ADHD and the Microbiome…and a Nutritional Supplement

A small pilot study, done by New Zealand researchers, was just published[i] that has me pretty excited.  (I love studies that involve nutrition!) The research involved 17 children (aged 7 to 12), diagnosed with ADHD.  10 of these were given micronutrients supplements for 10 weeks, while the others were given a placebo.  While the supplement did not lead to any changes in the structure or composition of the gut bacteria, it did lead to an increase in diversity (richness), which did not occur in the placebo group.  Perhaps most importantly though, there was a significant drop in Bifidobacterium.  A decrease in Bifido species is already associated, potentially, with an improvement in symptoms of ADHD (I’ll come back to this in a moment), and the authors of this study suggest that a multi micronutrient supplement may prove to be a completely safe way of downregulating Bifidobacterium, should there be a need.

Back to the association between Bifidobacterium and ADHD symptoms:

In 2017, a paper was published by an international team of researchers on the gut microbiome of children with ADHD.[ii]  They discovered, “… that the relative abundance of several bacterial taxa differed between cases and controls…A nominal increase in the Bifidobacterium genus was observed in ADHD cases.”  They hypothesize about the potential mechanism of action:  how might such an increased load of Bifido bacterium cause the symptoms of ADHD?  They theorize that this gut bacterium affects dopamine synthesis in such a way as to reduce the ability to await “reward,” which “…constitutes one of the hallmarks of ADHD.”  That is, essentially, the metabolic pathways influenced by the excess of Bifido increase the need for instant satisfaction.

In prior research, this New Zealand team of scientists looked at children with ADHD who stayed on the supplement long term – a year.[iii]  Of the 84 children who finished the study, 84% were “…identified as ‘much’ or ‘very much’ improved relative to baseline functioning…”  This is remarkable in that, only 50% of the children who switched to psychiatric meditations and 21% of those who discontinued treatment reported improvements.  In fact, a switch to medications was “…associated with deterioration in mood and anxiety.”  No side effects were reported with the supplement.

Of course, the link to high levels of Bifidobacteria is not yet confirmed.  The lead researcher of this paper states:  “More research is needed with larger groups of people with ADHD, and to understand the potential effect of diet, medications, age, ethnicity and gender on the results that have been reported.”  Still, remembering my philosophy, “If it can’t hurt and it could help, do it” – perhaps a trial of a broad-spectrum supplement is in order?

________________________________________

[i] Aaron J. Stevens et al. Human gut microbiome changes during a 10 week Randomised Control Trial for micronutrient supplementation in children with attention deficit hyperactivity disorder, Scientific Reports (2019). DOI: 10.1038/s41598-019-46146-3.

[ii] Aarts, E., et. al. Gut microbiome in ADHD and its relation to neural reward anticipation.  PLoS One. 2017:12(9).  doi: 10.1371/journal.pone.0183509

[iii] Darling, KA, Eggleston, MJF, Retallick-Brown, H, Rucklidge, JJ.  Mineral-vitamin treatment associated with remission in attention-deficit/hyperactivity disorder symptoms and related problems: 1-year naturalistic outcomes of a 10-week randomized placebo-controlled trial.

Polycystic Ovary Syndrome and the Bacterial Microbiome

I first learned about the concept of fecal microbiota transplant (FMT) a good 20 years ago, from my mentor who is a well-known functional medicine doctor.  I know some people are shocked by the idea but to me, it made sense from the get-go.  (For those unfamiliar, FMT means using stool (which is about made up of about 60% of bacteria from the intestines) to transfer bacterial contents.  Often it’s done via suppository, but nowadays, companies are working on purifying it into a non-noxious oral pill or solution.)

Many times, over the years, I’ve written about research and clinical studies using FMT on this blog.  As just one example, I wrote about a hugely successful study done on children with autism.  At this point (some studies in humans, some in animals), researchers have been able to transfer everything from the aforementioned autism to depression, anxiety, obesity, etc. by transferring the gut microbiome via FMT.

Thus, I was not all that surprised this morning to read about research recently conducted by scientists from China, the US’s National Institute of Health and Penn State University, in which they transferred polycystic ovary syndrome (PCOS) from humans to animals.[i]  For those of you not familiar with PCOS, it is a fairly common endocrine (hormone) disorder that affects women of reproductive age.  According to the Mayo Clinic, “Women with PCOS may have infrequent or prolonged menstrual periods or excess male hormone (androgen) levels. The ovaries may develop numerous small collections of fluid (follicles) and fail to regularly release eggs.”[ii]  It can not only cause incredibly unpleasant side effects for the affected woman (depression, anxiety, excess hair growth on the body, male-pattern balding, painful and prolonged periods, and more), it can also cause serious medical issues, including high blood pressure, gestational diabetes, infertility and miscarriage.  Research shows that this illness affects somewhere between 4% and 12% of women of reproductive age…which is a hell of a lot of women.[iii]

While the ultimate cause is unknown, low grade inflammation is known to be one of the contributing factors, and recently it’s been recognized that alterations in gut microbiome composition and gut barrier integrity (i.e. leaky gut) may play a major role in the development of PCOS.  The researchers involved in this study found that women with the syndrome had less bacterial diversity in their microbiomes, increased levels of the species, Bacteroides vulgatus, and a shift in genes affecting bile salts.[iv]

When they transferred the microbiome from affected humans to mice, the mice developed ovarian dysfunction, insulin resistance (a hallmark of PCOS), alterations in testosterone levels (another hallmark) and also had immunological changes including lowered levels of a cytokine called IL-22.  These bile acid changes and lowered levels of IL-22 are also seen in women with PCOS.  In fact, transferring just Bacteroides vulgatus to mice had the same effect.  The researchers state that this is the first evidence that gut microbiome alterations, and subsequent disruptions in bile acid synthesis, are directly responsible for the development of PCOS.

Giving the mice IL-22 and a bile acid (glycodeoxycholic acid) ameliorated the ovarian dysfunction and infertility, suggesting that this may potentially be a treatment for PCOS:  “This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.”  As there are no treatments right now, hopefully this new research will soon lead to one.  Will FMT end up being the answer for this illness?

_______________________________________________

[i] Xinyu Qi, Chuyu Yun, Lulu Sun, et al. Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome. Nat Med. 2019. doi: 10.1038/s41591-019-0509-0.

[ii] https://www.mayoclinic.org/diseases-conditions/pcos/symptoms-causes/syc-20353439

[iii] https://emedicine.medscape.com/article/256806-overview#a5

[iv] https://www.gutmicrobiotaforhealth.com/en/the-gut-microbiota-may-be-involved-in-ovarian-dysfunction-and-insulin-resistance-in-polycystic-ovary-syndrome/

Neurodegnerative and Neuropsychiatric Disorders: Prime Targets for Helminths

Within just a few weeks of each other, two papers have been published looking at the potential of using helminths to treat neurological conditions.  Not surprisingly, both focus on the powerful anti-inflammatory effect of helminths.

(For those of you new to helminths:  these are a kind of macrobiotic organism, intestinal worms, native to all mammals on this planet.  However, in the industrialized world, we have “de-wormed,” completely eradicating our native macrobiomes.  At this point, pinworms are the only one of these organisms that is still around in the westernized world, and when someone gets them, we instantly de-worm them (which is fair enough as they have nasty side effects).  However, there are benign helminths currently being used for “helminthic therapy” – using small, therapeutic doses of these organisms to modulate the inflammatory response.)

The first paper looks at helminths in neurodegenerative disorders like multiple sclerosis and Alzheimer’s disease.[i]  These authors believe that the upregulation (increase) in T regulatory cells (which produce anti-inflammatory cytokines, like IL-10) induced by helminths may play a pivotal role in treating these illnesses.

A few highlights from this paper:

  1. “…until now, helminth infections have not been demonstrated as necessary for proper host immune maturation in either humans or in animal models, and co-evolution over millions of years involves a form of mutualism where both the host and the parasite derive some benefit from their relationship..”
  2. I laughed when I read that sentence.  Isn’t it an oxymoron to say that a parasite is mutualistic?!  Maybe then they should call these therapeutic organisms mutualists, not parasites!
  3. Clinical data, experiments and clinical trials all support the notion that “…helminths not only prevent but also reverse allergy and asthma and autoimmune diseases…”
  4. Neurological inflammation is an important factor in the development of such illnesses as ALS, Parkinson’s, Alzheimer’s and multiple sclerosis. While the molecular mechanisms of brain damage in these diseases (as well as Lewy body dementia and frontotemperal dementia) are different, “the presence of neuroinflammation is a common feature of all these…”
  5. To effectively treat neurodegenerative diseases, anti-inflammatory treatments must be considered, but at the same time, oversuppression of the inflammatory response – which would open the individual up to infection – must be avoided. The authors refer to this as “precise tuning of the immune responses.”  They go on to say, “It seems a promising use for this immunomodulation of the work of our ‘old friends’: gut microbiotic bacteria and parasitic organisms…”

The thrust of the 2nd paper, which focuses on using helminths in the treatment of neuropsychiatric disorders (NPDs), is essentially the same.  They too state that helminths “…have shown to be protective against severe autoimmune and allergic disorders” and have been “…used for modulation of immune disturbances in different autoimmunity illnesses, such as Multiple Sclerosis (MS) and Inflammatory Bowled Disease (IBD).”[ii]

They go on to state that “…’helminthic therapy’ is able to ameliorate neuroinflammation of NPDs (neuropsychiatric disorders) through immunomodulation of inflammatory reactions and alteration of microbiota composition.”

A few high points of this one:

  1. Immune disturbances are well documented in many NPDs. For example, significant elevations of inflammatory cytokines have been found in the blood of children with autism, as well as major depressive disorder and schizophrenia.
  2. The link between autoimmune disease and NPDs is also well established. As just one example, those with inflammatory bowel diseases have nearly 6X the increased risk of anxiety issues.
  3. Treating NPDs with anti-inflammatory agents has been shown to have therapeutic benefit.
  4. Helminths not only directly modulate inflammation, but also, by positively altering the microbiome, have an indirect beneficial effect on the immune system.
  5. The authors point out that there is “…a big opportunity for helminth therapy in NPDs” as few studies have been conducted…but based on what information is in the literature, this looks like an extremely promising treatment.

They summarize all this in their conclusion stating again that inflammation seems to be a driving force behind many neuropsychiatric disorders and helminths are perhaps the most potent natural modulator of the inflammatory response.  Thus, “…helminth therapy may be a promising and new therapeutic option for resolution of neuroinflammation in NPDs.”

Here’s a question for you to contemplate: if neurodegenerative and neuropsychiatric disorders are, at least in large part, caused by out-of-control inflammation…why wait for them the start before working on the unregulated immune system?  As Dr. Jamie Lorimer, of Oxford University says, “Humankind eventually needs to move beyond the idea that helminths are best used as a drug or a therapy. Rather, we need to embrace the view that helminths are a necessary component of the ecosystem of a healthy body, and that helminths should be cultivated for population-wide biota restoration…”[iii]

_____________________________________________

[i] Donskow-Lysoniewska, K, Doligalska, M, Gasiorowski, K, Leszek, J. Parasitic worms for the treatment of neurodegeneration. Neuropsychiatry. 2019;9(2):2333-2346.

[ii] Abdoli, A and Ardakani,  HM. Potential application of helminth therapy for resolution of neuroinflammation in neuropsychiatric disorders. Metabolic Brain Disease. 2019. doi: 10.1007/s11011-019-00466-5

[iii] Lorimer, J. Hookworms Make Us Human: the Microbiome, Eco-immunology, and a Probiotic Turn in Western Health Care. Medical Anthropology Quarterly. 2018  Jul 13. doi: 10.1111/maq.12466

Breast Cancer and Metastases: Is Dysbiosis a Factor?

Yesterday, I read an article[i] in the University of Virginia’s online newspaper about the work of a team of their scientists and graduate students that I thought worth sharing with you.  The paper[ii] was just published in the journal, Cancer Research, and while it was conducted in an animal model, the findings are still very interesting and potentially very important.

First a fact:  the most common type of breast cancer, about 2/3rds of cases in fact, is called hormone receptor positive (HR+).  So, using a mouse model of this type:  for two weeks, the experimental group of mice were given non-absorbed antibiotics (that stay in the gut), wiping out much of their gut bacteria, while the control group was given water.  All the mice were then injected with breast cancer tumor cells.

They found that the mice given the antibiotics had “…enhanced tumor cell dissemination to lymph nodes, lungs, and peripheral blood at both early and advanced timepoints after tumor initiation.” That is, the cancer metastasized much more readily than in the control group.  They found too that dysbiosis “…promoted early inflammation within the mammary gland….”

Dr. Melanie Rutkowsi, lead author of the paper, is quoted as saying, “In this inflamed environment, tumor cells were much more able to disseminate from the tissue into the blood and to the lungs, which is a major site for hormone receptor-positive breast cancer to metastasize…”[iii]

To definitively determine that it was the disruption in the gut bacteria causing this phenomenon, the scientists transferred the abnormal gut bacteria to other mice via fecal transplant and sure enough, the receiving mice had the same issue:  aggressive metastasizing of tumor cells.

(By the way, for those of you familiar with breast cancers:  these findings only apply to hormone-positive breast cancer, not triple-negative.)

The authors of the paper point out that this study was not to look at whether or not the gut biome contributes to the initial development of breast cancer, but instead, to look at whether or not it affects the spread of the cancer cells, which ultimately will determine the long term prognosis.

Many chemotherapy drugs cause microbiome disruption and subsequent GI issues, raising several interesting questions.  Does this biome disruption ultimately put patients at risk for metastases?  And does this risk exist before the cancer diagnosis or is it the RESULT of the treatment for the cancer?  Trying to look at the bright side though:  if indeed microbiome alteration/depletion is a risk factor for the spread of breast cancer, then manipulating the microbiota should become a treatment option.  The next step for these researchers is to collect stool samples from women at high risk for metastatic breast cancer, and see if those with greater dysbiosis do indeed have a greater chance for the spread of the cancer.  (If they find some of the women do have high levels of dysbiosis, I sincerely hope they help them treat it!)

Obviously, there are the usual caveats to this research:  it’s early stage, it was done in mice, and so forth.  Whether or not it applies to humans remains to be seen.  However, I find myself concluding yet again, that it makes a hell of a lot of sense to take care of your biome now.  Can’t hurt, could help, as I always say.

__________________________________________________________

[i] https://www.cavalierdaily.com/article/2019/08/unhealthy-microbiome-found-to-be-linked-to-increased-spread-of-breast-cancer

[ii] Rosean, CB, et. al. Pre-existing commensal dysbiosis is a host-intrinsic regulator of tissue inflammation and tumor cell dissemination in hormone receptor-positive breast cancer. Cancer Research. 2019. DOI: 10.1158/0008-5472.CAN-18-3464

[iii] https://www.forbes.com/sites/victoriaforster/2019/06/11/disrupted-gut-microbiome-promotes-breast-cancer-spread-in-mice/#222a980d30de

Irritable Bowel: SIBO, Dysbiosis and Diet

In 2010, I read a paper in the journal, Nutrition, that really rocked my world:  “The concept of small intestinal bacterial overgrowth (SIBO) in relation to functional gastrointestinal disorders.” [i]  To summarize one of its many key points:  we don’t know how to test for it and, “Controversy will continue until concepts are broadened, consensus in definition is reached, and evaluation of efficacy of candidate therapies is more rigorous.”

I’ve been watching this research for over a decade now, and guess what – SIBO is just as controversial as ever.

For many years, SIBO was thought to be the cause of IBS-type symptoms, like constipation, diarrhea, gas, bloating and pain, and testing was mainly done by sampling breath to look for products of bacterial fermentation.  The “gold standard” was more invasive, probably done during endoscopies, I’d imagine: aspiration (collection through suction) and culture of bacterial content from the small intestinal contents (specifically from the duodenum, the upper part of the small intestine, next to the stomach). However, tremendous controversy surrounded this testing as its accuracy has always been in doubt, and for years the search has been “… on for alternative diagnostic strategies with much expectation surrounding the application of modern high-throughput molecular approaches to the study of the gut microbiome.”[ii]

A new paper has taken a step forward in sorting all this out.[iii]  I found the findings really surprising.

In the first part of this research, the scientists compared the results of the above-mentioned “gold standard” aspiration and culture of small intestinal contents to those of a much newer, RNA-based microbiome analysis, on 126 people with GI symptoms.  They also had 38 healthy controls in this study.

  1. The usual duodenal aspirate culture showed that only 52% of those with GI symptoms had SIBO (while none of the controls did). So there was not any kind of accurate correlation between this test and GI symptoms.
  2. There was a correlation, however, between SIBO and recent antibiotic exposure.
  3. Dysbiosis (defined as the biome being compositionally different from the controls) WITHOUT SIBO, as measured by the RNA testing, was much more accurate at diagnostically differentiating people with symptoms and without. Those with GI symptoms had reduced microbial diversity.
  4. SIBO does not correlated with microbial dysbiosis.
  5. In patients with symptoms, “…pathways associated with simple sugar metabolism were enriched…whereas complex carbohydrate degradation pathways were more prevalent in healthy individuals.” This suggests that healthy individuals eat more fiber than  those with dysbiosis.
  6. Believe it or not, some of the healthy individuals with no GI symptoms actually had SIBO,  which…”suggests that healthy individuals can have SIBO without any symptoms or alterations in microbial composition.”

The 2nd part of this paper talks about what happens in healthy individuals if they switch to a diet low in fiber, high in simple sugars.  They had 16  healthy people (who ate at least 11 grams of fiber per 1000 calories of food)  go onto a low fiber diet (less than 10 grams per day) for a week and then reanalyzed their microbiota using the RNA technology.  They also recorded any GI symptoms experienced and looked too at epithelial barrier function (i.e. the presence or lack of leaky gut).   “All patients developed new symptoms with 80% developing GI symptoms during the dietary intervention and the symptoms resolved within a week of discontinuing the diet.”  That is, in only a week of eating a low fiber diet, almost all developed GI symptoms which resolved as soon as they went back to eating their healthier, high-fiber diets.  They also found that,  “…diet-related changes in the small intestinal microbiome were predictive of symptoms (such as bloating and abdominal discomfort) and linked to an alteration in duodenal permeability”[iv] – so to the development of leaky gut.

To sum up their findings:  while SIBO exists, it does NOT necessarily correlate with patient symptoms.  Some people have it and are asymptomatic. Some people have IBS-type issues and don’t have SIBO.  But what does correlate is dysbiosis:  abnormal gut bacteria.  And once again, diet is a key factor in determining the composition of the gut bacteria and the avoidance of leaky gut:

“Diet has a significant influence on microbial composition and the enrichment of pathways linked to mono- and disaccharide metabolism in symptomatic patients supports this notion. Our pilot dietary intervention study showed that switching to a low fiber, high simple-sugar diet for a short period can trigger GI and systemic symptoms that improve upon resuming baseline diet. The correlation of decreased microbial diversity with increased duodenal permeability and appearance of symptoms suggests that this effect may be driven at least in part via gut microbiota…”

I wish these scientists had given more information on what exactly they mean by simple sugars.  For example, fructose – found in fruit and veggies – is a simple sugar.  I’ve double checked the methods section of the paper, but can’t find any information on exactly what diet they were fed.  I’m assuming they mean processed sugars, like table sugar, but they don’t specify and it’s never safe to assume anything, really.  And is it the sugars that are really the issue – or is it the lack of fiber?

As I mentioned earlier, I’ve been watching this research for many years now and will continue to do so.  Considering the number of people with GI issues these days, this is super important work.

____________________________________________

[i] Gibson, PR and Barrett, JS. The concept of small intestinal bacterial overgrowth in relation to functional gastrointestinal disorders. Nutrition. 2010. 1-6

[ii] Quigley, EMM.  Symptoms and the small intestinal microbiome – the unknown explored.  Gastroenterology & Hepatology. 2019:16;457-458.

[iii] Saffouri, GB, et. al. Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders.  Nature Communications. 2019. https://doi.org/10.1038/s41467-019-09964-7

In Honor of Ice Bucket Challenge Month: ALS and Akkermansia (yet again)

You know how it’s inevitable that when you learn something new, suddenly you see it everywhere?  Akkermansia muciniphila…I first mentioned it in a post back in May 2017, and things kind of revved up from there.  These days, it feels like it’s taking the microbiome world by storm.

I’ll come back to that in a moment.

August is ALS (Amyotrophic lateral sclerosis) fund-raising month.  In the USA, we often call ALS Lou Gehrig’s Disease, after one of the greatest baseball players ever, who died of ALS in 1941, days before his 38th birthday.  ALS used to be something that Lou Gerhig had, and then the great physicist, Stephen Hawking…but it seemed so very, very rare.  Not anymore…at least to me.  I already know 3 people with it, 2 whom have already died.  Like every other chronic disease, it feels like it is starting to become more and more common, appearing everywhere.  So at the moment, as a good friend battles this awful, awful disease, any good news is more than welcome.

Yesterday morning, I spotted an article on an ALS devoted site about research showing that the microbiome may influence the progression of the illness.[i]  It turns out that in a mouse model, a metabolite called nicotinamide (which is simply a form of Vitamin B3, niacin) produced by none other than our old friend, Akkermansia muciniphila, slowed the disease’s progression.  (They also found that 2 species, both of which are unfamiliar to me, worsened ALS symptoms:  Ruminococcus torques and Parabacteroides distasonis.)

Scientists at the Weizmann Institute of Science, in Israel (I can’t believe how many times I find myself writing about work coming out of this place!), are exploring how gut metabolites, which can cross the blood-brain barrier, may be used in the treatment of neurodegenerative illnesses.  In this study, they began by wiping out the gut flora of mice with ALS to see what would happen.  Doing so exacerbated the ALS, in terms of both symptom severity and decreased motor neurons in the brain, which had actually shrunk.

They then compared the gut bacteria of the ALS mice with healthy controls and found 11 potential organisms that could be factors.  They tested each, one by one, as oral supplements, giving them to the ALS mice who’d first had their microbiomes wiped out with major antibiotics.

Sure enough, 1 strain stood out:  Akkermansia muciniphila.  In the healthy controls, they discovered the nicotinamide produced by the bacteria in the blood and brain (cerebrospinal fluid), which was not there in mice treated with antibiotics.  To ensure that it was the nicotinamide having the palliative effect, they continuously administered it to the ALS mice and saw significant improvement.  They believe it could be because this vitamin B3 improved mitochondrial function.  (Mitochondria are the powerhouse of each cell in the body.)

The final step in their research was to figure out whether or not this applies to humans as well.  To determine this, they analyzed the microbiomes of 37 patients with ALS and 29 controls who live in the same households as the patients (as their microbiomes should, theoretically, be similar).  Not unexpectedly, they found that the humans with ALS had significantly different gut bacterial profiles.  More than that, they found that genes involved in producing nicotinamide were less active in the ALS patient  microbiomes and yes, nicotinamide levels were decreased in the brains of 60 patients with ALS studied, which was associated with more severe muscle weakness.  (By the way, I first wrote about microbiome differences in those with ALS back in March, 2017.  In that case, researchers found that giving the short chain fatty acid, butyrate, helped improve the quality of the microbiome, alleviating symptoms of ALS in  mice.)

This research did not involve giving human ALS patients nicotinamide so we don’t yet know if this will have any effect on people.  They write, “We suggest that environmentally driven microbiome–brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.”[ii]  Unfortunately, as you know, human trials can take years to happen…assuming  the millions of dollars necessary can even be raised.

Still, trying to look for a little ray of light:  this is a pretty remarkable finding, I think.  And once again…it leads me to wonder if and when Akkermansia will be available for purchase as a probiotic.

____________________________________________________

[i] https://alsnewstoday.com/2019/07/25/gut-microbiome-slow-als-progression-study/

[ii] Blacher, E, et. al. Potential roles of gut microbiome and metabolites in modulating ALS in mice.  Nature. 2019. doi: 10.1038/s41586-019-1443-5.

Diet, Diet, Diet and the Microbiome…and Did I Mention Diet? (And a Bonus: An Herbal Thing You Can Do Now)

A recent discussion on my Biome Buzz Facebook page, in response to a post about the benefits of boosting Akkermansia muciniphila in the gut,  has prompted me to once again write about the single most important thing when it comes to influencing the health of the bacterial microbiome – DIET.  Yesterday, the Baylor College of Medicine, which has done great biome research, came out with an article talking about some of the recent findings of their scientists.[i]  Dr.Li Jiao and colleagues have found “…an association between diet quality and microbiome composition in human colonic mucosa that provides a strategy that can contribute to reducing the risk of chronic diseases.”  I actually covered this research earlier this month.    The conclusion of this research:  “Diet is considered a principal factor influencing the structure of the microbiome in the gut, which in turn significantly affects the ability of beneficial or harmful microbes to colonize it.”

A 2nd article also appeared yesterday on Gut Microbiome for Health on the topic of the crucial importance of diet to the microbiome’s health, this one yet again emphasizing the importance of eating loads of fiber.[ii]  “…’of all the different major nutrient groups that we eat, fiber is the one component of our diet that directly feeds our gut microbiota.’ When we eat protein, for instance, we digest it and absorb it in our small intestine. The same thing happens with fats and most sugars. In the case of non-digestible fibers, we do not have the enzymes needed to break them down and digest them. Only gut bacteria can do that. They digest fibers and produce short chain fatty acids, whose beneficial effects on health are well documented…”  To sum up:  cut down on those animal products and replace some of them with more fruit, vegetables, whole grains, seeds and nuts.

Yesterday I also read a really interesting article about the effects of culinary spices on the bacterial microbiome.[iii] We all know that herbs have “medicinal” qualities and in fact, many pharmaceuticals are derived from them.  In this case, researchers looked at the effects on the bacterial microbiome of 2 kinds of pepper, black and long pepper (also known as pipli), as well as turmeric and ginger.  As it turns out, “All herbs analyzed possessed substantial power to modulate fecal bacterial communities to include potential prebiotic and beneficial repressive effects,”  meaning that they boost levels of various probiotic species while also inhibiting the growth of pathogenic ones.  Prior research has shown that, in vitro, ginger has strong antibiotic properties against inflammatory gut bacteria like E. coli and Klebsiella pneumonia, while both ginger and turmeric boost levels of Bifidobacteria and Lactobacillus.

These researchers looked at stool samples from 12 healthy, vegetarian or vegan donors.  They cultured the stools and, in vitro, added the herbs to see what would happen. They found that black pepper, ginger and pipli boosted levels of Bifido bacteria while turmeric boosted levels of Bacteroidaceae, Clostridium, Desulfovibrionaceae and several others, including butyrate-producing Lachnospiracceae.  All the herbs greatly reduced the levels of several species, including E. coli:  “…all culinary herbs analyzed resulted in reduced relative abundance of a number of pathogenic and opportunistic pathogens.”

Human trials are planned in the future.  As they state at the start of their paper, “Digestive disorders are increasingly prevalent in Western populations with over 60 million people affected in the United States alone.”

Yeah…we need research into the healing power of food alright.

In the meantime though, “things you can do now” (my favorite!):  the article mentions the Ayurvedic supplement Trikatu, which has been used for thousands of year in this traditional Indian medicine realm.  It is a combination of ginger, black pepper and pipli. For those of you with poor digestion: while you work on increasing your fiber intake and improving the quality of your diet overall, maybe a trial of this is in the cards?

_______________________________________________________________

[i] https://blogs.bcm.edu/2019/07/30/from-the-labs-your-microbiome-is-what-you-eat/

[ii] https://www.gutmicrobiotaforhealth.com/en/how-to-feed-your-gut-microbiota-with-the-fibers-it-needs/

[iii] Peterson, CT, et. al. Prebiotic potential of culinary spices used to support digestion and bioabsorption.  Evidence-Based Complementary and Alternative Medicine. 2019. OI: 10.1155/2019/8973704

Biofilms and the Mycobiome/IBD Connection: A Refresher and a Probiotic Treatment Finally?!

I’ve decided to start this week with some good news.

A few days ago, the headline of a little op-ed sort of piece on a science-devoted website caught my eye:  “It’s Time to Highlight Our Fungus Friends in Our Microbiomes.”[i]  The author gives a short explanation of the diversity of the human microbiome – a diversity which is in sharp contrast to what seems to be the research world’s single-minded focus on the bacterial element alone:  “…focusing solely on this one facet of the microbiome contributes to the misconceptions that only bacteria inhabit our guts and that bacteria are exclusively what gut microbes should look like….fungi, protists [ie. protozoa], and bacteria inhabit the same spaces in our guts and share and compete for resources. And even though studying all members of the microbiome is extremely challenging, it is the only way that we will begin to understand the complex interactions among them and do better science.”

Hear!  Hear!

Unfortunately, this author too only focuses in on the microbiome, neglecting to  mention our missing macrobiomes.  Still, I very much appreciated her vehemence in pointing out that science absolutely must look at the role other organisms play in the gut and in the development of disease. I have written about both fungi (mycobiome) and protists before on this blog but unfortunately, not nearly as much as I’d like, as there really is so little research happening out there.  Anyway, she points out – as I have  – that Crohn’s disease, for example, certainly seems to be associated with increases of fungi in the gut.

Which leads to me to a 2nd article[ii] that appeared the same day, this one describing a National Institute of Health grant just given to Dr. Mahmoud A. Ghannoum, a professor and researcher at Case Western Reserve School of Medicine and Cleveland Medical Center, to continue his research into this very association.   Several times, I’ve written about the increase in the yeast, C. tropicalis, being associated with flare ups in IBD.  (For example, here and here.)  In this latter post, I wrote about Dr. Ghannoum’s recent research:  “In a mouse model, fungi have been shown to aggravate the severity of inflammation in IBD.  This research supports the idea that the fungi work with the bacteria in such a way as to worsen IBD symptoms. In fact, another study in humans… showed that the fungi, C. tropicalis, and the bacteria E. coli and S. marcescens, work together to form a biofilm (kind of a slimy mass that protects the organisms inside – think about the plaque on your teeth) that evokes an inflammatory immune response.”  Dr. Ghannoum was will be looking at this in much greater depth, to figure out exactly how this yeast interacts with the gut bacteria to trigger Crohn’s.

  1. Dr. Ghannoum will look at the genes of these 3 organisms alone and then together, to see which increase in expression when they are together. He’ll then delete those genes to see if the biofilm still forms.
  2. Secondly, he’ll look at the metabolites secreted by the biofilm so see if this is the factor that leads to the increase in fungi.
  3. Finally, he’ll see how these 3 organisms in isolation, and together, affect inflammation levels. Plus, does giving anti-bacterial, antifungal, etc. agent affect inflammation levels?

Says Dr. Ghannoum, “”The long-term goal of this project is to develop novel antifungal and probiotic strategies that can be tested in pre-clinical and clinical studies to decrease the occurrence and duration of symptoms in patients…”

In fact, Dr. G and colleagues are already working on a probiotic mix to treat this overgrowth of C. tropicalis and the ensuing biofilm it forms.  They published a paper[iii] in April, in which they tested a mixture “…consisting of Saccharomyces boulardii, Lactobacillus acidophilus, Lactobacillus rhamnosus, and Bifidobacterium breve…that would prevent and treat PMB [biofilm].”  And yes, this probiotic mix successfully and significantly reduced the thickness of the biofilm.  In their concluding paragraph, the authors state, “The antibiofilm activity of our probiotic has significant health implications given that biofilms are increasingly being recognized as primary contributors to host infections and certain GI diseases (e.g., Crohn’s disease and colorectal cancer). According to the World Health Organization, biofilms are implicated in 65 to 80% of microbe-based diseases.”

Holy smokes, right?!

Hopefully, human clinical trials are on the near horizon.  Stay tuned.

__________________________________________________________________

[i] https://massivesci.com/articles/fungi-protists-in-microbiome-research-mycobiome/

[ii] https://www.eurekalert.org/pub_releases/2019-07/cwru-hdi072519.php

[iii] Hager, CL, etc.  Effects of a Novel Probiotic Combination on Pathogenic Bacterial-Fungal Polymicrobial Biofilms.  mBio.  2019.  10(2).  doi: 10.1128/mBio.00338-19

Allergy and Asthma Risk in Children: A Gut Bacteria Metabolite Culprit Identified

Two weeks ago, I wrote  about a retrospective study out of Loyola University in which researchers looked at the relationship of the early introduction of antibiotics to the development of allergy and asthma. If you recall, they found, “Exposure to these medicines in their first year was significantly correlated with the development of asthma, but not with allergic rhinitis.  However, there was a significant association of lifetime antibiotics to the development of both diseases.”

I thought it would be a good follow-up to report to you the results of a 2nd study on the topic, this one out of the University of California at San Francisco.[i]  Apparently, a particular fat molecule (12,13-diHOME) has been found at high levels in the feces of babies at high risk for developing asthma and allergy in childhood.  Previous research found that this particular molecule actually lowers both activity and levels of regulatory T cells (Treg) – which, as you know, are the “off switch” to the proinflammatory system, producing various anti-inflammatory cytokines (chemical messengers). These scientistis found,  in animal studies, that delivering this fat molecule into the guts of mice causes a direct reduction of Treg in their lungs while also increasing lung inflammation.

The researchers tracked down the production of  12,13-diHOME to a few bacterial genes, and when bacteria with those genes were introduced to the microbiomes of mice, sure enough, Tregs in the lungs were adversely affected.  (The genes were found overexpressed in specific strains of E. coli (E. faecalis), and 2 species of B. bifidum.)

They then looked at fecal samples from 1 month old babies and found a distinct association between bacteria with those genes and the subsequent likelihood of the baby developing asthma – and allergy and eczema:  “…12,13-diHOME was present in all neonatal stool; however, significantly higher concentrations were detected in the stool of neonates who subsequently developed atopy [by 2 years of age] and/or asthma [by 4 years of age], even after adjusting for potential confounding factors.”  This finding was replicated in a second group of babies.

Interestingly, the stool samples came from cohorts of babies that were collected years ago for research purposes. They were from ethnically diverse babies, collected in different places in California and years apart.  The researchers did indeed take into account factors known to influence asthma and allergy risk, like maternal smoking or breast feeding in that first month of life.  Essentially though, they were able to conclude that these did not sway the results:  elevated levels of 12,13-di-HOME was the deciding factor. Unfortunately, there was no information that I spotted in the article about antibiotics in that first month of life. That would be darn interesting to know, wouldn’t it?

At this point, we have no information as to how to lower levels of this molecule.  Would probiotics help, for example?  The authors conclude that this one fat molecule, and these 3 genes, are undoubtedly not the only factors involved in the development of allergy and asthma in children.  (They also didn’t look at whether or not any other inflammatory chronic diseases developed in the children.)  We’ll just have to wait for more research.  Still – this is an awfully compelling bit of work, isn’t it?

__________________________________
[i] Levan, SR, et. al. Elevated faecal 12,13-diHOME concentration in neonates at high risk for asthma is produced by gut bacteria and impedes immune tolerance.  Nature Microbiology. 2019. doi: 10.1038/s41564-019-0498-2

Autism and Clostridia: Mounting Evidence of a Connection

As you know, I’ve been following the research of Dr. Derrick MacFabe for a good 20 years now.  I’ve described it before on this blog, several times, including this first post 2 ½ years ago – to which, if you remember, Dr. MacFabe was kind enough to respond.

A short refresher:  the Clostridial family of bacteria have both probiotic and pathogenic members, including C.difficile, which you likely have heard of as a serious, potentially lethal, species which causes severe diarrhea. The bacteria that causes botulism are also in this family.  Various kinds of Clostridia are normal members of our bacterial microbiome, and are known to be major producers of the short-chain fatty acid, proprionic acid (PPA), which can easily cross the blood-brain barrier.  Because it’s a normal, and usually beneficial, metabolite of gut bacteria, and has potent anti-fungal properties, PPA is frequently used as a preservative in food.  So while short-chain fatty acids, like PPA, are usually great for us, to old adage still holds true:  you can have too much of a good thing.

In light of the differences in the gut bacteria of those with autism, including very high levels of Clostridia, Dr. MacFabe and colleagues injected PPA directly into the ventricle of the heart (so into the blood stream) in rats to see what would happen and found that it induced, “…abnormal motor movements, repetitive interests, electrographic [EEG] changes , cognitive deficits, perseveration [repetitive behaviors], and impaired social interactions. The brain tissue of PPA-treated rats shows a number of ASD-linked neurochemical changes, including innate neuroinflammation…”  The animals also went on to “…display brain electrical changes resembling some types of human epilepsy, which often co-exists with autism.”  Repeated administration of PPA over time, increases the severity and effects, which suggests “…that PPA can exert permanent effects on brain and behavior.”[i]

For those of you who want to learn more, definitely take a little time to watch Dr. MacFabe talk – for example, here.  Pay particular attention to the slides starting around minute 33, where you can actually footage of these “autistic” rats.  It’s mind blowing.

The mechanism of action though, as to how and why PPA exerts a toxic influence was still not entirely known but yesterday, I read a paper that moves this research forward to a whole new level.[ii]  Noting Dr. MacFabe’s work, and his finding that PPA led to increased glial cells (I’ll define this in a moment) in rats’ brains –  and that previous research also shows abnormalities in the autistic gut biome (including elevated levels of the species Clostridia, Bacteroidetes and Desulfovibria (which I have also written about in the past)), researchers from the University of Central Florida introduced PPA to human neural stem cells to see what would happen.  In people, these stem cells develop into the different kinds of cells in the brain, including neurons…and glial cells, which are a part of the brain’s immune system, pump out inflammatory cytokines when the brain is damaged or under attack, and also “…play a role in neurons development, connectivity, and protection.”

These researchers hypothesized that exposure to excessive levels of PPA, starting in utero, may cause these stem cells to excessively product glial cells which, in turn, increases inflammation in the brain and disturbs neural connectivity.  Their theory was based on 20 years of mounting evidence of PPA’s role in autism, and also, the incredible parallels between autism and a condition called neonatal Proprionic Acidemia, in which a genetic mutation leads to PPA accumulation in the blood.  This causes “…severe seizures, movement disorders, gastrointestinal issues, aloofness, and overall developmental delays.”  In fact, growing evidence “…suggests that ASD may stem from a disorder in glial cells.”

In this in vitro experiment, these researchers indeed found that PPA induced excessive differentiation of the neural stem cells into glial cells and raise brain inflammation levels. This led them to propose that exposure to PPA during fetal gestation, in the early stages of brain development, leads to gliosis (excessive glial cell formation), inflammation and thus, abnormal brain connections:  “Overall, the data in this study suggest that microbiome shift in maternal gut leads to formation of by-product such as PPA which then interferes with neural patterning during the early stages of the fetus’ neural development.”

They suggest that it is the mother’s diet that leads to excessive PPA in her gut, potentially harming the fetus:  “During the early stages of pregnancy, increased consumption of PPA-rich processed foods combined with pre-existent dysbiosis may lead to accumulation of PPA in the maternal GI, travel through general circulation, cross the placental barrier, and interfere with neural differentiation…”  Certainly, this may well be a factor.  As this article points out, the numbers of children with autism in the United States has gone from 1 in 150, in 2000, to 1 in 59, in 2018.  Several decades ago, it was 1 in 10,000.  And yes, PPA has become a more and more common food additive.  However, this does not explain why children on the spectrum have altered gut microbiota, and are themselves producing excessively high levels of PPA from their earliest days, even while not eating processed foods…nor does this explain why children from mothers who eat healthy, unprocessed food diets are also having children with autism.  That dysbiosis is a multi-generational problem in the industrialized world is a given at this point.  (You can read more about this on The Biome Buzz as well.)

So, while it certainly takes us a step closer to an answer, it’s not the whole answer.  It certainly seems likely that the maternal biome may play a role in some cases of autism.  We still need though to take into account the early introduction and overuse of  leading to alterations in the infant biome.  After all, we know that people who have been on antibiotics tend to be very prone to Clostridia infections.  Perhaps this explains some of the enormous variability found in the autism population:  perhaps it’s all a matter of timing?  And the number and severity of the pro-Clostridia events in the baby’s life?

______________________________________________________________

[i] Parracho, HMRT, Bingham, MO, Gibson, GR, McCartney, AL. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children.  Journal of Medical Microbiology: 2005, 54, 987-991.

[ii] Abdelli, LS, Samsam, A, Naser, SA. Proprionic acid induces gliosis and neuro-inflammation through  modulation of PTEN/AKT pathway in autism spectrum disorders.  Scientific Reports. 2019. 9(8824).  doi.org/10.1038/s41598-019-45348-z