The Deworming Question: A Good Idea? Pointless? Detrimental? The Evidence Mounts…

Last month, a meta-analysis paper came out searching the medical literature through the year 2018, looking for evidence of the benefits promised by the worldwide efforts at deworming school children, recommended by all global advocacy organizations including WHO.  The authors, from the Department of Public Health and Policy at the University of Liverpool, UK,  state their objective is, “To summarize the effects of public health programmes to regularly treat all children with deworming drugs on child growth, haemoglobin, cognition, school attendance, school performance, physical fitness, and mortality.”[i]  Their conclusion is not what you  might expect…at all:

“Public health programmes to regularly treat all children with deworming drugs do not appear to improve height, haemoglobin, cognition, school performance, or mortality… Studies conducted in two settings over 20 years ago showed large effects on weight gain, but this is not a finding in more recent, larger studies. We would caution against selecting only the evidence from these older studies as a rationale for contemporary mass treatment programmes as this ignores the recent studies that have not shown benefit.”

(This, by the way, was an update from their 2015 paper…which concluded the same.  There is no health or cognitive benefit to deworming programs.  They did not, of course, look at whether there are any detrimental health effects of such programs, as that was beyond the scope of the paper.)

I’ve been considering sharing that paper for the last few weeks and after reading another really interesting paper on the effects of deworming today, I decided that the time has come.

The paper I finished reading this morning dates back to this past February, and these scientists – most of whom are at the National Institute of Health – looked at the effects of deworming on the bacterial microbiome.[ii]  There were a few really interesting points that I want to convey.

In this study the researchers collected stool from 5 villages in Kenya prior to administering anti-helminth drugs, then again 3 weeks after the drugs were administered and then 3 months after the drugs were administered.  They considered the presence of only 2 kinds of helminths:  Ascaris lumbricoides and Necator americanus (hookworm). They found that neither “…significantly altered the overall diversity of the microbiota.”  (They point out that it is likely that all participants at some point were colonized by helminths, even if not at the exact time of testing.  This likely plays a role in the fact that significant variability was not found among the participants.  In other papers, like the one I discuss in this post, the biomes of native populations with helminths was compared to people in industrialized countries and the differences in microbiomes was vast.)

Following treatment with the anti-helminth drug, “…there were significant increases in the proportion of the microbiota made up by Clostridiales and reductions in the proportion made up by Enterobacteriales…” and even significant changes in those individuals who did not have helminths on board at the start of the trial.  (This is how mass deworming programs work:  everyone is treated, without first testing to see who is colonized.)  However, they do conclude that clearing helminths (in this case, the N.americanus more than the A.lumbroicodies) from the human body does lead to alterations in the microbiome…and that the health effects of this must be considered going forward.

As far as we know as of this moment, it appears that changes to the bacterial microbiome depend on the species of helminth.  (Since most studies are done in native populations where helminths are still endemic, the exact size of the colony inhabiting the individuals is unknown.  Do larger numbers of helminths induce more changes?  We don’t yet know.)  The authors acknowledge this:  “…there is still no clear consensus of the impact of STH [soil transmitted helminths] on microbiota diversity and composition.  This could be in part because of differences in the STH species, prevalence, and intensity of infection in these different locations…”

In a section the authors entitle “Importance,” they state:  “Intestinal worms may have an important impact on the composition of the gut microbiome.  Without a complete understanding of the impact of deworming programs on the microbiome, it is impossible to accurately calculate the cost-effectiveness of such public health interventions and to guard against any possible deleterious side effects.”  They agree that “…the presence of  helminth infections has been linked with increases in microbial diversity.”  In their discussion, they also mention a study in which pregnant women in Africa with helminth colonies were given anti-helminth drugs and their children showed an increase in allergy risk. They conclude that this deleterious effect was the result of the drug use during pregnancy but neglect to mention that those authors also state, “The detrimental effects of treatment suggest that exposure to maternal worm infections in utero may protect against eczema and wheeze in infancy.”[iii]

These scientists conclude their paper stating, “…the next step will be to understand the impact of the identified differences on human health…” of mass deworming.  Prior to posting this, I have 58 articles on this blog regarding the established health benefits of the human macrobiome. Anyone want to put money on what those future studies will find?

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[i] Taylor-Robinson, DC, Maayan, N, Donegan, S, Chaplin, M, Garner, P.  Public health deworming programmes for soil-transmitted helminths in children living in endemic areas.  Cochrane Database of Systemic Reviews. 2019.  doi: 10.1002/14651858.CD000371

[ii] Easton, AV, et. al. The impact of antihelminthic treatment on human gut microbiota based on cross-sectional and pre- and postworming comparisons in Western Kenya. mBio: American Society for Microbiology. 2019;10(2).   DOI: 10.1128/mBio.00519-19

[iii] Mpairwe H, Webb EL, Muhangi L, Ndibazza J, Akishule D, Nampijja M,Ngom-Wegi S, Tumusime J, Jones FM, Fitzsimmons C, Dunne DW,Muwanga M, Rodrigues LC, Elliott AM. 2011. Anthelminthic treatmentduring pregnancy is associated with increased risk of infantile eczema:randomised-controlled trial results. Pediatr Allergy Immunol 22:305–312.https://doi.org/10.1111/j.1399-3038.2010.01122.x

Probiotics for Breast Cancer? (or…Talking About Needing More Research…)

I was surprised, but not surprised, by an article I read last night on the potential use of probiotics in treating breast cancer (BC).[i]  As several friends have already battled BC, this is a topic of particular interest to me.  I knew there was a known inflammatory component to some forms, and a microbiome connection, and have actually written before about this  on this blog.

First, some statistics, for those of you who don’t know just how prevalent BC is:  breast cancer “…is the most frequent cancer in women, the second most common cancer worldwide, and the second primary cause of cancer-related deaths.”  So yes, I think research into anything that might help is more than merited!

A bit of education, in case you are unfamiliar with breast cancer:  the most common kind is hormone (estrogen and/or progesterone) receptor positive. Excess estrogen is a known risk factor for the development of BC:  “The increase in the amount of free estrogens for reabsorption contributes to the risk of development of hormone-driven malignancies such as BC.”  Gut bacteria play a major role in modulating this reabsorption and the circulation of estrogens.

As I mentioned in my last post on this subject, antibiotics and dysbiosis appear to be a major risk factor for the development of BC, and indeed, factors which affect the gut bacteria, such as diet, also affect BC development.  For example, “Strict vegetarians have increased fecal excretion of conjugated estrogens compared with non-vegetarians, leading to decreased plasma estrogen concentrations and protect against subsequent BC risk.”  High cholesterol levels are another known risk for the development of BC, so this may be the connection.  A vegan diet is typically much higher in fiber than other diets, and certainly affects the composition of the gut flora.  Alcohol consumption, which is another established risk factor, also alters gut bacterial composition in animal models and, at the very least, in humans who abuse alcohol (and/or have alcohol cirrhosis of the liver).   In humans, “…alcohol intake after BC diagnosis is associated with both increased risk of recurrence and deaths. There doesn’t seem to be a lot of research on the microbiome and occasional use of alcohol.

Basically all studies on the potential benefits of probiotics to treat this awful disease have been done in animals, and the results have been really very promising.  Here are 2 examples:

  1. Lactobacillus acidophilus was given to rodents starting 2 weeks before they had BC tumors transplanted into them, and the probiotic was continued for 30 days afterwards.  “The results showed a significant increase in the survival time among the L. acidophilus group compared to that of the controls, demonstrating that this treatment can promote the immune responses…Additional animal studies confirmed that oral administration of acidophilus displays anticancer activity to mice bearing breast tumors.”
  2. Another, particularly virulent form of breast cancer – not associated with hormones – is called triple negative. Mice with triple negative tumors were fed kefir, which led to greatly reduced tumor size.
  3. Other studies which have shown positive effect were done with Lactobacillus casei, yogurt and Lactobacillus plantarium.

Thus far, there has been very little clinical work done with humans.  One Japanese study asked 306 women with BC, and 662 women without, about their diets, lifestyles and other risk factors and found that regular and long-term consumption of L. casei Shirota (found in Yakult yogurt, and which I have written about before – for example,  here ) was “…significantly associated with decreased BC risk in Japanese women.”

The conclusion of the article:  the results of what in vivo and in vitro studies that we have is that, “…probiotics may have an anticancer systemic property, enhancing the systemic immune system, useful for interventions to prevent and control progression of BC.”  Sounds like it might be yet another, “can’t hurt and could help, so why not do it” scenario.

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[i] Mendoza, L. Potential effect of probiotics in the treatment of breast cancer.  Oncology Review. 2019;13(422).  doi: 10.4081/oncol.2019.422

Pancreatic Cancer and the Mycobiome

A brief post today as I find myself way behind on, well, everything!

I found this really interesting and I don’t often get to write about the mycobiome. New research has just come out which shows that a particular form of pancreatic cancer – which, as you may know, is one of the deadliest  that exist – may be the result of fungi moving into the pancreas from the gut.[i]  Scientists have k nown for some time that bacteria, viruses and parasites may play a role, but until now, fungi/yeasts were not suspect.

Pancreatic ductal adenocarcinoma is cancer of the tube of the pancreas, which allows its digestive juices to flow into the small intestine.  This appears to be the exchange site for the movement of fungi into the pancreas.

The scientists treated mice that already had pancreatic tumors with antifungals, and the tumor shrank 20-40% in 30 weeks.  They then looked at the species of fungi in the intestines of mice with and without pancreatic cancer in order to figure out which kind were moving into the pancreas of those affected.  They found that certain types of fungi moved at a much higher rate, including one called Malassezia, which is usually found on the skin and scalp and is responsible for dandruff and some kinds of eczema.  However, this species has also been linked to colon and skin cancers.  Incredibly, when Malassezia was allowed to grow unchecked, pancreatic cancers grew 20% faster in mice.  Candida, Saccharomyces, Aspergillus did not have this same effect.[ii]

They believe the mechanism of action is that the fungi stimulate the immune system in such a way as to lead to the growth of abnormal tissue.

As you know, abnormalities of the mycobiome are associated with other illnesses including autism and inflammatory bowel disease, and even perpetuating C.difficile infections.  You have to believe that with the explosion of research into the human biome, this list is going to get longer and longer.

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[i] https://www.webmd.com/cancer/pancreatic-cancer/news/20191004/fungal-invasion-may-drive-some-pancreatic-cancers#2

[ii] Aykut, B, et. al. The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL.  Nature. 2019;574:264-267.

Glyphosate and Human Health: Is the Bacterial Microbiome the Connection?

In various posts, I’ve explored different potential mechanisms that may play a part in the epidemic of biome alterations we have experienced in the industrialized world, including diet, formula feeding, chronic stress, and so forth.  Another potential mechanism, environmental toxins, is another area of interest and something I have been keeping an eye on.

Over the weekend, I got an article[i] that looks at glyphosate (gly) as one possible culprit. This is, of course, a hugely controversial subject but as always, I work hard to maintain scientific objectivity.  It’s all too easy to get caught up in the hype.  But you know me – I want the facts.

I think it would be best to report on this article from conclusion and go backwards from there.  So the conclusion first:  we have no definitive proof at this time that glyphosate is harmful to human health.  There is a paucity of studies, and those that have been done have been useless, in some ways: for example, the amounts used on animals have been far beyond what humans might regularly be exposed to, invalidating their usefulness in truly determining gly’s toxicity to the ordinary person:  “…relating to most studies, the main limitation is the use of high doses of gly…which is difficult to obtain in mammalian tissues, calling into question clinical relevance.”  What we have at this time seems to be a growing body of evidence that there are indirect adverse effects via the chemical’s ability to alter the human bacterial microbiome:  “…the lack of information, contradictory data and independency of studies have generated controversy concerning the safety of Gly for humans….We have assessed the mechanism by which a Gly induced intestinal microbiome disturbance could be involved in emotional disorders and neurological diseases such as ASD [autism spectrum disorders].  However, more research is certainly required to expound the role of Gly on the gut’s bacterial community…”

It is important for you to understand that gly works on plants by disrupting a particular enzyme of the intestine that blocks the formation of certain amino acids.  However, this enzyme is absent in humans and we obtain these amino acids from our diet.  That said, many of the yeast and bacteria, such as exist in the human microbiome, do express this enzyme and thus, are affected directly by gly.

Here are a few of the points they made that really struck me as interesting:

  1. Glyphosate is used in the commercial product Roundup, and studies have shown that it can permeate the water supply and cause changes in animal’s (including mammalian) behavior.
  2. It is found in our food supply: “Traces of the herbicide have recently been found in formula milk, honey, cereal grains or soy…”  It’s also been found in beer and wine.
  3. Toxicity has been demonstrated in other mammals. For example, gly led to infertility and birth deformities in pigs.
  4. There is some correlative data associating the increased use of gly with human diseases including cancer, ADHD, autism, depression, anxiety, Alzheimer’s and Parkinson’s diseases.
  5. Gly is known to damage DNA in rodents as well as in vitro human cell lines.
  6. In mice, chronic ingestion of gly leads to a decrease in the overall number of intestinal bacteria; maternal exposure leads to biome alteration in the pups.
  7. I didn’t have time to get this article to find out who these crazy people are LOL: “…A striking case of voluntary ingestion of gly was reported and indicated a predisposition to the development of Clostridium tertium bacteraemia in humans together with an effect on intestinal mucosa.” People ingested this stuff voluntarily?!
  8. “Few studies have been performed on gly…on microbiota in mammals, but so far, all findings indicate an overgrowth of gly resistant microorganism such as Clostridum spp [species] and possibly several Salmonella Strains…”
  9. “…Gly severely depletes manganese (Mn) levels in plants. Glyphosate’s disruption of the Mn homeostasis selectively affects Lactobacillus and can lead to several disorders such as PD.”
  10. “Evidence of correlations between neurodevelopmental disorders and Gly perinatal exposure were reported in pregnant rodents treated with Gly….” Interestingly, these scientists saw an increase in the release of the neurotransmitter, glutamate, which is similar to what is seen in those with autism.

So to summarize:

  1. Animal studies such as I mention above, and others (including, for example, one which showed that oral exposure to Gly, “…reduces the abundance of Firmicutes, Corynebacerium, Baceroidetes and Lactobacillus…” while also altering mouse behavior) suggest that gly can be detrimental to humans via altering the composition of the bacterial microbiome.
  2. Considering the number of diseases now known to be associated with the depleted biome, and considering how ubiquitous in our diets are sources of exposure (including baby formula which is obviously used very early in life when the biome is developing), this is potentially a huge issue that needs to be actively and diligently researched.
  3. Gly, in the form of Roundup, is “…the most utilized herbicide in agriculture.”
  4. Gly adversely affects probiotic species of bacteria but pathogenic ones, like certain species of Clostridium and Salmonella, are resistant, potentially leading to dysbiosis.
  5. Many more studies must be conducted before conclusions can be drawn.

I’ll continue to monitor this research, of course!

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[i] Rueda-Ruzafa, L, Cruz, F, Roman, P, Cardona, D. Gut microbiota and neurological effects of glyphosate. Neurotoxicity. 2019;75:1-8.   doi: 10.1016/j.neuro.2019.08.006

Fecal Microbiota Transplant: the Answer for Alzheimer’s Disease?

Ok, yeah…more on fecal microbiota transplants (FMT).  This is my obsession for the week. But after reading my last post…can you blame me?!

In that post, in case you missed it, I talked about a new article reviewing the potential of FMT to treat a huge variety of illnesses, and included in that list was Alzheimer’s disease (AD).   Imagine my joy, then, when I spotted a brand new bit of research looking more in depth at FMT’s effects on AD.  Yes, this is a mouse model but still – it’s very promising.

This study[i], out of South Korea, used mice that have been genetically created to develop the same type of neurological issues (amyloid plaques, neurofibrillary tangles, and memory deficits) as those with AD. They refer to this group of mice as “ADLP mice.”  As controls, they used healthy wild-type (WT) mice, with normal bacterial microbiomes. In comparing the two, they found that early in life (by 2 months), the microbiome of the ADLP mice begins to shift from the norm.  The gut bacteria of ADLP mice did not so much differ from the WT mice in terms of specific types of bacteria, but rather, total composition of the flora, on a community-wide level.  However, these differences, from a functional point of view, are extremely significant:  “These gut-associated changes may mutually contribute to the increased gut barrier permeability and chronic inflammation seen in the intestine of ADLP mice; these problems are considered potential risk factors of AD.”

Which brings me to the next major difference between the two kinds of mice. ADLP mice display a “…loss of epithelial barrier integrity [leaky gut] and chronic intestinal and systemic inflammation.”  By looking at the blood of the ADLP mice, they determined that indeed, metabolites (including highly toxic lipopolysaccharides (LPS)) produced by gut bacteria were making their way into the  circulatory systems of the animals, causing a body-wide inflammatory response. High gut permeability “…can deteriorate the blood-brain barrier, and CNS [central nervous system] is easily exposed to the contents of the altered gut microbiota.  LPS has been found in the brain and participates in AD pathology.”

The crux of the experiments: the scientists orally gave the ADLP mice fresh feces from the WT mice nearly daily for 16 weeks.  Within 2 months, the gut bacteria of the mice was significantly altered, and after 4 months, the microbiota of the two groups of mice were indistinguishable.  They then tested the mice’ memory, both long and short term, and found significant improvement in cognitive function.  They also found that the amyloid plaques were “significantly decreased” as were the other neurological alterations in the ADLP mice.

Another interesting finding:  the researchers discovered altered gene expression in in tissue from the colons of the ADLP mice, which was normalized by FMT.  The genes that were altered “…are associated with ageing-related tissue degeneration and deterioration of mucosal immunity…Specifically, the genes unregulated in ADLP mice contribute to decreased cell proliferation, cellular senescence and cell growth arrest, which are well-characterized ageing-related phenotypes.  The downregulation of genes related to mitochondrial and ribosomal activities in ADLP mice…are considered key features of ageing and neurodegenerative diseases.”

The authors state, “These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLP mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.”

In doing my usual snooping around, I found a 2nd article – also just published – looking at the effects of FMT on a different mouse model of AD.  And guess what?  “We also found that FMT treatment reversed the changes of gut microbiota and SCFAs. Thus, FMT may be a potential therapeutic strategy for AD.”[ii]

So the question I asked myself, in reading, and rereading the paper – and writing this blog post – is:  AD is currently an incurable terminal illness that brings heartbreak to the affected person and their families.  (You can read about my own devastating personal experiences with it here.) Where are the clinical trials in humans?!  And good news, for once, everyone:  the University of Wisconsin is conducting one right now, as I type this.  The study concludes in May 2022.  If this blog still exists in 3 or so years, I’ll let you know the results!

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[i] Kim, MS, et. al. Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model. Gut. 2019;0:1-12. doi: 10.1136/gutjnl-2018-317431.

[ii] Sun, J, et. al. Fecal microbiota transplantation alleviated Alzheimer’s disease-like pathogenesis in APP/PS1 transgeneic mice.  Nature. 2019;9(189).

The Promise of Fecal Microbiota Transplant

Over the weekend, I read a great little article about the potential applications of fecal microbiota transplant (FMT) in treating a huge variety of diseases.[i]  Of course, we are sorely lacking in clinical trials for almost all but still, there is hope to be had in this treatment for illnesses for which there is precious little now.  So, it’s still worth writing about where the science is at present.

Before I tell you about all these potentials though, I just want to share a sentence in the introduction that really struck me and I think will resonate with you too.  It sums up what we currently know about the role the gut bacteria play in the human body:  “In addition to breaking down foods and synthesizing nutrients, microbiota play an important role in the immune system, provide colonization resistance [to pathogens], protects against epithelial [the intestinal wall] injury, promotes both angiogenesis [development of new blood vessels] and fat storage, modulates human bone mass density, modifies the nervous system, and metabolizes therapeutic agents into active compounds.”   Reading that list, it really hit home: there is truly astounding just how much our gut bacteria do for us!  (And we probably only know the half of it right now.)

So, back to the treatment potential of FMT, I’ll write this in the form of a list to make it easy for you to scan.  I’m not going to go into detail for some of these as there’s apparently not a huge amount of data right now – only common sense and science suggesting that more research should be done because of the known relationship of the bacterial microbiome to that disease. But I’ll list everything, nonetheless, as it’s still exciting to contemplate just how much FMT may help in the future with “incurable” illnesses.

  1. Clostridium difficile infection:  “Increasing evidence, including meta-analyses, systematic reviews, and randomized controlled trials, has confirmed that FMT is effective for the treatment of recurrent Clostridum difficile.”  Currently, this is the only truly accepted use of FMT.
  2. Inflammatory bowel diseases:
    1. Ulcerative Colitis: There is some clinical trial data supporting use in ulcerative colitis. For example, one study showed that 6 patients with relapsing UC experienced, “…complete clinical, colonoscopic, and histological improvement after FMT,” and another meta-analysis study showed that 63% of patients with UC achieve remission, while 76% could at least stop taking medications for IBD.  However, other studies have been less convincing so that, to date, it is difficult to definitively determine efficacy.
    2. Crohn’s: Case reports support the efficacy of FMT in Crohn’s.  However, there are no clinical trials as yet.  (There are many articles on The Biome Buzz that talk about the microbiome’s connection to IBD.  Here is just one example.)
  3. Irritable Bowel Syndrome: Studies on mice are positive, as was a clinical study on 12 patients with IBS (intermittent diarrhea and severe bloating).  9 (75%) responded positively, and improvements were sustained upon being reexamined a year later.  However, much more work needs to be done in this.  (Just one example here of one of my posts on IBS and the microbiome.)
  4. Liver diseases: Very, very early results look very promising for illnesses like non-alcoholic fatty liver, alcoholic fatty liver, etc.  (A related post here on non-alcoholic fatty liver and gut bacteria.)
  5. Metabolic diseases: I already wrote about the first clinical trial using FMT to treat obesity here.
  6. Chronic kidney diseases
  7. Neuropsychiatric disorders:
    1. Parkinson’s disease: I’ve written about the connection of the gut biome to PD many times. (This is just one example. ) Dr. Borody, an Australian researcher and the father of modern FMT, treated a male PD patient with constipation (common in this disease) with FMT and found that the symptoms of PD improved.  Mouse models also support the theoretical use of FMT in this illness.
    2. Alzheimer’s disease: I’ve also written about the connection of the gut biome to AD. (Here, for example.) Again, animal models suggest that FMT may help.
    3. Epilepsy: There is a published case study of a girl with Crohn’s and a 17 year history of seizures who was treated with FMT:  “During a 20 month follow-up, FMT proved its effectiveness on preventing the relapse of seizures after withdrawal of antiepileptic medications.”  (You can read more about the  microbiome/seizure connection here, for example.)
    4. Autism: I’ve already written about the first, and very successful, clinical trial using FMT to treat autism.
    5. Depression: There is good reason to believe FMT will be successful in treating this, and this is also supported by animal models, but thus far, no human clinical trials have taken place.  (I’ve covered the biome/mental health topic extensively on The Biome BuzzHere is one example.)
    6. Multiple sclerosis:   (I’ve also written about the microbiome connection to this illness:  here for example.)
    7. ME/CFS: Myalgic encephalomyelitis/chronic fatigue syndrome  very likely have their etiology in the gut biome. A study was recently conducted on 60 CFS patients with GI symptoms.  70% (so 40 of the 70) responded positively to FMT.  7 of 12 patients who were followed after a 15-20 year follow up had achieved and sustained complete remission.  (The connection of the microbiome to ME/CFS is also covered frequently on The Biome Buzz, like here for example. )
  8. Autoimmune disease: with the incredible wealth of information relating gut biome alterations to these illnesses (including lupus, rheumatoid arthritis, Hashimoto’s thyroiditis, etc.), there is good reason to believe FMT will prove very beneficial.
  9. Allergic disorders: there have been no clinical trials, but again, the known relationship between the microbiome and these illnesses suggest that FMT will be effective.  (Another topic covered in depth on The Biome Buzz.  One example here.)
  10. Hematological diseases: Ditto
  11. Tumors and Cancers:  There is a definite connection between the gut bacteria, inflammation and the development of some cancers. More than that, we also know now that the gut bacteria affect how people will respond to cancer treatments, including radiation.  (There is more info on The Biome Buzz on the gut bacteria/cancer connection.  One example, here.)

To conclude then, we need WAY more clinical trials, and these trials need to be better standardized in terms of the screening of donors, the preparations of the donations, frequency of dosing, delivery  methods of doses, and so on.  The great news though is that, “…increasing studies have shown that FMT also presents potential and promising clinical indications for the treatment of many other disorders related to gut microbial dysbiosis.”  And actually, if you think about it, there are probably many, many more illnesses that could be added to this list.  Fibromyalgia, perhaps?  Spondyloarthritis? Post-traumatic stress disorder?   ALS? Celiac?…and the possibilities list goes on and on and on.

Considering the total lack of effective treatment for pretty much everything on the above list, this is at least a spot of light at the end of a very long and dark tunnel.

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[i] Zhou, Y, et. al. Are there potential applications of fecal microbiota transplantation beyond intestinal disorders?  Biomed Research International. 2019. Article ID 3469754. https://doi.org/10.1155/2019/3469754

Probiotics for Chronic Fatigue and Fibromyalgia? Probably, but the Science Isn’t Yet There

As regular readers know, I’m always on the lookout for “things you can do now.”  I’m especially happy then when actual clinical trials happen as we can get some idea of the effectiveness of treatments.  About 18 months ago, a paper was published reviewing studies that looked at the use of probiotics in fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS). [i]  I’ve written before (here and here, for example) about bacterial microbiome changes that have been noted in both illnesses, but have not had much opportunity to write about what can be done about it.  Unfortunately, as it turns out, there’s a reason for that.

First a quick review for those unfamiliar: fibromyalgia is a chronic pain disorder of unknown origin. The primary symptoms are body wide muscle pain, morning stiffness, fatigue, sleeping issues and it is more often than not, accompanied by both gastrointestinal symptoms (about 81% of patients report issues) and all too often, depression and anxiety.  In fact, a large percentage of those with FMS fit the diagnostic criteria for irritable bowel syndrome.  There is tremendous overlap with chronic fatigue, which is also a chronic condition of unknown origin characterized by persistent fatigue, which is the predominant symptom, as opposed to the pain of FMS.  That said, both illnesses involve pain and fatigue, and like FMS, CFS is also, more often than not, accompanied by GI symptoms (92% fit the criteria for IBS).  CFS too often produces affective issues, including depression and anxiety, and in both illnesses, nervousness, memory loss, confusion are not uncommon.

Some research has shown that those with CFS have intestinal overgrowth of d-lactic acid producing bacteria which, if you remember (from this post of mine awhile back ), often produces cognitive dysfunction and neurological issues.  Research published in 2004 showed that small intestinal bacterial overgrowth (SIBO) occurs 100% of the time in those with FMS, compared to 84% of the time in those with IBS and 20% of the time in healthy controls.  SIBO is, as you know (from this post), difficult to diagnose accurately and  may or may not result in symptoms, as shown yet again by the fact that 20% of healthy controls in this study are asymptomatic.  However, this does give a good picture of the relationship of biome alterations to the disease, FMS.  It makes sense then that probiotics might help those suffering from these illnesses.

The researchers in this review study looked for randomized controlled clinical trials and pilot studies using probiotics in humans with FMS or CFS performed in the previous 10 years, so between 2006 and 2016. While originally coming up with 537 articles on CFS and FMS using their search terms, they ended up with a whopping 2 that actually met the necessary criteria to be included.  These were both 8 week long studies on adults, randomized and double-blinded.  Neither study looked at FMS at all, only CFS.  One had 35 participants, the other 48.

The first study found that Lactobacillus casei (Shirota strain, such as is found in Yakult)  had beneficial effect on anxiety but not depression) in those with CFS.  This, by the way, completely coincides with the research I wrote about in the past, on stress and anxiety and probiotics.  The second study used B. infantis, and the scientists found that treatment led to decreased inflammatory markers, including C-reactive protein (CRP), tumor necrosis factor alpha and interleukin-6.  (I’ve also written in the past about B. infantis and its ability to reduce inflammation resulting from stress.)

The researchers conclude the obvious:  “The available research concerning the potential usefulness of probiotic treatment for FMS or CFS is limited.”  (Ya think?)  “Nevertheless, it seems, from the results of the two studies review here…that some probiotic strains might improve the symptoms of anxiety and inflammation in these populations.”  They go on to point out that neither study actually focused on fatigue…the core symptom of CFS.   Other studies, not included in their review because they did not meet the necessary criteria, have also not demonstrated improvements in fatigue.  For example, one trial tested several Lactobacillus and Bifido species on 15 CFS patients, and while improvements in short-term memory and concentration were noted, there were no significant benefits in health.  Another study done on those with spondyloarthritis (Ankylosing, psoriatic, etc.) with a combination of B.lactis, L.acidophilus and a strain of Streptococcus, also showed no improvement in fatigue.

Toward the end of the paper, the researchers note that new clinical trials may help further research into this area, including “…the one that Roman and colleagues are performing from 2017.”

So, I had a look and indeed, found this trial which is now published.[ii] This was an 8 week long double-blind, placebo-controlled, randomized trial of a multi-species probiotic on 40 patients with FMS (although only 31 ended up finishing). The scientists looked at cognition, emotional symptoms, quality of life, anxiety and depression:  “Our results indicated that probiotics improved impulsivity and decision-making in these patients.”  There were no statistical differences between the placebo and the treatment group in self-reported symptoms of FMS, including physical function, depression and anxiety:  “Expectation of symptom improvement could be the primary factor underlying this ‘placebo effect.'”  The only statistically significant improvement in the treatment group was in cognitive performance.

There was, by the way, a major drawback in this study, as I see it.  Diet was not accounted for, meaning that probiotic containing foods like yogurt were not prohibited in the control group.  That surprised me as it really could potentially explain the lack of statistical significance in results from the treatment and placebo groups – which these authors acknowledge.  Seems to me that this is poor study design…but what do I know.

For those interested, this is the probiotic used in the study, which seems to be low potency (only 6 million units) containing the following strains, Lactobacillus rhamnosus GG ATCC 53103, Lactobacillus paracasei LMG P-21380,  Lactobacillus acidophilus DSM 21717, Bifidobacterium bifidum DSM 22892.  The subjects took 2 pills at least 30 minutes before breakfast and 2 pills at least 30 minutes before dinner.  I do not know why they selected this particular probiotic, and not one including the strains in the 2 studies mentioned above.

So to conclude:  we know basically nothing about how probiotics may or may not  be used to treat either CFS or FMS.  For the moment, we are on our own.

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[i] Roman, P, Carrillo-Trabalon, F, Sanchez-Labraca, N, Canadas, F, Estevez, AF, Cardona, D. Are probiotic treatments useful on fibromyalgia syndrome or chronic fatigue syndrome patients? A systematic review. Beneficial Microbes. 2018:9(4);603-611. doi: 10.3920/BM2017.0125

[ii] Roman, P, Estevez, A, Miras, A, Sanchez-Labraca, N, Canadas, F, Vivas, AB, Cardona, D. A pilot randomized controlled trial to explore cognitive and emotional effects of probiotics in fibromyalgia. Scientific Reports. 2018;8(1).  DOI: 10.1038/s41598-018-29388-5

Prebiotics: Yet Another Layer of Biome Complexity

I regularly receive FB messages and emails from people asking me what probiotic or prebiotic they should be taking.  If I knew the answer, I’d be rich.  The answer is…no one knows.  We are so at the tip of the iceberg on all this, it’s mind boggling.

Over the weekend, I read a paper that took an in-depth met-analysis look at the differences in bacterial content between control and autistic children’s guts.  These scientists reviewed 9 studies, with a total of 254 patients, and found “…that children with ASD had lower percentages of Akkermansia, Bacteroides, Bifidobacterium, and Parabacteroides and a higher percentage of Faecalibacterium in the total detected microflora compared to controls. In contrast, children with ASD had lower abundance of Enterococcus, Escherichia coli, Bacteroides, and Bifidobacterium and higher abundance of Lactobacillus.”[i] The differences were highly statistically significant.

How many illnesses now have been shown to have bacterial microbiome differences?  On this blog alone I’ve talked at length about not just autism, but everything from obesity to chronic fatigue syndrome to depression, etc. etc. etc.  The list feels endless somedays. And this is just the bacterial microbiome.  Don’t forget that differences have also been found in the mycobiome (yeasts)…and the virome (viruses)…and in the metabolome (the secretions from all these various organisms)…and I still haven’t even touched on the parts played by the macrobiome, protozoa, and so on.

As though this is not all complex enough, as it turns out, even prebiotic fiber is unbelievably complex.

So back to the question:  what probiotic and/or prebiotic should I take?  Well…obviously, that is ultimately going to come down to what is already in your gut.  I’ve already written, more than once, about how some day in the not-terribly-distant-future, we will know enough to individualize treatments using diet, probiotics, prebiotics, and so forth that are tailored to the exact needs of each person.  I think we took one step closer to that, in research just out Washington University in St. Louis, wherein scientists began the laborious process of figuring out just which prebiotic fiber (and individual components of a prebiotic fibers) affect which bacterial species, and how.[ii]

These scientists took sterile rats, without microbiomes, and colonized them with 20 strains of the common gut bacterial strain, Bacteroides. They had the rats eat a “westernized” diet for 4 weeks, with high saturated fat and low fiber (fruit and vegetables) content, but to this they added one of 34 different kinds of prebiotic fiber, including pea protein, citrus peel, pectin, apple fiber, oat hull fiber, chia seeds, and many more. In total, they tested 144 different diet combinations as to how they affected those 20 bacterial strains.  21 of those 144 combinations had significant effect:  citrus pectin and pea fiber enormously increased B. thetaiotaomicron while B. ovatus levels increased dramatically from barley bran.  Some kinds of inulin, resistant maltodextrin and psyllium also had significant effects on certain strains.

As I mentioned previously, they also analyzed what it was in the fiber’s carbohydrate content that had the bioactive properties.  Pea fiber, for example has a polysaccharide called arabinan that seems to affect bacteria, whereas in citrus pectin, it was something called homogalacturonan that led to the increase in specific bacterial strains.

Says Dr. Gordon, the lead researcher on this study, …fiber is actually a very complicated mixture of many different components. Moreover, fibers from different plant sources that are processed in different ways during food manufacturing have different constituents…Unfortunately, we lack detailed knowledge of these differences and their biological significance.”[iii]

 They also found that there were interactions between species as they fed on the fiber, leading to a distinct hierarchy of bacteria.  Some species were stronger competitors than others, in their fight for the nutrients:  “…it’s important to understand how the presence of a particular organism affects the dining behavior of other organisms — in this case, with regard to different fibers. If we are going to develop microbiota-directed foods aimed at providing benefits to human health, it’s important to find ways to determine which food staples will be the best source of nutrients and how the microbiota will respond.”[iv]

While obviously we’re not there yet, you can imagine how someday soon, we may be able to easily analyze the bacterial content of each person’s gut, and then have a tailor-made prebiotic that address their specific needs.   I’m looking forward to the day I won’t have to respond with “I don’t know” again.

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 [i] Xu, M, Xuefeng, X, Li, J, Li, F. Association between gut microbiota and autism spectrum disorder: a systematic review and meta-analysis.  Frontiers in Psychiatry. 2019.   doi: 10.3389/fpsyt.2019.00473

[ii] Michael L. Patnode, Zachary W. Beller, Nathan D. Han, Jiye Cheng, Samantha L. Peters, Nicolas Terrapon, Bernard Henrissat, Sophie Le Gall, Luc Saulnier, David K. Hayashi, Alexandra Meynier, Sophie Vinoy, Richard J. Giannone, Robert L. Hettich, Jeffrey I. Gordon. Interspecies Competition Impacts Targeted Manipulation of Human Gut Bacteria by Fiber-Derived Glycans. Cell, 2019; 179 (1): 59 DOI: 10.1016/j.cell.2019.08.011

[iii] https://www.medicalnewstoday.com/articles/326402.php

[iv] https://www.sciencedaily.com/releases/2019/09/190919142342.htm

Propionic Acid: A Culprit in Obesity and Metabolic Dysfunction?

As promised on Tuesday, today is the last post in my continuing propionic acid series  as we wrap up not-celebrating the Biome Buzz’ official First Annual Propionic Acid week.  Today’s post is about just how suspect it is for all our health.

A study published this year by Harvard scientists in the journal, Science Translational Medicine, showed that the propionic acid (PPA) adversely affects metabolism by raising blood sugar levels.[i]

The scientists looked at both animal and humans, and the latter were involved in a double-blind trial with 14 healthy volunteers.  The researchers discovered that PPA stimulates the liver to produce more glucose by increasing levels of the hormones, glucagon and fatty acid-binding protein 4, which signal the liver to release sugar into the blood.  PPA seems to not directly cause this increase but instead, has an effect on the sympathetic nervous system which, in turn, signals to the body that a raise in blood sugar is needed.  Says one of the study’s authors, “…the most interesting thing we determined in these experiments is that a single dose of propionate can increase the hormones in the body that are designed to stimulate glucose production from the liver…There are times when that’s needed, like when you’re starving or have dangerously low blood sugar. But here, it was almost tricking the body into thinking that it needs to produce glucose when it doesn’t.”[ii]  The study in mice did demonstrate that chronic exposure to PPA thereby led to weight gain.

In the humans in the study, this continued release of unneeded blood sugar led  to insulin resistance:  their bodies no longer responded optimally to insulin, which lowers blood sugar levels.  Insulin resistance, over time, leads to metabolic disorders like obesity and type 2 diabetes.

While of course this research has the usual caveats  – it needs to be replicated in larger cohorts and so forth – it really does get you thinking.  PPA is a common food preservative found regularly in cheeses and baked goods (and artificial flavors).  It is also produced by various gut bacteria…and alterations to our bacterial microbiome are almost ubiquitous in the industrialized world. Over the past few decades, we have watched rates of not just autism rise (as I talked about in my last 2 posts – bearing in mind, PPA can cross both the blood-brain barrier and through the placenta), but also rates of obesity and type 2 diabetes.  Is PPA a major factor?

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[i] Tirosh, A, et. al.  The short-chain fatty acid propionate increases glucagon and FABP4 prdocution, impairing insulin action in mice and humans.  Science Translational Medicine. 2019:11(489).  DOI: 10.1126/scitranslmed.aav0120

[ii] https://gizmodo.com/a-common-preservative-in-cheese-and-bread-could-negativ-1834278066

Ameliorating the Adverse Effects of Excess Propionic Acid

I am officially declaring this Biome Buzz’ first annual Propionic Acid Week! (Unfortunately, this is not a cause for celebration.)

If you remember, propionic acid (PPA) is a short-chain fatty acid produced by gut bacteria.  Ordinarily, PPA , like the other SCFAs, is great for you:  it is highly anti-inflammatory, beneficial for the gut flora, and so forth.  However, to disprove the old adage, “you can’t have enough of a good thing,” excess amounts are linked to severe neurological issues, including autism.

As a follow up to last week’s post about PPA and autism – really out of sheer curiosity – I took a look to see if there were any known treatments to alleviate the effects of excess PPA in autism and was absolutely floored. Just published, in July of this year, there was an article about using a medication called pioglitazone (brand name, Actos) to do just this.[i]

Why was a floored? Well, therein lies a tale:

Back in the early-ish 2000’s, back when my son, Alex, was really, really sick, we were working with a whole team of doctors.  Our immunologist was Dr. Marvin Boris, a wonderful man who – completely coincidentally – had been my pediatrician when I was a child, and who I adored even back then.  Also in that practice was my friend, his physician assistant, Alan Goldblatt.  Brilliant men, both of them. They were looking at immune issues in the autism population and hypothesized that using pioglitazone would be highly beneficial to deal with the major inflammatory problems in this population that were already accepted by the scientific community, even back then.  I’m going to make a long story short here: they did a clinical study on 25 children for a few months, which was published in 2007, measuring behavioral symptoms (hyperactivity, inappropriate speech, irritability, lethargy, and stereotypy), and found “…apparent clinical improvement without adverse events…behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity).”[ii]

(We were among the first to try it and yes, Alex responded very favorably to pioglitazone. In fact, it was one of the few things that helped him, prior to me finding the Specific Carbohydrate Diet, when he was at his sickest.)

These findings have now been replicated several times.  Just a couple of examples:

  1. In 2015, a study assessed the efficacy of adding pioglitazone to a treatment regime of children with autism already on the atypical antipsychotic, Risperdal.  The study was 10 weeks long, double-blind, placebo- controlled, on 44 patients.  They found that adding the pioglitazone led to a marked decrease in irritability, lethargy/social withdrawal and hyperactivity/non-compliance.[iii]
  2. In 2018, a 16 week long single blind study with 25 children found, again, no serious adverse effects and  “…statistically significant improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors…”[iv]

The point is, we’ve known for over 12 years now that pioglitazone  has a very beneficial effect on those with autism and we’ve also known, for at least that long, that excess PPA is common in the population has has extremely adverse effects, both on the immune system and neurologically.

Back now to the findings of this propionic acid/ pioglitazone study:

As I mentioned last week, PPA can easily cross the blood-brain barrier and get into the central nervous system causing brain inflammation.  In fact, patients with elevated PPA levels in stool and blood show similar symptoms to those with autism.

These scientists took rats that would be equivalent of 3-4 years old humans and gave them PPA for 3 consecutive days. They then broke them up into a total of 8 groups, testing the potential effects of different substances.  Yet again, PPA caused marked decreases in sociability, exploratory behaviors, hyperactivity, and worsening anxiety, etc. The rats also had much lower levels of the antioxidant, glutathione (which is also one of the major detoxification molecules in our bodies), and “significant elevation” in inflammatory cytokines as well as a dramatic decrease in the regulatory cytokine, IL-10, which modulates inflammation:  “This indicates the neuroinflammation in PPA treated rats as compared with control rats.”  However, those treated with pioglitazone showed significantly lowered levels of those inflammatory cytokines and increased IL-10 in the brain.

However (and this is upsetting but not unexpected):   “…pioglitazone significantly ameliorated PPA induced changes but this is only partial and not complete as results of pioglitazone treatments in rats are still significantly different from control rats.”

In other words – in rats at least – the changes induced by abnormally high levels of PPA were not entirely reversible.  The damage had been done.

They conclude that their results are in line with everything we already know.  PPA is a significant factor in causing autism; pioglitazone appears to be way to reduce the subsequent neuroinflammation.

On the bright side then, perhaps pioglitazone is a way to at least ameliorate the effects of excess PPA at an early point in life, when perhaps we can make the most difference in the future of children.  On the not so bright side, none of this explains the reasons for the excess PPA issue in the first place.  Antibiotics?  C-sections?  Formula feeding?  Maternal diet?  We just don’t know yet.

In my next post, to continue not-celebrating PPA week, I will describe to you other new study into adverse effects of PPA on humans.

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[i] Mirza, R, Sharma, B. A selective peroxisome proliferator-activated receptor- γ agonist benefited propionic acid induced autism-like behavioral phenotypes in rats by attenuation of neuroinflammation and oxidative stress.  Chemico-Biological Interactions. 2019; 311:108758. doi: 10.1016/j.cbi.2019.108758.

[ii] Boris, M, Kaiser, CC, Goldblatt, A, Elice, MW, Edelson, SM, Adams, JB, Feinstein, DL.  Effect of pioglitazone treatment on behavioral symptoms in autistic children.  Journal of Neuroinflammation. 2007;4(3). doi: 10.1186/1742-2094-4-3

[iii] Ghaleiha, A, Rasa, SM, Nikoo, M, Farokhnia, M, Mohammadi, MR, Akhondzadeh, S. A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: effects on aberrant behavior in children with autism.  Psychiatry Research. 2015;229(1-2):181-7. doi: 10.1016/j.psychres.2015.07.043.

[iv] Capano, L, Dupuis, A, Brian, J, Mankad, D, Genore, L, Hastie Adams, R, Smile, S, Lui, T, Odrobina, D, Foster, JA, Anagnostou, E. A pilot dose finding study of pioglitazone in autistic children. Molecular Autism. 2018;9(59). doi: 10.1186/s13229-018-0241-5