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.
Firstly, let me apologize for not forewarning you that I wouldn’t be posting last week. I did this absolutely K-RAAAAZY thing last week – I took a vacation. I am not sure that in the almost 5 year history of this blog, such insanity has ever happened.
As my regular readers know, while all biome research interests me, there are several subjects that I particularly obsess over: autism, Parkinson’s, Alzheimer’s, phages, the obesity epidemic, to name just a few. Today’s research is about that latter one: obesity. I have written many, many times before about the staggering numbers involved: see here and here, as just two of (at the moment) 71 examples. Remember that obesity is defined as a BMI of 30 and over, and according to the CDC, in the USA alone, 42.2% of the population was obese between 2017 and 2018. Obesity related conditions like heart disease, stroke, type 2 diabetes, some kinds of cancer are among the leading causes of death in the country.[i] The numbers, worldwide, are equally terrifying: according to the World Health Organization in 2016, 2 billion adults are overweight, with 650 million being classified as clinically obese. That is about 39% of the world’s adult population.[ii]
Today’s research is not directly involved with the inhabitants of the gut, but it involves the digestive system, and is just so interesting that I feel compelled to tell you about it. It was published in the eminent journal, Nature, and really blew me away. Remember my posts about the adverse biome-effects of processed sugars – mainly high fructose corn syrup? (Here are two examples of many: here and here.) The exact causes of the growing obesity epidemic are not as yet known, but more and more research suggests that increased consumption of these is at least one of the major causes: “Fructose consumption is linked to the rising incidence of obesity and cancer, which are two of the leading causes of morbidity and mortality globally.”[iii]
It turns out that there is evidence that the small intestine acts as a gatekeeper, preventing the excess accumulation of fat in the liver (fatty liver) that can be causes by excess consumption of fructose. Moderate amounts like you’d find in fruit, are broken down by the intestinal cells. However, excess amounts such as you’d find in sugar-laden sodas, overwhelm the intestine’s ability to absorb the fructose, which then leaks into the bloodstream (making its way to the liver, still intact) or it makes its way down to the colon.
Fructose in the colon is broken down by our gut bacteria, which produce molecules that can fuel lipid synthesis (creation of fat) in the liver. To boot, fructose in the intestines compromises the epithelial lining, leading to leaky gut, “…a condition in which loose connections between gut cells enable ingested nutrients, and toxins from bacteria in the colon, to escape to the liver, where they activate inflammatory signals from immune cells…”[iv] Thus, excess fructose is known to harm the liver both directly and indirectly through changes in the intestines.
But wait – there’s more. It gets way worse. In the research I’m reporting to you today, scientists have found that excess fructose has a previously unknown effect on the actual structure of the intestine. Knowing that high-fructose corn syrup (HFCS) “…promotes metabolic pathways that support the formation of colon tumours…,” they wondered what it might do to non-cancer cells. What they found is astounding: mice fed HFCS had longer villi (the microscopic, finger-like projections of the small intestine, which absorb nutrients) and thus, the small intestines of the mice absorbed more dietary nutrients from food compared to controls. What does that mean? It means that they got much, much fatter. And if the scientists added large amounts of fat to the HFCS diet, the mice gained even more weight. That is, increased fructose consumption also led to increased fat consumption.
I’m going to go into the explanation of why this happens but yes, the scientists did figure it out. Very simply: fructose prevented the normal death of old cells in the villi. And, by the way, they also discovered that the same mechanism that makes the villi longer also causes increased tumor size. Thus, they conclude that, “The ability of fructose to promote cell survival through an allosteric metabolite thus provides additional insights into the excess adiposity generated by a Western diet, and a compelling explanation for the promotion of tumour growth by high-fructose corn syrup.”
You all know how much I love cool science by now – and how much hope I have for using bacteriophages to positively alter the bacterial microbiome. I’m excited then to report to you super cool science leading to major progress on the phage front.
For those new to the term bacteriophages: these are viruses that kill bacteria. They are specific to one kind of bacteria, like a key fitting into a lock, and for a hundred years have been recognized as a potential way to treat bacterial infections. Unfortunately, once antibiotics were developed, interest in phages waned along with research into them. I wrote a post on the history of phage therapy last year– see here. Anyway, with the ever increasing issue of antibiotic resistance around the world, phage therapy has come back into fashion and I see an increasing number of articles appearing in the last couple of years.
Today’s research is out of the UK: scientists at the Institute of Food Research in the town of Colney – near Norwich – have discovered a completely new bacteriophage which looks very promising for treating Clostridium difficile, which is a horrific bacterial infection of the gut that is very hard to treat, and recurs with great frequency. C.diff causes potentially deadly diarrhea: according to the CDC, almost half a million people in America alone are infected each year, and approximately 29,000 of those people die within a month of contracting the infection.[i] It is commonly contracted during a course of antibiotics and, ironically, is treated with more antibiotics, leading to greater and greater antibiotic resistance: “Clostridium difficile infection is increasing in both frequency and severity, with the emergence of new highly virulent strains highlighting the need for more rapid and effective methods of control.”[ii]
These scientists 27 different strains of C.diff looking for phages that are the natural enemy of the bacteria, and found one they named ΦCD27 (phiCD27) – a completely new, never-before-isolated – kind of bacteriophage. It has been named after the town in which it was discovered: Colneyvirus. Since it was first isolated, 4 other species of Colneyvirus have been identified, and now is considered an official genus of virus unto itself.
News Medical Net has an interesting summary of the research in which they explain how phages work: they “…exist and reproduce by injecting their genetic material into bacteria, and using the host’s own machinery to construct new viruses inside the cell. They then release enzymes called endolysins that destroy the bacterial cell wall, releasing the new viruses.”[iii] In this case, the researchers found the gene for ΦCD27’s endolysin, and went on to produce the enzyme. They found it was active against 30 different strains of C.diff, including the most virulent strains, while not bothering other species of bacteria in the slightest.
Obviously, more work needs to be done first, but this is certainly one of the most promising bits of research I’ve seen in a long time on this front: “In contrast to conventional antibiotic treatments, treatment with the CD27L C. difficile endolysin, with its exquisite specificity, offers a novel approach to the destruction of the pathogen with the maintenance of an effective GI tract microbiota.”
[ii] Mayer, M. J., et al. (2021) Molecular Characterization of a Clostridium difficile Bacteriophage and Its Cloned Biologically Active Endolysin. Journal of Bacteriology. doi.org/10.1128/JB.00686-08.
As my regular readers know, I love to report the results of double-blinded, randomized, placebo controlled trials in human to you: they represent bringing us a major step forward toward better treatments for, well, everything. Today’s paper is on a subject near and dear to my heart: autism: my son Alex was diagnosed 25 years ago, and for a quarter of a century I have stayed abreast of biomedical research in the field. This one is super interesting.
We’ve known for many years now that those on the autism spectrum have alterations in their microbiomes, and those alterations are now accepted to be a likely cause – or at least one of the causes – of the developmental disorder. Thus, probiotics have been studied in the population, as has fecal microbiota transplant, with some good degree of success. (There are many posts on The Biome Buzz: for just two examples, see here and here.). “Gut microbiome composition and inflammation have been reported to be involved in the pathogenesis of ASD through the gut–brain axis. Recent evidence demonstrates that alterations in the gut microbiota of ASD individuals changes both gastrointestinal (GI) physiology and behaviors via the gut–microbiome–brain axis. Probiotic varieties used in both animal studies and clinical trials have demonstrated efficacy in improving ASD core symptoms.”[i]
Another treatment that has proven somewhat useful in ameliorating some of the social difficulties some on the spectrum have is the hormone oxytocin, which plays a huge role in bonding mother to baby, as well as being associated with empathy, trust, relationship-building, and more. It is produced in the hypothalamus, and as this paper says, it is “… well known for its ability to modulate emotional and social communication, bonding, and reward-related behaviors.” It is believed that oxytocin is producible by probiotic bacteria, such as Lactobacillus reuteri, which I have actually mentioned in relationship to favorable outcomes in autism in previous posts. So, while both have shown some efficacy, no one has ever tested them both being used together.
This was a stage two pilot trial of 35 individuals with ASD, aged 2-20 years. They were randomly assigned to receive daily 60 billion units (so a sizeable dose) of Lactobacillus plantarum PS128 probiotic or a placebo for 28 weeks. Starting on week 16, both groups received oxytocin. Outcomes were measured by multiple assessments: primary outcomes were socio-behavioral severity and aberrant behaviors. Secondary outcomes also included fecal microbiome analysis, blood levels of inflammatory markers and oxytocin levels. The two groups were compared at baseline, 16 weeks and 28 weeks.
The results were striking: in those receiving both treatments, statistically significant improvements were seen in socio-behavioral severity and aberrant behaviors in comparison to those only receiving the probiotic. Significant improvement was also seen in the gut microbiome and interestingly, they were even able to isolate the bacterial species that seemed most correlated with these improvements: “The favorable social cognition response of the combination regimen is highly correlated with the abundance of the Eubacterium hallii group.”
Of course, this was a small trial of only 35 individuals – a much larger trial is warranted, certainly. After all, the authors conclude that the combination of this probiotic and intranasal oxytocin “…in participants with ASD may reduce ASD core socio-behavioral symptoms and clinical global functioning. Statistically significant improvements in ASD-related outcomes over the treatment course via combined therapy are attributed to the proposed synergistic interactions between the two treatments, which are mediated via the gut–brain axis. Furthermore, participants receiving combined therapy showed significant improvements in gut.” Seeing as there have been precious few advances in autism treatment in the 25 years+ since Alex was diagnosed, I am always glad to see something new, different, low risk and promising.
[i] Kong XJ, Liu J, Liu K, Koh M, Sherman H, Liu S, Tian R, Sukijthamapan P, Wang J, Fong M, Xu L, Clairmont C, Jeong MS, Li A, Lopes M, Hagan V, Dutton T, Chan SP, Lee H, Kendall A, Kwong K, Song Y. Probiotic and Oxytocin Combination Therapy in Patients with Autism Spectrum Disorder: A Randomized, Double-Blinded, Placebo-Controlled Pilot Trial. Nutrients. 2021 May 5;13(5):1552. doi: 10.3390/nu13051552. PMID: 34062986; PMCID: PMC8147925.