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.

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[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.

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[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?

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[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.

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[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?

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[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 well over a decade 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, propionic 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 Propionic 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?

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[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. Propionic 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

Cancer, Diet and Gut Bacteria

On Monday, I read a little article on Medical Express about a multi-center research study done in Spain, just published in the journal, Nutrients, which took an in-depth look at the association between diet and the development of both breast and colorectal cancer.[i]   Thousands of cases of cancer, as well as healthy controls, were analyzed and the scientists found that those who ate an inflammatory diet (which included a high consumption of red and processed meat, saturated and trans fats, and refined carbohydrates) had twice the risk of developing colorectal cancer than those who ate an anti-inflammatory diet (consisting of predominantly plant-based foods, like vegetables, fruit, legumes and nuts).  Interestingly, they did not find an association with breast cancer.  (They intend to look into this further in the future.)

Ordinarily, while interesting, this wouldn’t merit a blog post from me as it is hardly surprising, but within minutes of finishing reading it, I read a second article, this one out of the Baylor College of Medicine, on the exact same topic:  the relationship of diet to colorectal cancer.[ii]  As it is the 4th most common cancer in the world, well…now this relationship did seem worth reporting to you, especially since there is such synergy between the two studies.

The Baylor researchers, noting this relationship, are actually trying to figure out the mechanism of action.  How does diet influence the risk of this cancer?  These scientists had already shown, in a previous study, that a healthy diet was associated with a decrease in the risk of pancreatic cancer.  They now have taken that research a step further.

It turns out that there is an association between “…diet quality and microbiome composition in the gut mucosa.”  These scientists found that “…a high-quality diet is linked to more potentially beneficial bacteria; while a low-quality diet is associated with an increase in potentially harmful bacteria.”  While this too is hardly shocking, what IS really interesting about this Baylor study is that rather than looking at individual diets, they looked at dietary patterns (I’ll come back to this in a moment), and secondly, they looked directly at the gut bacteria in the mucus lining of the intestines (from consenting adults having colonscopies), as opposed to analyzing fecal samples.  Since the gut bacteria influence, “…nutrient uptake, synthesis of vitamins, energy harvest [i.e. how calories are derived from food and used or stored], chronic inflammation, carcinogen metabolism and the body’s immune and metabolic response…,” well, obviously the microbiome has tremendous influence on the development of disease.

In terms of dietary patterns, they compared the foods the participants ate to the Healthy Eating Index (HEI)-2005, and looked at how particular groups of foods affected the gut bacteria.  Lower scores on the index are given for whole fruits (HEI 1 and HEI 2), while added sugar, trans fats and alcohol are HEI 12s.  They found not only that there were distinct differences for let’s say, HEI 7 (lower Faecalibacterium and Fusobacterium but higher Bacteroides) as compared to, for example, HEI12 (lower Subdoligranulum but higher Escherichia and Fusobacterium), but also that “A lower score for total HEI–2005 was significantly associated with reduced relative abundance of potentially beneficial bacteria but increased potentially harmful bacteria in the colonic mucosa of endoscopically normal individuals.”[iii]

The bacteria in the mucosa are associated directly with both immunity and host-microbiome interaction, apparently more so than fecal bacteria.  These researchers found “…a good-quality diet as the one recommended by the Dietary Guidelines for Americans to be high in fruits, vegetables and whole grains, and low in added sugar, alcoholic beverages and solid fats is associated with higher abundance of beneficial bacteria such as those with anti-inflammatory properties. A poor-quality diet, on the other hand, is associated with more potentially pathogenic bacteria, such as Fusobacteria, which has been linked to colorectal cancer.”

Essentially, they conclude that by affecting the structure of the mucosal microbiome, diet affects immunity, thus inflammatory status…thus the risk of cancer and other chronic diseases.

This of course, completely coincides with the findings of the Spanish scientists, I mentioned early.  And you all know how much I love coincidences!

Going forward, this team wants to look in greater depth at bacterial metabolites (like short chain fatty acids, for example) to see how these affect the growth of tumors, as well as looking how we can modify the gut bacteria using pre- and pro-biotics,  even in those with a poor diet.

In the meantime though – not exactly a news flash: eating a healthy diet seems like a pretty good idea.

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[i] https://medicalxpress.com/news/2019-07-inflammatory-diet-colorectal-cancer.html

[ii] https://www.bcm.edu/news/research/diet-influences-microbiome-colonic-mucosa

[iii] Liu, Y, et. al. Dietary quality and the colonic mucosa – associated gut microbiome in humans. The American Journal of Clinical Nutrition. 2019.  https://doi.org/10.1093/ajcn/nqz139

Yet MORE on Akkermansia, This Time as a Pasteurized Probiotic!

A few weeks back, I shared a post about a recent study that looked at using our old friend, Akkermansia muciniphila (a quick summary of some of the findings re:  this probiotic bacteria are in a postscript below) to improve glucose tolerance and insulin levels.  (I had written about this before once, back last October.) As many of you know, there’s a bi-directional association between poor glucose control and weight gain.  And as I’ve been writing about extensively, obesity is one of the great health epidemics of our time – as is type 2 diabetes and its predecessor, metabolic syndrome. Akkermansia is also one of my biggest interests, as a growing body of research shows it has powerful health effects, including helping with weight loss.

A quick primer on insulin before I proceed.  Firstly, remember that in order to be absorbed and utilized by your body, all carbohydrates – which are just long strings of sugar molecules – must be broken down to individual molecules in your intestines, before making it into your blood stream to feed every cell of your body.  Remember too that insulin is released when those sugars hit your blood, to keep that glucose at a steady level.  Blood sugar, in fact, is incredibly tightly regulated in the body as even a little too much or too little has enormously detrimental effects on us.  To rapidly remove excess glucose from your blood, insulin quickly stores it away in your liver…but if your liver is “full,” it stores it as fat.  If you’ve ever heard of the glycemic index, well, this is essentially the theory behind it:  rapid rises in glucose cause a huge burst of insulin, which then rapidly stores the sugar as fat, so the avoidance of foods that cause this – in favor of foods that cause only slow rises in blood sugar (reducing the need for insulin release) – are thought to be helpful for weight loss.  (That said though, we are learning that because of differences in the composition of gut bacteria, people have entirely different glucose responses to the same foods.  I’ve written about that here. So even this gets to be an awfully complicated picture!)

Anyway, back to Akkermansia and this new research:

After I posted that story, one of my regular followers asked me what “pasteurized” A.municiphila  meant, and I responded that it was heat sterilized.  He wrote back saying, “But won’t that kill the bacteria?”…which yes, I assumed it would and like him, didn’t really understand why dead probiotics would have a beneficial effect.  And that’s been wearing on me…but I simply haven’t had time to do more research into it. (Please, all of you understand – this blog is a labor of love.  I make no money from it…and I already am a single mom caring for a profoundly autistic son…and work 2 “real” jobs as well.  I’m just a little swamped for time!  So Stephen, I’m sorry it’s taken me a couple of weeks to get back to you on that!)

Therefore, though, I was very excited when an article appeared yesterday on Gut Microbiota for Health explaining this phenomenon.[i]

The article was actually written by one of the researchers involved in these studies.  He starts by stating that in 2017, his team found that “…a pasteurized form of A. muciniphila led to a stronger reduction in fat mass development, insulin resistance and dyslipidemia in mice when compared with the live bacterium.”  Since they didn’t know if it would have the same effect in humans, he just led a 3 month long randomized, double-blind, placebo-controlled study (so the gold standard) looking at this in 32 overweight or obese people and found, again, that this heat-inactivated (you read that right:  INACTIVATED) form of A.muciniphila, “…helps to limit the increase of different cardiovascular risk factors in subjects who are overweight and obese.”  How crazy is that?![ii]

The people in the study did not change anything else during the trial, so no diets and no increase in physical activity.  They were then, in randomized fashion, given 100 billion of either live A.muciniphila or this inactivated, pasteurized form.  Only those treated with the latter – the inactive form – had “…lower circulating insulin levels, reduced insulin resistance indices, lower total blood cholesterol and lower circulating dipeptidyl peptidase IV (DPP-IV) when compared with the placebo group. The enzyme DPP-IV has been involved in modulating glucose homeostasis, satiety and emotional-affective behavior.”  So it not only improved glucose control – it also improved feelings of being full?! This inactive form also reduced white blood cell counts (which are apparently elevated in obesity and “associated with glucose intolerance”); AND reduced the amount of proinflammatory byproducts from gut bacteria (lipopolysaccharides, or LPS); AND it reduced liver inflammatory markers.

Wait…what?!  How is this possible?!

Well, they don’t know for sure but…here’s the theory.  They know from previous studies that the outer membrane of A. muciniphila contains a protein called Amuc_1100 which seems to induce many of the benefits associated with giving mice and humans pasteurized A. muciniphila. The researchers therefore believe that this mild heat inactivation, or pasteurization, allows the components of the bacteria’s cell wall greater freedom to exert these benefits.

Both forms of the A. muciniphila were well tolerated, by the way, and as you’ve read on this blog before (see below), the live form also exerts huge benefits.  So…you’ll be happy to read the last sentence of this article:  “Our next steps include planning larger-scale tests and commercializing the bacteria in the form of food supplements.”

Whoopa!

p.s.  As promised, here are just 3, of several, other posts on The Biome Buzz related to Akkermansia muciniphila:

  1.  It appears to have an anti-aging effect as I wrote about here on November 20, 2018.
  2. In May 2018, I wrote about the finding that boosting levels of Akkermansia, via the ketogenic diet, seems to have anti-seizure effects.
  3. Akkermansia may also be beneficial in neurodegenerative diseases, like Alzheimer’s as I wrote about here, in October 2018.

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[i] https://www.gutmicrobiotaforhealth.com/en/akkermansia-muciniphila-helps-improve-features-of-metabolic-syndrome-in-overweight-and-obese-subjects/

[ii] Depommier C, Everard A, Druart C, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med. 2019. doi: 10.1038/s41591-019-0495-2.

Antibiotics in Early Childhood: The Road to Asthma and Allergy

When my son was just 36 hours old, he was re-hospitalized with a fever and put onto 5 days of IV antibiotics.  (You can read more about his history here.)  He was given more oral antibiotics right before his first birthday. Once I learned about the gut-brain-immune connection, several years later, I began to wonder what effect those antibiotics had had on him, especially in light of his diagnoses with both autism and then, several years later, with inflammatory bowel disease.

As you can imagine, I’ve always followed research into the effects of early introduction of antibiotics closely.  I remember, when Alex was very young, I found myself sitting in a psychiatrist’s waiting room reading an article in a lay publication about the burgeoning realization that there is a relationship between early use of these medications and the development of allergy. And 20 years later, I’m still reading more of the same.  There is a massive amount of evidence at this point.  I’ve addressed this issue several times before on this blog, for example, here – but it’s such an incredibly important topic that I want to keep you up-to-date as the evidence accumulates.

Last night I read a study done at Loyola University’s Medical Center that used a retrospective look at children’s medical charts, between the years of 2007 and 2016, to further delve into this association.[i]  Before I go into their results though, I want to tell you a couple of astounding statistics the paper provides.  Firstly, in spite of the fact that the overuse of antibiotics is known to be detrimental to health, and that there is a relationship between “…early antibiotic exposure and dysbiosis of the gut microbiota [which] may have significant implications for the health of children now and as they grow into adults,”  the use of these medicines continues to grow in hospitals. They are also the “…most frequently dispensed outpatient prescription medication, accounting for approximately 25% of all pediatric medication prescriptions.”  A recent large study showed that 30% of the antibiotics prescribed for respiratory tract infections are unnecessary.  11.5 million antibiotics are prescribed annually for illnesses without a bacterial component.

Unbelievable, right?

The article goes on to state that the first year of life is crucial in the development of a normal bacterial microbiome, and that by 3 years of age, it is fully mature.  Early disruption of the microbiome has been definitively linked with disruptions of the immune system and to the development of atopic (allergic) and inflammatory respiratory diseases, like asthma and allergic rhinitis.  This particular study is meant to add data to the investigation into the question of the timing of the antibiotics and its relationship to these illnesses: “…we hypothesize that children exposed to antibiotics during the first year of life will be more likely to be diagnosed with asthma or allergic rhinitis later in childhood, compared to children not receiving antibiotics during their first year of life.”

The researchers analyzed the data from 7224 children born at the hospital and  once they narrowed it down to those who had at least 2 subsequent visits there, were left with 2398 of them.  Believe it or not, a whopping 44.2% of these children were exposed to antibiotics in their first year!  And in the course of the 9 years covered by this study, the children averaged about 4 rounds of antibiotics.  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.  This, the authors suggest that this may mean that the early developing gut flora “… may still be sensitive to insult as the child grows, or that the insults may be cumulative and irreversible.”  That is, the more antibiotics a child is exposed to in those first early years, the worse the permanent damage, and the greater their chances for developing these diseases during the course of their lives.

In my son’s case, his antibiotic exposure, which of course is just one factor in his medical history that was likely detrimental, did not lead to allergy or asthma, which are the only two illnesses looked at in this research.  I’d bet money though that more such studies, looking at other diseases, will be conducted in the near future.  I’ll read them, of course, and report to you. But…I’m not looking forward to it.

p.s.  Don’t you wonder why the physicians prescribing the antibiotics didn’t have the parents put the babies on infant probiotics or synbiotics (i.e. a combination of pro- and prebiotics)?  Or…if they did, did it have a protective effect at all?  I also wonder how many of these babies were breast fed…???

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[i] Ni, J, Friedman, H, Boyd, BC, McGurn, A, Babinski, P, Markossian, T, Dugas, LR.  Early antibiotic exposure and development of asthma and allergic rhinitis in childhood.  BMC Pediatrics. 2019. 19:225.  https://doi.org/10.1186/s12887-019-1594-4

More on Helminths and the Prevention of Cancer

Last October, I wrote about a study that looked at the effects on cancer of the immune modulation afforded by helminths (intestinal worms), which are the main component of the mammalian macrobiome.  That paper provided a very positive initial review of the mechanisms by which helminths may exert their anti-cancer effect, but obviously, a massive amount of data and studies needed to be done before any conclusions could be drawn.

Previous research has shown that there is a correlation between the lack of a strong Th2 immune response and the development of cancer.  Nowadays, the Th2 family of cytokines (chemical messengers) is associated with allergy (an inappropriate inflammatory response to benign environmental stimuli), but in fact, from an evolutionary stand point, these chemicals are there to keep our helminths in check.  (Some are good, some are bad, and too many of even the benign ones are not good.  Our bodies needed to develop a mechanism of action to deal with their presence in a way as to ensure our survival.) As I have written about before many times (here, as just one example), all mammals on the plant evolved with a macrobiome – our native animal life – as well as the much better known microbiome.  However, in the last 50 to 75 years or so, those of us living in the industrialized world (and our domesticated pets) have effectively been de-wormed.  As the Th2 cytokines also include those which are regulatory, which moderate inflammation, we are now perpetually low in regulatory chemicals and prone to out-of-control inflammation.  Some scientists have now come to believe that the loss of our helminths is one of the biggest factors in our current epidemic of inflammatory diseases, ranging from allergies to autoimmunity to autism to cancer.  Unlike a swift (i.e. acute) “allergic” response, helminths provide a strong and continual stimulation to the Th2 system, which as I said, over months and years, modulates inflammation. De-worming humans is akin to going into a rainforest and removing all the insects.  We abruptly killed off an entire species from our ecosystem.  And humans, like all ecosystems, were in a delicate balance…that we have destroyed.

In May, a new animal study came out looking at the effects of a helminth, H. Nana (which is native to rodents) on cancer. [i] The scientists broke the mice up into 4 groups:

  1. The first group was given DMSO cutaneously (through the skin)
  2. The 2nd group were given only the H.nana
  3. The 3rd group was given another chemical, DMBA, again cutaneously. DMBA is known to induce tumor growth.
  4. The 4th group was given both the helminth, H. Nana, and the cutaneous DMBA.

The chemicals given  the mice did indeed induce tumor growth, and the tumor load, as well as blood levels of various  immune components were assessed by the researchers.

The results showed that the group that had first been colonized by the H.Nana had “…a reduced amount of tumors with smaller size…”  More than that, they found that they had significantly lower levels of proinflammatory immune cells in their blood.  They concluded that the reduction in tumor growth may be due to the increase in certain kinds of immune cells (eosinophils and neutrophils) that they found in the animals.  It is unlikely to be from anything secreted by the H.Nana because the protective effect lastedeven after the mice had eliminated the helminth.

One item of particular interest to me:

As my regular readers know, interleukin-10 (IL-10) is one of the predominant regulatory cytokines that is very much responsible for modulating the inflammatory response and balancing the immune system.  It is also thought to perhaps be associated with cancer, as lowering the inflammatory response may prevent the body from fighting cancer cells effectively.  (That is, an increase in IL-10 for people who already have cancer may be a bad idea.  This thinking , however, is still very controversial as IL-10’s relationship to cancer, should it exist, is poorly understood.)  What these researchers found though is pretty amazing.  The highest levels of IL-10 were found in the mice who were only given the carcinogenic DMBA, and this actually replicated the findings of previous studies!  Those who also had the helminths on board actually had a “significant reduction” in IL-10 levels, even though helminths are usually a potent stimulator of its production.  What does this suggest? It appears that helminths not only do not actually suppress immune response, but instead, seem to modulate it so that it is appropriate for the given situation.  Therefore, in the face of a carcinogen, the helminths stimulate the immune system in such a way as to help it fight cancer – and thus, the reduction in tumor growth seen in this group.  In fact, the tumors induced by DMBA typically start as benign and progress toward carcinoma (cancer).  However,  the few tumors that did grow in the mice with helminths on board did not progress toward malignancy.

That is a major WOW.

According to a 2017 article out of the University of Adelaide, in Australia (which, by the way, has the highest rates of cancer in the world)[ii]:  “…the 10 countries with the lowest opportunities for natural selection (among the “better” countries of the world) are: Iceland, Singapore, Japan, Switzerland, Sweden, Luxembourg, Germany, Italy, Cyprus, and Andorra….The 10 countries with highest opportunities for natural selection (among the “worse off” countries of the world): Burkina Faso, Chad, Central African Republic, Afghanistan, Somalia, Sierra Leone, Democratic Republic of the Congo, Guinea-Bissau, Burundi, and Cameroon.”[iii]

Their explanation , which of course is very likely a part of the picture, is that because we live longer in the industrialized world – ie. we don’t die from acute infections like malaria and the like, have better medical care, and so forth – we get cancer more often.  But it also strikes me that what they call the “worse off” countries are also those where helminth colonization is still the norm.

As I say to you  all the time – there are no simple answers.  The cancer question is undoubtedly going to turn out to be one of those cases where many factors,  from the two I just named, to our food, our chemical exposure, etc. are all a part of the picture.

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[i] Ramos-Martinez, E, et. al. The immune response to Hymenolepis nana in mice decreases tumorigenesis induced by 7,12 dimethylbenz-anthracene.  Cytokine. 2019. 123:154743.  doi.org/10.1016/j.cyto.2019.154743

[ii] https://www.wcrf.org/dietandcancer/cancer-trends/data-cancer-frequency-country

[iii] https://www.sciencedaily.com/releases/2017/10/171011100708.htm