For your reading pleasure (NOT), two distressing pieces of research.
New research out of Ohio State University is truly horrifying.[i] These scientists have traced a link between low dose exposure to the heavy metal, cadmium, and the activation of the antibodies that cause allergies. The link consists of – you guessed it – gut bacteria. After exposure to cadmium, certain gut bacteria produce an enzyme that degrades vitamin D, leading to a condition that mimics vitamin D deficiency. In mice that have been sensitized to a specific antigen, exposure to ingested cadmium leads to high levels of antibodies against the allergen, as well as inflammatory immune cells that lead to respiratory symptoms. Prior epidemiology has already shown an association between vitamin D deficiency in children and an increased risk of asthma and allergy.
But wait – it gets so much worse. A Congressional report, released on September 29th, broke the news: cadmium is being found commonly in children now, and it’s from a horrific source: baby food, if you can believe it. And like that’s not bad enough, other heavy metals have also been found in baby foods. Cadmium does not degrade easily, and it has a half-life in the human body of 15 years; thus, if you are exposed to even low doses, it accumulates.
The scientists exposed mice to a very low dose of cadmium for 28 days. The mice were genetically predisposed to develop egg allergy. After cadmium exposure, the mice were exposed to egg protein and sure enough, the mice developed a heightened allergic response. They then did the same to germ-free mice: without microbiomes, the mice did not develop allergy. Thus, they were able to conclude that gut bacteria were the source of the issue. The lead researcher states that this is the main finding: …after exposure to subtoxic doses of heavy metals, the pollutants remain in soft tissue, including in the gut. And what they do is make cells more reactive. In the gut, specifically, bacteria will make certain cells produce more of the enzyme that degrades vitamin D…” (Honestly though: what on earth is a subtoxic dose of heavy metal?! They are absolutely toxic to us!)
These Ohio State researchers propose two possible ways of dealing with the situation: one is to supplement with vitamin D. However, that will only help before cadmium has a chance to cause allergy issues. The second idea is to find a way to change the offending bacterial enzymes that cause the allergic response. Seems to me that ensuring that baby food is not contaminated with heavy metals should also make that to-do list.
And just when you think that I can’t make your day worse…I’ll drop this little pearl into this post as an FYI:
A paper came out of George Washington University last week that shows that those fast food chicken nuggets, burrirtos, and more, that people love so very much have been found to have potentially harmful levels of industrial chemicals, including phthalates (which are used to make plastics soft) and other plasticizers. [ii] These chemicals are known to disrupt normal endocrine functioning.
And then we wonder why over a third of people on this earth are overweight, why allergies and asthma are at epidemic levels, and why the rates of diseases that are ultimately due to inflammation (heart disease, many cancers, many mental health issues, etc.) are increasing exponentially.
The link between inflammatory bowel diseases (IBD) and mental health issues has long been observed, and I have covered the topic before on this blog. (Look here and here, for example.) On the one hand, it makes sense: living with persistent pain, diarrhea, fatigue, etc. would affect anyone’s emotional well-being. But that is not the whole story. About 40% of those with IBD experience anxiety and depression: this is not a rare issue. As my old mentor, a well-known physician, always said, “Inflammation is inflammation,” meaning, of course, that inflammation is body-wide, and everything in the body affects everything else.
According to an article on Medical News Today, at least 30% of people with IBD experience depression, anxiety or both.[i] Says Dr. Honig, the director of research innovation at the Crohn’s and Colitis Foundation. And not surprisingly, those who experience anxiety and depression tend to have worse outcomes. It makes sense when you consider that likely, these people have the most inflammation – and too, our emotions of course, also cause systemic bodily changes.
A new study in the journal, Science, has found that (in an animal model, thus far) inflammation actually closes down the gut-brain axis by adversely affecting the communication signals between the two via the cerebrospinal fluid. This back-door passageway – between the blood and the CSF – allows smaller molecules to make their way through the brain, unimpeded by the blood-brain barrier which prevents large molecules passing into the brain through the blood stream. At the base of the brain is a membrane called the choroid plexus, which serves as a barrier between the CFS and the bloodstream. When someone is healthy this membrane connects the brain with the rest of the body for nutrient and gut metabolite exchange. However, during cases of extreme inflammation, the barrier closes down. The study’s authors believe that shutting this pathway down is a protective mechanism: the body’s attempt to protect the brain from damage. When the choroid plexus shuts down, anxiety increases, as does memory defects.
Thus, any treatment that reduces inflammation should help to restore normal communication between the gut and the brain, via the choroid plexus.
Interestingly, these same scientists previously found a barrier that prevents gut bacteria from passing into another vital organ, the liver, via the bloodstream. During periods of inflammation in the intestines, this barrier is disrupted which allows gut bacteria to make their way into the liver, further promoting systemic inflammation. People with ulcerative colitis, it has been found, have disrupted gut-vascular barriers.
A second paper, published in Pharmacological Reviews, found that even low-grade inflammation, via poor diet and poor life choices, affects brain chemicals and circuits that lead to a loss of motivation and an unwillingness to engage in formerly pleasurable activities – symptoms so often seen in those with depression.[ii] In this case, the belief is that this is an adaption on the part of the brain to conserve energy – which of course, leads to a vicious cycle. A lack of motivation leads people to continue to engage in the very behaviors (being too sedentary, making bad food choices, etc.) that lead them to have a lack of motivation in the first place.
To sum it up – yup, excessive inflammation is really bad.
Well, I just learned something new. Did you know that, “Over a century ago, Elie Metchnikoff theorized that health could be enhanced and senility delayed by manipulating the intestinal microbiome with host-friendly bacteria found in yogurt”? I had absolutely no idea that healthy aging had been linked to the microbiome and probiotics that long ago! I have mentioned before on this blog, that the first I ever heard of the concept of probiotics was decades ago, watching the old Dannon yogurt commercials showing unbelieavably spry-looking centenarians in countries like Georgia, who credited their longevity to their yogurt consumption.
Dr. Metchnikoff’s contentions have continually proven correct and today, a quick review of a new paper that I read about on Gut Microbiota for Health. Dr. Metchnikoff was not only the first to recognize the relationship of the bacterial microbiome to brain health; he also “…predicted the existence of bacterial translocation and anticipated theories linking chronic inflammation with the pathogenesis of atherosclerosis and other disorders of the aged.” But wait, there’s more! He also laid down the scientific justification for fecal microbiota transplant! What a visionary! By the way, it was obviously his work that gave Dannon the idea for that commercial: “In contemplating questions related to senility, Metchnikoff’s attention was drawn to the residents of Eastern Europe, in particular those of the Balkan States and Russia, among whom there existed an unusually large number of centenarians.” It struck him that these people lived a simple, healthy life: plenty of fresh air, exercise, peace and quiet, no alcohol…and lots and lots of fermented foods.
Multiple recent studies show that the gut microbiota in those who live to extreme old age are different from other elderly people. Starting at age 60-65, “…gut microbiota diversity generally begins to decrease, while enrichment of previously non-dominant bacteria (e.g., potentially pro-inflammatory bacterial groups) and a drop in the number of Bifidobacteria strains occur.” This is not a benign issue: these bacterial changes have been linked now to frailty and health. And surprising to exactly no one, diet is probably the most significant factor in determining the state of the microbiome as we age.
Another study in Japan done on people with an average age of 107, found that these individuals who lived to extreme old age, “…have a distinct gut microbiome that is enriched in microorganisms involved in generating unique and previously unknown bile acids—compounds in bile that aid in fat digestion—that have antimicrobial properties, in particular against Clostridioides difficile, which causes severe diarrhea and colitis.”
However, no study has yet proven definitively that gut bacteria is the direct reason for prolonging life. A recent animal study shows that giving aging mice a fecal transplant with stool from young mice reverses cognitive decline and reverses brain and body-wide inflammation. Even more remarkable, “The transplantation of the young mice’s gut microbiota also reversed age-related enlargement in microglia cell body size. These cells are the brain’s resident immune cells, which are shaped by the gut microbiome and have been involved in one of the mechanisms that underlie aging.”
While thus far, the relationship between aging and the microbiome is not absolutely proven in humans, what has become clear, is that “…taking care of your gut microbiome is important for a healthy brain and immune system from cradle to grave.” The good news is that because lifestyle and diet are by far, the most important factors, you have at least some measure of control over the aging of your biome, and thus, inflammaging. Do as Dr. M did: “The specific regimen recommended by Metchnikoff for suppressing putrefactive colonic bacteria consisted of daily doses of probiotics in the form of “soured milk (i.e., yogurt) prepared by a group of lactic bacteria, or of pure cultures of the Bulgarian bacillus (Lactobacillus bulgaricus).”
Several months ago I came across a paper[i] that really interested me on the probiotic yeast, Saccharomyces boulardii, and its effect on cognitive declines associated with gut dysbiosis, but I am so swamped with work that I never got a chance to read it. Finally, at 11:30 pm Sunday night I decided enough was enough – the time had come. (What I don’t do for all you biome fans…)
As you know from previous posts, the bacterial microbiome changes for the worse as we age, taking insult after insult: antibiotics, poor diet, stress, medications, and so forth. (Look here and here for just two posts on the topic.) You know too that dysbiosis is known to lead to an increase in the gut of pro-inflammatory toxins from bad bacteria like LPS (lipopolysaccharides); inflammatory cytokines; increased intestinal permeability (i.e. leaky gut); and intestinal disorders. To make a bad situation worse, we also know that increased LPS and inflammatory cytokines which enter circulation through the leaky gut contribute to mood disorders, neurodegenerative disorders and memory dysfunction. (You can read more about that on The Biome Buzz as well: here is just one example.)
Antibiotics and poor diet are considered the major causes of bacteria dysbiosis in the gut; we know too that probiotics like Lactobacillus and Bifidobacterium may “…improve central nervous system (CNS) functions altered by gut dysbiosis…” including showing neuroprotective effects against declines in learning and memory. Little research though has been done looking at the effects of the probiotic yeast, Saccharomyces boulardii on age-related cognitive decline. We already know that S. boulardii helps good bacteria establish themselves in the gut, has anti-inflammatory properties and also boosts IgA levels, which help keep pathogen levels down. But more than that, according to this paper, S. boulardii also improves gut barrier dysfunction and restores normal levels of short-chain fatty acids by improving the quality of the gut bacteria.
Thus, these researchers decided to explore (in an animal model for reasons you will learn shortly) the effects of S. boulardii on cognitive decline brought on by dysbiosis. They separated mice into four groups: a control, a group which received antibiotics only; a group which received antibiotics along with S. boulardii; and a group which received S. boulardii alone. The results were striking, as I’m sure you guessed. Here are a few of the results:
Their conclusion then: “S. boulardii which is an established probiotic yeast commonly prescribed against inflammatory bowel disease and antibiotic associated diarrhea is being shown for the first time to ameliorate gut dysbiosis associated cognitive decline in mice. Administration of S. Boulardii was associated with an increase in beneficial gut bacteria, restored intestinal barrier integrity, reduced inflammation and oxidative stress in both gut and brain, protecting the hippocampal cholinergic neurons and preventing gut dysbiosis associated cognitive decline.” Yes, it’s an animal study, but as we already know that antibiotics cause similar issues in humans, taking S. boulardii seems to me to be one of those things you can do for yourself that can’t hurt, could help.
[i] Roy Sarkar S, Mitra Mazumder P, Chatterjee K, Sarkar A, Adhikary M, Mukhopadhyay K, Banerjee S. Saccharomyces boulardii ameliorates gut dysbiosis associated cognitive decline. Physiol Behav. 2021 Jul 1;236:113411. doi: 10.1016/j.physbeh.2021.113411. Epub 2021 Mar 31. PMID: 33811908.
This past weekend, I finished reading a paper in the journal, Environmental Research, which was an overview of what we know about the relationship of pesticide exposure to the development of autism.[i] Interesting that it came out of China, where, “According to University of Melbourne and Zhejiang researcher Baojing Gu, China is the world’s largest consumer of agricultural chemicals, using more than 30 percent of global fertilizers and pesticides on only 9 per cent of the world’s crop land.”[ii]
Highlights of the paper for you:
The conclusion of these Chinese researchers is that the astronomical increase in the rate of autism makes it “…it is urgent to comprehensively explore the risk factors and potential mechanisms of ASD to provide a scientific basis for ASD prevention.”
[i] He X, Tu Y, Song Y, Yang G, You M. The relationship between pesticide exposure during critical neurodevelopment and autism spectrum disorder: A narrative review. Environ Res. 2021 Aug 17;203:111902. doi: 10.1016/j.envres.2021.111902. Epub ahead of print. PMID: 34416252.
Helminths, helminths and more helminths here at The Biome Buzz today.
Study #1: from the European Journal of Neurology which shows that infection with Toxoplasmosis (an infection with the parasite, Toxoplasma gondii) has a protective effect against the development of multiple sclerosis (MS). That is, those who have had T.gondii in the past have a whopping 32% less chance of ever developing MS.[i]
As you know from prior posts like this one, we already know that exposure to helminths has a massive anti-inflammatory effect and those with MS show fewer new, or the enlargement of already existing, brain lesions. T.gondii is the world’s most common parasite. It can be transmitted by eating under cooked contaminated meat, from mother to fetus, or through exposure to infected cat feces (“outdoor” cats can pick up the parasite through exposure to infected animals, etc.) and it is generally considered harmless. Most people do not develop any side effects. (That said, as with any “invading” organism, some will develop symptoms (flu-like symptoms is most common), and those with weakened immune systems may develop serious complications.)[ii]
Researchers in Italy and France worked together to evaluate the effects of the T.gondii by reviewing all the published studies through November of 2020. 7 were selected covering a total of 751 MS patients and 1282 people controls (without MS). The results clearly showed that those who had been infected with T.gondii were 32% less likely to develop MS than those with no history of infection. Yet another example of the immune modulating effects of helminths.
Study #2: it essentially yet another that shows that biome depletion is a major factor affecting biome diversity in the industrialized world. Researchers looked at stool samples from 219 volunteers in Madagascar.[iii] Their main goal was to describe the microbiomes of individuals in a developing country and to “…identity potential associations between bacterial taxa and parasites colonizing the digestive tract…” What they discovered should surprise no one: “The gut microbiome of Malagasy strongly differs from that of Westernized countries.” The main drivers of the differences were asymptomatic protozoa as well as dietary habits. Westernized countries’ microbiota can be clustered into three or so enterotypes: Bacteroides, Prevotella and Ruminococcus. In those in Madagascar, of these three, only Ruminococcus was a major presence. In their case, the other two major types were Escherichia/Shigella and Clostrium. High protein and animal fat dies have been associated with higher abundance of Bacteroides, but since few in Madagascar ate such a diet they showed low levels. Anyway, the really important take-away message from this research: the main finding “…is the robust link between the cumulative number of colonizing parasites and the increase gut microbial diversity and richness.” Their results, in many ways, parallel those found by Dr. Loke: see here if interested.
Paper #3: Finally, I’ll wrap up on just a fun and K-RAAAZZY note. I’d actually posted something about this awhile back so this is sort of an update. On September 14th, the company Charles River Analytics announced that DARPA (Defense Advanced Research Projects Agency) has given them a large grant to research novel ways of protecting soldiers from chemical and biological threats. How? By exploring how helminths can secrete chemicals that specifically target chemical and biological threats including neurotoxins and microbial pathogens. Major universities such as Baylor, George Washington, James Cook in Australia (where hookworm have been studied to treat celiac disease for many years now), the University of California at Irvine, and Washington University in St. Louis are involved in the work. The premise: “We are thinking of parasitic helminths as internal molecular foundries, producing and delivering drugs within and throughout the body continuously, or on demand, if we so choose…”[iv]
Like…whoa. Go helminths.
[iii] Mondot S, Poirier P, Abou-Bacar A, et al. Parasites and diet as main drivers of the Malagasy gut microbiome richness and function. Sci Rep. 2021;11(1):17630. Published 2021 Sep 3. doi:10.1038/s41598-021-96967-4
The last time I wrote about research on the biome and rheumatoid arthritis was last February so it’s about time for something new and exciting. A paper was just published by researchers at the University College London that shows that bacterial dysbiosis may lead to damage to the lining of the gut, which correlates to joint inflammation and the severity of arthritic disease: “…in arthritis, there is profound damage to the gut lining, which fails to work properly as a barrier, as well as an accumulation in the gut of white blood cells that cause inflammation. The authors show that, in arthritis, bacteria cross the prohibited border of the intestinal lining and that repairing gut permeability defects with specific drugs inhibits joint inflammation.”[i]
Their research shows, firstly, that mice bred to be genetically predisposed to have gut permeability (leaky gut) developed severe arthritis. In a different type of mouse, engineered to develop collagen-induced arthritis, reducing leaky gut resulted in reduced joint inflammation. They then looked at humans: those with RA have increased levels of lipopolysaccharide (LPS, which is a toxic metabolite from certain types of gut bacteria) was found in their blood, as were two other significant molecules: LPS binding protein and intestinal fatty acid binding protein. All three are markers for intestinal damage (compromised epithelial barrier integrity) and the scientists found that the blood level of these molecules correlated with disease severity: “RA patients display increased levels of serum markers of gut permeability and damage and cellular gut-homing markers, both parameters positively correlating with disease severity.”
Science has already shown that those with RA have abnormal gut bacteria. For example, high levels of Collinsella aerofaciens, bacteria which is known to increase gut permeability, has been found in the population. The mice in these experiments had markedly increased Prevotella and reduced Lactobacillus, which, interestingly, became more pronounced as the disease progressed. Also of note: some treatments currently used for RA, including NSAIDS (non-steroidal anti-inflammatory drugs), are known to increase gut permeability.
Now for some good and genuinely hopeful news:
Treating arthritic mice with a molecule called AT-1001, which is known to reduce intestinal barrier permeability, ameliorated the arthritis. I looked it up and found out that AT-1001, also known as larazotide acetate, appears to currently be in phase 3 clinical trials for celiac disease, via the company 9 Meters Biopharma, located in Raleigh, NC. “Larazotide acetate is designed to tighten the adhesions between cells lining the small intestine, called tight junctions…This ‘leaky gut’ is thought to be the gateway to many autoimmune diseases, including celiac disease. Larazotide acetate makes the tight junctions more secure, keeping gliadin from passing through.”[ii] The authors of this RA paper state that because of this effect, it may prove very useful in rheumatic diseases as well.
The conclusion: “We suggest that breakdown of gut-barrier integrity contributes to arthritis development and propose restoration of gut-barrier homeostasis as a new therapeutic approach for RA.” Perhaps help is really on the horizon.
[i] Matei, DE, et. Al. Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease. Med. 2021. 9(7):864-883. doi: 10.1016/j.medj.2021.04.013..
Exciting news! It’s been ages since I had any good research on the macrobiome to report to you, and this paper is a all kinds of awesome.
To start, the justification for this research: “The increased prevalence of auto-inflammatory conditions, such as diabetes, arthritis, multiple sclerosis, and inflammatory bowel disease (IBD), coupled with a lack of cures for these conditions underscores the need for innovative approaches to manage idiopathic disease.”[i] The authors go on to point out that the inverse relationship between hosting helminths and developing auto-inflammatory diseases is well established.
“The concept of helminth-therapy to treat idiopathic auto-inflammatory disease is intriguing because it seeks to harness eons of host–parasite co-evolution—that is, the hosts’ natural immune response to infection with a parasitic helminth has the bystander effect of affecting the course of concomitant disease. While seemingly counterintuitive, Desowitz (1980) elegantly presented the concept of the “Harmonious Parasite” and numerous studies with helminth–rodent model systems have shown that deliberate infection with parasitic helminths can reduce inflammation.”
Using a mouse model (for reasons you will understand in a moment), Canadian researchers tested the effects of the helminth Hymenolepis diminuta cysticercoid (HDC) on colitis. HDC is a kind of tapeworm native to rats: it’s a mutualist, benefiting its rat host by improving immune status, while the rat provides it comfortable living conditions. In non-native hosts, it lives only a week or two. The scientists state that they zeroed in on this organism since it, “…is an intriguing candidate as a ‘therapeutic helminth. Infection is by ingestion and the worm does not migrate through the host; rather, it seeks to establish in the small intestine. Bearing no teeth or hooks, it does no obvious abrasive damage to the host. It is not auto-infective and its life-cycle requires an invertebrate host, so there is no direct person-to-person spread. Natural infection is rare in humans, typically restricted to malnourished or immunocompromised individuals and can treated with antihelminthics.”
The researchers had two questions they wished to answer with this study. Firstly, what is the window of opportunity to treat colitis with helminths? Secondly, they wished to see if already existing intestinal inflammation inhibits the host’s ability to eradicate the helminths.
The results: mice that received the HDC prior to the researchers chemically inducing colitis in the animals showed markedly less disease manifestation. For example, the HDC-mice had a much smaller drop in body weight, less shortening of the colon, and the average disease score was reduced by 50%. The HDC-mice, to no one’s surprise, had increased levels of regulatory cytokine production, modulating the inflammatory response, as opposed to the non-HDC-mice, which had reduced levels of regulatory cytokines, including IL-10.
The scientists were also able to establish that adding HDC to a treatment regimen for mice with induced colitis “hastened recovery.” They point out that there is natural variability in mice’ ability to recover from chemically induced IBD. The non-HDC-mice, at 11 days after induction, had recovered their body weight, but at 14 days still showed mild signs of disease. However, the HDC-mice not only recovered their body weight: they also were thriving and were “…not different from control naïve mice at 14 days…” post induction of colitis. What’s really amazing is that even giving mice HDC 3 days after having colitis chemically induced, led them to be indistinguishable from non-treated controls 14 days later. That is, giving HDC both before and shortly after colitis has been induced led mice return to perfect health in 2 weeks.
The answer to the second question: having the inflammatory bowel disease did not change the mice’ ability to expel the HDC.
So to sum up their findings:
A poorly designed study on humans with IBD done years ago was abandoned half way through because there was no statistically significant differences between the control group and the treated group, who were being given the helminth TSO (Trichuris suis – a whipworm native to pigs)…even though earlier studies had shown excellent results. Upon the failure of that trial, efforts to research helminthic therapy for treating humans was mostly abandoned. The authors of this paper point out that the failure of one type of helminth in one study was not enough to give up research. Thus, they conclude that, “…we suggest it is premature to abandon the potential of helminth therapy and that in-depth analyses of helminth infection in murine models of disease will aid in unraveling the complexity of immunoregulation, with the potential to identify targets for therapeutic intervention in auto-inflammatory disease.”
Let’s hope that their amazing results spur the scientific community to revisit the idea of helminth therapy, as the current array of treatments is completely inadequate, fraught with side effects (see here and here for more on this) and all too often, ineffective.
[i] Li, S.; Rajeev, S.;Wang, A.;McKay, D.M. Infection with Hymenolepis diminuta Blocks Colitis and Hastens Recovery While Colitis Has Minimal Impact on Expulsion of
the Cestode from the Mouse Host. Pathogens 2021, 10, 994. https://doi.org/10.3390/pathogens10080994.