or vitamin D supplements and lower risk of testing positive for SARS-CoV-2.“ No clear associations were seen in men. There are several potential explanations for this difference between the sexes. Firstly, “… biological explanations include discordant immune systems between sexes that could respond differently to supplements. Indeed, a sexual dimorphism in nutrient metabolism has been previously reported, with females having a more robust immune response than men. Moreover, females typically possess a more resilient immune system than males with higher numbers of circulating B cells when matched for age, BMI and clinical parameters, as well as a slower age-related decline in circulating T cells and B cells.”
This difference between the sexes may also have to do with male versus female behavior. The authors state, “Polling reveals that a greater percentage of females versus males are anxious for the health of themselves or their family and therefore are more precautionary, cancelling plans and staying home more often. Females who purchase vitamins may also be more health conscious than males, such as having greater use of wearing face masks and hand-washing. Indeed, in our data, we found that women tended to wear masks more often than males (44% of women report wearing a mask at least some of the time when outside, compared with 36% of men, p<0.001).”
This same pattern was seen in both the USA users (almost 46,000) and Swedish users (almost 28,000), but interestingly, in the USA probiotics were associated with an 18% reduction in risk, while in Sweden, they led to a whopping 37% reduction in risk.
There are obvious limitations to this study: for, example as the results were self-reported, there was no way to ascertain accuracy, and brands/types/doses of the supplements used is also unknown. Still, the results are significant enough that the researchers are calling for large-scale clinical trials: “Given the interest in supplements during the pandemic, large randomised controlled trials of selected supplements testing their protective effects, and also possible adverse effects, on disease severity are required before any evidence-based recommendations can be made. We eagerly await the result of ongoing trials, including of vitamin D, omega-3 fatty acids and probiotics and COVID-19 risk.”
I am eagerly awaiting those studies too.
[i] Panayiotis Louca, Benjamin Murray, Kerstin Klaser, Mark S Graham, Mohsen Mazidi, Emily R Leeming, Ellen Thompson, Ruth Bowyer, David A Drew, Long H Nguyen, Jordi Merino, Maria Gomez, Olatz Mompeo, Ricardo Costeira, Carole H Sudre, Rachel Gibson, Claire J Steves, Jonathan Wolf, Paul W Franks, Sebastien Ourselin, Andrew T Chan, Sarah E Berry, Ana M Valdes, Philip C Calder, Tim D Spector, Cristina Menni. Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 Symptom Study app). BMJ Nutrition, Prevention & Health, 2021; bmjnph-2021-000250 DOI: 10.1136/bmjnph-2021-000250
A week ago or so, I got an email from a physician who follows my blog. He reminded me of research I had seen a few years back, but at that time, had not read the paper myself. On his recommendation I took a fresh look; I was surprised that I hadn’t reported on it actually, as it’s out of the Weizmann Institute of Science in Israel, and I try my best to follow research coming out of there.[i] Certainly their results are worth reporting to you so I apologize for missing the boat on this one.
These scientists wanted to test the effects of reconstituting the microbiome after a round of antibiotics using probiotics, as so many of us do nowadays. They tested two methods of reconstitution: oral probiotics and fecal microbiota transplant (FMT). 21 volunteers were given a course of antibiotics and then randomly assigned to one of 3 groups. The first group (7 people) was given nothing to reconstitute the biome. The second group (8) was given a multi-strain oral probiotic and the third group (6) was treated with autologous (self-donated before antibiotics were administered) fecal microbiota transplants. Their results were pretty shocking. The oral probiotics effectively colonized the volunteers’ intestines which had the effect of preventing the gut biome from returning to its normal state: “…our study highlights an important previously unappreciated tradeoff in which improved probiotic gut mucosal colonization under disruptive antibiotic conditions led to a markedly delayed indigenous gut mucosal reconstitution in terms of composition, function and bacterial load, and prolonged dysbiosis that lasted at least 5 months following the cessation of probiotic exposure.” The FMT, on the other hand, had the gut return to normal within days.
Said the senior author of the study, “Contrary to the current dogma that probiotics are harmless and benefit everyone, these results reveal a new potential adverse side effect of probiotic use with antibiotics that might even bring long-term consequences…”[ii]
There are of course, many questions remaining. Firstly, are all probiotic species problematic? The paper states that there is “…antagonistic activity of some probiotics species…,” which does not mean all species, or all combination of species, would have the same effect. They tested only 1 kind of broad spectrum probiotic (with 11 strains) in only 8 people. (By the way, if the dose of the probiotic was in the paper, I couldn’t find it.) Anyway, so while their findings are significant, obviously we need way more research before drawing conclusions. They clearly state this in their discussion: “Our study features several important limitations. We tested, in mice and humans, a single combination of broad-spectrum antibiotics and one (albeit diverse) orally administered probiotics mixture. Other combinations of antibiotics, probiotics, and treatment routes and timings merit further studies.”
Still, their point is that the use of probiotics may not be “risk free,” and that other treatments like FMT may do a better job of reconstituting the biome after a round of antibiotics. (FMT is, of course, invasive so not likely to become the standard any time soon.) This is a really important area of work considering the potential detrimental health effects of antibiotic use (which I have written about frequently), so let’s hope more research is forthcoming.
[i] Suez J, Zmora N, Zilberman-Schapira G, Mor U, Dori-Bachash M, Bashiardes S, Zur M, Regev-Lehavi D, Ben-Zeev Brik R, Federici S, Horn M, Cohen Y, Moor AE, Zeevi D, Korem T, Kotler E, Harmelin A, Itzkovitz S, Maharshak N, Shibolet O, Pevsner-Fischer M, Shapiro H, Sharon I, Halpern Z, Segal E, Elinav E. Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT. Cell. 2018 Sep 6;174(6):1406-1423.e16. doi: 10.1016/j.cell.2018.08.047. PMID: 30193113.
Researchers at Ben-Gurion University in Israel are working on isolating specific molecules from kefir that can combat pathogenic bacteria and treat inflammatory bowl disease, as well as halt cytokine storms such as seen in severe cases of COVID.[i] For those unfamiliar with kefir, it is a probiotic milk product, typically fermented with lactic acid-producing bacteria and yeasts. Kefir is well-known to have health benefits for humans, and has long been thought to potentially be capable of protecting against bacterial infections. The mechanism, however, has not been fully understood. These researchers wanted to isolate the specific molecules in kefir that can combat bacterial infections and modulate inflammation.
The scientists analyzed the microbiome of kefir: this revealed a predominance (70%) of a fungus called Kluyveromyces marxianus. The kefir also contained 24% Lactobacillus species, and the rest was comprised of other bacterial types. They discovered a new fungus-secreted metabolite which they called tryptophol acetate which appears to inhibit bacterial communication and virulence by blocking something called “quorum sensing” (QS) of several kinds of bacteria. QS is a process of cell-to-cell communication which bacteria use to adjust gene expression. For years, this has been researched as a means of controlling the virulence of infection by pathogens.[ii] In this paper, the authors state that QS plays a “…major role in the synchronized production of virulence factors..,” and thus, “…significant efforts have been directed in recent years towards development of anti-bacterial therapeutic strategies based upon identification of antagonists or agonists in QS cascades…”
Thus far, these scientists have been able to demonstrate that this metabolite can reduce the virulence of the bacterium Vibrio cholerae, which causes cholera: “These results are notable, since this is the first demonstration that QS in human pathogenic bacteria can be modulated by molecules secreted by probiotic yeast.” Disrupting bacterial communication is also a promising way of treating antibiotic-resistant bacteria. They have also demonstrated these the molecules are highly anti-inflammatory, and in a mouse model, healed mice who were subjected to a cytokine storm (a barrage of inflammatory chemicals in the body) such as has proven the main cause of death in those with severe COVID. The metabolite also restored balance to the immune system.
The scientists conclude that this fungus-derived novel compound, tryptophol acetate, can interfere in pathogenic bacteria’s quorum sensing and thus, “…may play important roles in enabling microorganism co-existence in multi-population environments, such as probiotic foods and the gut microbiome. This discovery may account for anti-virulence properties of the human microbiome and could aid elucidating health benefits of probiotic products against bacterially associated diseases.”
For now, maybe we should be adding kefir regularly to our diets!
[ii] Rutherford ST, Bassler BL. Bacterial quorum sensing: its role in virulence and possibilities for its control. Cold Spring Harb Perspect Med. 2012;2(11):a012427. Published 2012 Nov 1. doi:10.1101/cshperspect.a012427
In the last week, my son fell down the steps and broke his foot and my hot water tank failed, flooding my basement and ruining the floor of my professional offices. This, as you can imagine, has put me into a pretty bad mood and since misery loves company, I figured I’d write depressing posts this week so you can all commiserate. So on Tuesday I told you all about how bad food is correlated with specific species of inflammatory bacteria and inflammatory metabolic pathways. Today I’ll tell you all about the relationship between household chemicals and adverse changes to the biomes of children.[i]
The research was conducted by scientists at Washington State University. They measured the levels of ubiquitous chemicals in the blood and urine of 69 toddlers and preschool-aged children, as well as analyzed the fungi and bacteria in their stools. The chemicals they specifically looked at were called semivolatile organic compounds (SVOCs), which includes phthalates – which are found in detergents, plastic clothing (like raincoats), shower curtains, shampoos, soaps, hair sprays. They also looked at polyfluoroalkyl substances (PFASs), which are used in stain- and water-repellent fabrics, carpets, furniture, non-stick cooking products, paints and cleaning products. In other words – these chemicals are everywhere and we are all exposed to them in the air and dust of our homes: “…SVOCs and their metabolites have been consistently measured in biological samples at concentrations spanning several orders of magnitude, and research suggests that the indoor environment is a significant source of human exposure to SVOCs.” Children are especially vulnerable to exposure because they spend much more time on the floor, crawling and playing, as well as putting things into their mouths. There is no real research on the long-term exposure to these chemicals.
Their results are not hugely surprising really. The higher the levels of chemicals in the bloodstreams of the children, the greater the differences in their microbiomes. High levels of PFASs was associated with reduced diversity and overall amount of bacteria. Increased levels of phthalates reduced the mycobiome (fungi) population. These changes were highly statistically significant and, as the lead researchers says, extremely concerning. The main bacteria and yeasts of the gut were not affected; the changes were seen more in the less abundant species: “Less abundant taxa like Thermogemmatisporales, Stigonematales, and Legionellales, which play critical and beneficial roles in the assimilation of nutrients in omnivores were strongly linked to PFASs. Thus, alterations to gut microbiome structure and function may be felt most by taxa that play more subtle roles rather than those thought to be large drivers of host health…”
Another finding: the children with the high levels of chemicals in their blood also had high levels of different kinds of bacteria that are used to clean up toxic chemicals. For example, the children had measurable levels of a bacteria used to clean dry cleaning solvents from the environment, which are not typically found in humans. The scientists believe that the presence of these kinds of bacteria is a sign that the gut biome is trying to correct itself.
Their conclusion: “Gaining a more holistic understanding of the interactions among anthropogenic chemicals, the gut microbiome, and human health is a critical step in advancing public health.” Yeah, I’d say so.
________________________ [i] Gardner, CM, Hoffman, K, Stapleton, HM, and Gunsch, CK. Exposures to Semivolatile Organic Compounds in Indoor Environments and Associations with the Gut Microbiomes of Children. Environmental Science & Technology Letters 2021 8 (1), 73-79. DOI: 10.1021/acs.estlett.0c00776