Gut Bacteria, Exercise and Insulin Resistance

I found this really interesting:  did you know that some people “…do not respond or negatively respond to exercise in terms of insulin sensitivity and blood sugar balance for reasons that remain unknown”?  I did not, although I suppose I would have guessed as much.

Researchers from the University of Hong Kong looked at the gut microbiomes of 39 prediabetic (so already showed signs of insulin resistance) overweight or obese men, half in an exercise group, half kept sedentary for the 12 week study.[i]  At the end of the study, the men were classified as either responders or non-responders depending on blood sugar levels and insulin sensitivity.  Those who responded to exercise had higher amounts of the kinds of bacteria that produce short-chain fatty acids (SCFAs), which are critically important in regulating energy and glucose levels, as well as inflammation levels: “…responders were characterized by a 3.5-fold increase of Lanchospiraceae bacterium (a butyrate-producer)…”  They also had an “…increased growth rate of several species in Bacteroides genus, most of which are propionate producers…”

The non-responders in the exercise group, on the other hand, showed “…increased production of metabolically detrimental compounds,” i.e. an increase in the production of the amino acid, glutamate, which is found to be increased in those with insulin resistance and higher levels of inflammation.  Their gut bacteria profiles similar to the sedentary group.

All the participants in the exercise group did achieve some weight loss, an improvement in lipid profiles (i.e. triglycerides and cholesterol), cardiovascular fitness and so forth.  However, the non-responders did not show response in fasting glucose and insulin levels.  The increased SCFA production seen in the responder group is really interesting, I think:  the anit-diabetic drug, Metformin, which I have written about before, is thought to work by increasing the production of SCFAs.  Remember though:  while some studies have shown that supplementing proprionate reduced fasting glucose levels, others have shown the opposite.  Remember my post from last September on that Harvard proprionate study?

That’s the thing about SCFAs:  too much is just as bad as too little.  Read this post on the subject.

It gets even more interesting.  The scientists used fecal microbiota transplant to transfer the gut bacteria from the responders and non-responders into mice.  Not surprisingly, only the microbiomes of the responders alleviated insulin resistance in obese mice.  Other studies have shown, by the way, that FMT from healthy individuals into those with metabolic syndrome has worked as well.

Why people undergo different microbial changes doing the same thing, i.e. exercising, is currently unknown.  These researchers theorize that there may be subtle differences in the gut bacteria of people that cause varying response to increased oxidative stress from exercise, for example.  Remember that people do respond differently, in terms of insulin response, to the same foods; it’s all based on individual microbiome composition.  (You can read about that here.)

The hope is, of course, that some day soon, microbiome analysis will reach the stage wherein programs to achieve and maintain health (i.e. the right diet, the right exercise, the right probiotic to tweak the biome, etc.) will be the  norm.

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[i] Liu et al., Gut Microbiome Fermentation Determines the Efficacy of Exercise for Diabetes Prevention. Cell Metabolism, 2019. doi:  10.1016/j.cmet.2019.11.001

 

A New Gut-Brain Connection: Obsessive-Compulsive Disorder

I continue to monitor any new research into the connection of the gut biome to “mental illnesses.”  My son, Alex, who is diagnosed with autism, suffers from terrible anxiety at times.  It’s heart breaking to see.  Obsessive compulsive disorder (OCD) is generally considered a subset of anxiety disorder – and it’s a nightmare for both the affected person and those who love him/her.

As my regular readers know, many so called psychiatric disorders are now associated with gut microbiome differences including, “…autism spectrum disorders (ASD), major depressive disorder (MDD), bipolar disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, psychosis and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS)/pediatric acute-onset neuropsychiatricsyndrome (PANS).”  I have written about all of these at one time or another on this blog.

A quick note then about a newly published paper.  Researchers in Australia and Canada have done the first gut biome study on obsessive compulsive disorder.  They sampled blood and stool from 21 patients with OCD (who were not on medications) and compared these samples to those from 22 control patients, who were not diagnosed with any kind of mental disorder.[i]  The findings were highly significant.

The patients with OCD had less gut bacteria diversity, and distinctly lower levels of 3 bacteria which produce the short-chain fatty acid, butyrate (Oscillospira, Odoribacter and Anaerostipes).  They also found signs of inflammation, in that blood levels of CRP (c-reactive protein) were highly elevated in the OCD group:  “CRP revealed moderate to strong associations with psychiatric symptomatology.”  That is, the higher the CRP level – the higher the level of inflammation in the person – the greater the OCD symptoms (and, not surprisingly, the greater the level of anxiety as well).

The authors point out the probiotics have shown in studies to reduce obsessive-compulsive scores.  In children with abrupt onset of OCD, as in the case of PANDAS or PANS, gut microbiome alterations have already been measured.   (See links above for more on these subjects.)

Butyrate, which I have mentioned many times before, is known have anti-inflammatory properties, as well as improving the integrity of the gut barrier (ie. preventing leaky gut):  “Increased intestinal permeability is one of the leading hypotheses for microbial dysbiosis in psychiatric conditions, as it permits translocation of intestinal contents into systemic circulation resulting in a potential inflammatory reaction.”

There is an extensive section in the paper pointing out areas for future research, as establishing that these differences exist is really just a first step.  There are no suggestions yet as to what to do about the problem.  We can only hope research into this progresses rapidly.

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[i] Turna J, Grosman Kaplan K, Anglin R, et al. The gut microbiome and inflammation in Obsessive-Compulsive Disorder patients compared to age- and sex-matched controls: a pilot study [published online ahead of print, 2020 Apr 20]. Acta Psychiatr Scand. 2020;10.1111/acps.13175. doi:10.1111/acps.13175

A Traditional Japanese Herb, Akkermansia muciniphila, and Health

One of my regular readers (you know who you are, S.!) has written to me several times asking about ways to increase the probiotic species Akkermansia muciniphila, which is not as yet available in probiotic form. I’ve written before about whatever research I could find on the subject (for example, here), and continue to look out for whatever may pop up.  Thus, today’s post.

I’ve mentioned this species many times on my blog, as it  is associated with many health benefits.  To highlight just a few: this post was about the role it may play in slowing the progression of ALS. It seems to protect against atherosclerosis. Low levels are associated with the development of Alzheimer’s disease and also, autism.

So how’s this for interesting? There is new research out of Japan on a traditional Japanese herb called Bofutsushosan (BTS).[i] A pharmaceutical-grade product has already been shown in animals and humans to help with obesity, which I find interesting enough in and of itself. In this study, researchers tested BTW in mice genetically engineered to become obese to see its effects on obesity, liver damage (i.e. non-alcoholic fatty liver disease (NAFLD), which is often the result of obesity), and the gut microbiome.  Of everything I have ever seen that boosts levels of Akkermansia, none has come close to this.

First a definition for those not familiar:  according to the Mayo Clinic, non-alcoholic fatty liver disease encompasses “…a range of liver conditions affecting people who drink little to no alcohol. As the name implies, the main characteristic of NAFLD is too much fat stored in liver cells.  NAFLD is increasingly common around the world, especially in Western nations. In the United States, it is the most common form of chronic liver disease, affecting about one-quarter of the population. Some individuals with NAFLD can develop nonalcoholic steatohepatitis (NASH), an aggressive form of fatty liver disease, which is marked by liver inflammation and may progress to advanced scarring (cirrhosis) and liver failure.”[ii]

The first line of treatment for NAFLD is, of course, life style changes, including weight loss.  As you have read on my blog many times, the development and remediation of obesity is NOT a simply issue of “eat less.”  Many factors are involved, including alterations to the microbiome, inflammation, additives in our foods, and more.  As I have read various bits of research over the years, I’ve more and more come to appreciate just how multi-factorial is this issue, and how difficult it is to fix this growing epidemic.  As these authors write, “Recent research suggests the gut microbiota is deeply involved in human health and various disease states including obesity and NAFLD.”

Akkermansia muciniphila, they go on to state, is “…anticipated to be the next generation of beneficial microbe.”  We are still, however, awaiting it to become available in the consumer marketplace.

Traditional Japanese medicines are standardized with regard to both quantity and quality, according to these scientists, and are approved by the Japanese Ministry of Health and Welfare.  BTS has a long history of being used to treat obesity and obesity-related issues, and has been tested in multiple placebo controlled trials in humans.  It has been shown effective in helping with obesity as well as constipation, and its mechanism of action is believed to be via the gut biome.  This study involved a closer look at that action.

There were 3 groups of mice in this study:  a control group of mice genetically engineered to be obese who were fed a standard diet, a group of mice genetically engineered to be obese also fed a standard diet, and a group of similar obese mice given BTS for 4 weeks.  The obese group fed a standard diet showed a huge increase in body weight.  However, the group fed BTS gained weight much more slowly, similar to the normal “wild” mice group.  The BTS group also had markedly lower levels of liver damage than did the control obese group.

In terms of the changes to the microbiome, what really stood out was the increase in A. muciniphila.  It was present at “minor levels” in the obese mice fed a standard diet, but mice fed BTS had a huge increase in this species:  “Among genera whose relative abundance was above 1% in either group, those of the genus Akkermansia were most altered in the BTS group (93-fold higher).”

The authors go on to state:  “The rapid increase in the level of A. muciniphila was the most interesting finding in this study.  Many reports indicate the positive effect of A. muciniphila in preventing obesity or metabolic disorders.”  They state that it is known to improve insulin resistance, plasma cholesterol levels, and liver health in humans.  It is also known to improve the integrity of the gut epithelial lining (i.e. remediate leaky gut).

The scientists state that the improvement in levels of A. muciniphila are not the sole cause of the improvement in body weight profile.  The picture is, as always, more complex.  (Nothing is ever easy!)  Other gut bacterial levels were also altered, which may play a role, and BTS also seemed to reduce appetite which certainly played a role.  They were, however, able to conclude that in these obese animals, BTS reduced liver injury, attenuated weight gain, and greatly increased levels of A. muciniphila.

I have found that BTS is available for sale via Japanese companies.  Here is one example.    I have never tried it, and until I read this study, I had never heard of it.  If any of you do decide to give it a shot, please let us all know how you fare!

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[i] Nishiyama, M., Ohtake, N., Kaneko, A., Tsuchiya, N., Imamura, S., Iizuka, S., … Kono, T. (2020). Increase of Akkermansia muciniphila by a Diet Containing Japanese Traditional Medicine Bofutsushosan in a Mouse Model of Non-Alcoholic Fatty Liver Disease. Nutrients, 12(3), 839. doi:10.3390/nu12030839

[ii] https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/symptoms-causes/syc-20354567

An Introduction to a New “Old Friend”: Christensenella (to Treat Anxiety and Depression?)

Last week I found what amounts to a business news press release announcing that a microbiome company called LNC Therapeutics has licensed the use of a specific strain of a gut bacteria called Christensenella (which I had never heard of) from the National Research Council in Spain, giving them “…exclusive research, manufacturing, and commercialization rights of the microbiome-based therapies when developed for the treatment of mood disorders.”[i]  As you all know, one of my many particular interests is in natural treatments for these so-called “mental” disorders, which are for the most part, actually physiological in nature, often stemming from alterations in the gut biome.  So I decided to do a little investigation.

Scientists at the Spanish council have done preclinical work on this bacteria; they’d found that it “…regulates the stress response, reducing the overproduction of [the stress hormone] corticosterone [cortisol]…”  The mechanism is currently unknown, but what we do know now, apparently, is that the species is a keystone organism of the human biome, very much responsible for ensuring the health of the biome as a whole, including promoting the growth of other beneficial species of bacteria.  This seems to help the body regulate serotonin levels (bearing in mind that at least 90% of the serotonin in the body is produced in the gut), which, in turn, helps regulate inflammation and mood.

The idea is for LNC Therapeutics to create a new “drug” for anxiety and depression with this particular strain of Christensenella that appears most effective.   I’m sure I’ll be reading about clinical trials in the not-very-distant future, so stay tuned for that.

Not having ever heard of Christensenella, I looked around for some information on it for all of us.  I found a great article from National Geographic, from 2014, which was absolutely fascinating.[ii]  Believe it or not, the Christensenella family was only discovered in 2011.  This article describes research out of Cornell University wherein the gut microbes of 416 pairs of British twins was analyzed in order to look at which gut microbes are most strongly influenced by our genetics.  The big standout was a bacterium called Christensenella minuta: “Christensenella also seems to sit at the centre of a large network of microbes; if it’s there, these others are likely to show up too. And it influences our weight: it’s more common in lean people, and it can reduce weight gain in mice.”

Christensenella is the most inheritable bacteria:  “…some people have it and others don’t, and around 40 percent of that variation is down to our genes.”  And that leads to a myriad of other questions:  what genes affect the presence of the bacteria and how?  Is this why some families seem more prone to obesity/thinness than others?  How much does diet then affect the situation?

I cannot find a lot of research on Christensenella in PubMed, but it seems like a pretty important bacteria; I will most certainly watch to see where the research into using it for mood disorders goes.

Two  more interesting facts that I also came across in snooping around:

In 2017, a study in the journal Gut Pathogens mentions that “Gut microbiome studies have indicated that Christensenella minuta controls obesity in mice, Faecalibacterium prausnitzii protects mice against intestinal inflammation and Akkermansia muciniphila reverses obesity and insulin resistance by secreting endocannabinoids.”[iii]  Three years had gone by between that National Geographic article and the publication of this one, and still, the relationship of Christensenella to obesity had still only been studied in mice.  I can find nothing of note on this in the 3 years following the Gut Pathogens article, which I find odd.

I also found an article looking at the fecal microbiota of those with rheumatoid arthritis (RA) versus osteoarthritis (OA), which is worth mentioning (I’ve added the bold highlights to make it stand out for you):  “At the species level, the abundance of certain bacterial species was significantly lower in the RA group, such as Fusicatenibacter saccharivorans, Dialister invisus, Clostridium leptum, Ruthenibacterium lactatiformans, Anaerotruncus colihominis, Bacteroides faecichinchillae, Harryflintia acetispora, Bacteroides acidifaciens, and Christensenella minuta. The microbial properties of the gut differed between RA and OA patients, and the RA dysbiosis revealed results similar to those of other autoimmune diseases, suggesting that a specific gut microbiota pattern is related to autoimmunity.”[iv]

Autoimmune disease is highly associated with high levels of inflammation, as are both obesity and depressing and anxiety.  It will be really interesting to follow all this, as the upcoming trials using  Christensenella  for depression and anxiety may well yield positive results in other unexpected ways.

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[i] https://www.labiotech.eu/microbiome/lnc-therapeutics-microbiome/

[ii] https://www.nationalgeographic.com/science/phenomena/2014/11/06/the-most-heritable-gut-bacterium-is-wait-what-is-that-2/#close

[iii] Shivaji, S. We are not alone: ac case for the human microbiome in extra intestinal diseases. Gut Pathogens. 2017;9(13). doi: 10.1186/s13099-017-0163-3

[iv] Lee, JY, et. al. Comparative analysis of fecal microbiota composition between rheumatoid arthritis and osteoarthritis. Patients. Genes. 2019;10(10):748.  doi: 10.3390/genes10100748.

More On the Microbiome and Bile Acids: Colon Cancer Prevention?

In February, I entitled a post “Bile Acids, Inflammatory Bowel Disease, and the Microbiome:  A Rapidly Developing Story.”  Well, that rapidly developing story has taken another leap forward.  A new paper was just published in the journal, Nature, that shows that a metabolite produced by gut bacteria, called isoDCA, boosts levels of regulatory T regulatory cells (Tregs) in the intestines.[i]  (You’ll all remember that the regulatory part of the immune system modulates our inflammatory response so that we can keep it in check.  In humans and our domesticated animals living in the industrialized world, the regulatory system tends to be too low to keep us from experiencing excessive inflammation…and thus, the epidemic of autoimmune, allergic and  other inflammatory disorders.)   By suppressing excessive inflammation in the colon, this molecule may lower the risk for colon cancer.

Remember that bile acids, which we use to digest fat, are converted into secondary bile acids by gut bacteria and these secondary bile acids are themselves immune signaling molecules:  “Although most bile acids are transported back into the liver via enterohepatic circulation, a small fraction of this pool (roughly 5%) escapes reabsorption in the ileum and is subject to further bacterial transformation in the colon, giving rise to secondary bile acids.”

These scientists looked at how these  metabolized bile acids influence the local immune system of the intestines, including how they affect the production of Tregs and dendritic cells, “…which help direct the generation of Tregs”[ii]  They discovered that two secondary bile acid molecules (ω-MCA and isoDCA) boost the conversation of precursors of Tregs into Tregs themselves. Since isoDCA is more abundant in humans, they focused in on it and discovered that it actually works by influencing how dendritic cells work:  instead of expressing genes that lead to a pro-inflammatory response, isoDCA  directs them into an anti-inflammatory state in which they drive a greater production of Tregs.

They proceeded to test this in vivo, in mice, giving the animals a variety of bacteria (Bacteroides) engineered to make isoDCA and discovered that indeed, this led to greater numbers of Tregs in their intestines.

Says the lead researcher:  “People have been thinking about using commensal microbes to treat inflammatory disorders of the colon…One approach is to develop a new class of drugs made from defined consortia of microbes that would limit inflammation and promote colonic health, reducing the risk of colon cancer in people. Bacterial consortia that produce isoDCA and other metabolites that promote anti-inflammatory activity in colon-resident immune cells could be one of the components of such interventions.”

According to the CDC, colorectal cancer is the third  most common cancer as well as the third leading cause of cancer related deaths in the United States[iii].  A new means of reducing the rate of this cancer via a probiotic sounds like a pretty darn great idea to me.

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[i] Clarissa Campbell et al, Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells, Nature (2020). DOI: 10.1038/s41586-020-2193-0

[ii] https://medicalxpress.com/news/2020-04-reveals-bile-metabolite-gut-microbes.html

[iii] https://www.cdc.gov/cancer/colorectal/statistics/index.htm

Gut Bacteria, the Immune System and the Development of Cancer

As I mentioned last week, there isn’t a whole lot of great new biome research coming out these days, for obvious reasons.  The only story over the last few days that really interested me was out of the University of Michigan, which looked at how specific gut bacteria affect susceptibility to colon cancers.[i]

Certain gut bacteria stimulate the production of a kind of immune cell called CD8+, which ordinarily help protect against the formation of cancer.  However, excess stimulation of the CD8+ cells can actually cause inflammation which promotes cancer development.  Like so many things in the body, balance is key.

These researchers compared two groups of mice with different microbiota compositions and found that when exposed to a carcinogen, one group developed an average of 5 tumors whereas the other developed an average of 15, and had a much higher level of inflammation.  To definitively ascertain that the causative agent was the differing gut bacteria, the scientists transplanted the gut bacteria from these 2 groups into new mice that were genetically identical but had been raised in a germ-free environment.  Sure enough, the group given gut bacteria from the mice that had averaged more inflammation and more tumors showed exactly the same, faring far worse than the mice that had received fecal transplants from the less-susceptible group.

Some of the bacterial differences discovered:   “The less-susceptible mice had increased levels of Anaeroplas-mataceae, Erysipelotrichaceae, Clostridiales, and Sutterellaceaebacteria.  The mice with more tumors and inflammation had increased levels of Prevotellaceae and Helicobacteraceaebacteria.  Further research led them to isolate 9 specific bacterial populations that “…may have tumor-suppressive or tumor-promoting activities.”  To name a few, high tumor susceptibility was associated with Bacteroidetes Alistipes, Firmicutes Ruminoccus, whereas low susceptibility was associated with Firmicutes Lachnospiraceae.  Interestingly, their findings do overlap some known dysbiotic elements already associated with disease in humans.  For example, low levels of “…Lachnospiraceae have been found in IBD [inflammatory bowel disease] and CRC [colo-rectal cancer] patients…”  whereas, “…a member of the Ruminococcaceae was associated with high tumor burdens, and Ruminococcaceae have also been found to be enriched in IBD and CRC patients.”

In order to understand exactly what was causing the high levels of inflammation and increased cancer susceptibility in the second group of mice, the researcher took a closer look at their immune systems.  They discovered that the animals had more T immune cells in their colon tissue, including way more CD8+ cells.  This was puzzling since, as I mentioned above, ordinarily CD8+ cells help us fight cancer.  To find out then whether or not the increased number of these cells was driving the development of cancer, they transplanted gut bacteria from these animals into mice that were genetically engineered to lack CD8+ cells and sure enough, these latter mice develop far fewer tumors.  “Although CD8 T cells are known for their cytotoxic, anti-tumor activity, our results suggest that in the presence of dysbiosis, they can also have a pathogenic role by promoting damaging, chronic inflammation and consequently tumor development.”

The scientists discovered that “…that these cells get over-activated in the presence of certain bacteria and then exhausted, leaving them less capable of killing tumor cells.”[ii]

The authors conclude that “…these studies suggest that microbial dysbiosis can contribute to colon tumor susceptibility by hyperstimulating CD8 T cells to promote chronic inflammation and early T cell exhaustion, which can reduce anti-tumor immunity.”  Once again, we see that incredible effect of the microbiome on the immune system and the development of disease.

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[i] Amy I. Yu, Lili Zhao, Kathryn A. Eaton, Sharon Ho, Jiachen Chen, Sara Poe, James Becker, Allison Gonzalez, Delaney McKinstry, Muneer Hasso, Jonny Mendoza-Castrejon, Joel Whitfield, Charles Koumpouras, Patrick D. Schloss, Eric C. Martens, Grace Y. Chen. Gut Microbiota Modulate CD8 T Cell Responses to Influence Colitis-Associated Tumorigenesis. Cell Reports, 2020; 31 (1): 107471 DOI: 10.1016/j.celrep.2020.03.035

[ii] https://labblog.uofmhealth.org/lab-report/identical-mice-different-gut-bacteria-different-levels-of-cancer

A Brief History of Phage Therapy: The Good Side of Viruses

For some peculiar reason, I have viruses on my mind a lot lately.  (I live in New York State.  ‘nough said.)  As I walked from my kitchen to my office, and back again, and again and again and again, like a caged animal, I decided that perhaps a better use of my time would be to read an article I’d downloaded weeks ago entitled The Forgotten Tale of Brazilian Phage Therapy.[i]  Firstly, as you know, I am fascinated by the very idea of phage therapy as it simply uses the body’s natural defense system against bacterial infection and overgrowth.  Secondly, the article sounded like a ripping yarn, and who doesn’t love a good story?  (It did turn out to be a great read, by the way!) Thirdly, since the worldwide lock-down and the closure of universities, there hasn’t been a huge amount of new and interesting biome research published.  It’s COVID-19 and more COVID-19.  And I think we all could use a mental break from it.

A quick refresher first:  phages, short for bacteriophages, are viruses that attack only bacteria. The word actually means “bacteria eater.”  The biome is full of them, comprising what is now known as the virome. Each is specific to only one kind of bacteria, so can theoretically be used in a highly targeted way as an alternative to antibiotics.  They keep our bacterial microbiome healthy.  Alterations to the virome is now associated with the development of disease.  (You can read a couple of my posts on this here and here.)

Phages were discovered in the early part of the 1900s, and researchers immediately saw their potential value.  Back then, the bulk of research was going on in Eastern Europe and, as it turns out, Brazil. Unfortunately, much of the South American research has been lost…but what the authors of this article managed to dig up is pretty fascinating.

Dr. Jose da Costa Cruz was a leader in the field in the early part of the 20th century,  and began to treat, very successfully, dysentery (an often fatal bacterial infection of the intestines that causes massive, sometimes bloody, diarrhea).  In 1923, Cruz wrote in the medical literature that “…anyone who sees the in vitro activity of phages is ‘filled with hope that a new therapeutic against infectious disease will immediately appear’.”  The first attempt to treat Sigella dysenteriae, a bacteria that causes dysentery, was not successful but the second testing later that year, on 24 patients, showed improvement within 4-5 hours after the start of the therapy:  “It was concluded that phages were recommended for dysentery for being easy to administer, innocuous for the patients, and efficient in patients for whom other treatments had failed.”

In 1924, 10,000 vials of these phages were produced and showed positive results throughout the country, ameliorating symptoms within hours, curing the disease within a day or two.

In 1929, at a Brazilian medical conference, another physician, Dr. Oscar Pereira, pointed out that phage therapy was also important because it cleared stool of live bacteria, thus alleviating it has a potential carrier of disease.  He also presented a successful case of using phages to treat E.coli; 9 cases of pyodermitis (bacterial infections of the skin including impetigo); and 32 cases of furunculosis (boils on the skin) on people treated with anti-staph phages.  These doctors were not only safely giving phages orally, but also using them topically and by injection.  By the late 1930s, Dr. Cruz was treating septic patients with phages:  “Mortality was lower than predicted in phage-treated patients”

So what happened to continued use and research into phages?  The short answer – antibiotics:  “The first half of the 1940s was marked by an increase in publications about other antibacterial substances.”  The authors describe a kind of slow fade out in the use of phages, as antibiotics became more and more de rigueur. It’s not that there were any publications denouncing their use, nor were any regulations passed preventing doctors from acquiring or prescribing them.  It was simply another case of out-with-old-in-with-the-new, even though there were tremendous benefits to the old.  As I mentioned earlier, because phages are targeted to only one kind of bacteria, they do not wipe out the microbiome – nor do they cause antibiotic resistance.

And thus, an interest in using phages began a resurgence in the 1980s, and is escalating now, as resistance to antibiotics – and our understanding of the dangers of overusing antibiotics – grows:  “Many research groups and modern clinical trials have focused on this subject of growing importance…”  In 2010, there were 188 million cases of dysentery in the world cause by shigella, and this was the second leading cause of death by diarrhea.  Staph infections are still a major problem, and are becoming dangerous because of antibiotic resistance.  As these authors write, “The safe and efficient use of phages against these targets, as suggested by the Brazilian experience shown in this Historical Review, can be taken as a guideline to develop modern phage therapy trials and shape phage use in our time…this Historical Review might serve as an inspiration to look into a successful past and aim for a better future.”

It always strikes me as a shame that the wisdom of the past is all too often disregarded, as though simply by being new, something is by definition, better.

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[i] Almeida GMF, Sundberg LR. The forgotten tale of Brazilian phage therapy [published online ahead of print, 2020 Mar 23]. Lancet Infect Dis. 2020;S1473-3099(20)30060-8. doi:10.1016/S1473-3099(20)30060-8

What You Eat: the Main Factor in Determining Your Microbiota

A new study out of Washington University in St. Louis shows, yet again, that even species matters less than what you eat and your lifestyle in determining the composition of your gut bacteria.[i]

These researchers analyzed the fecal microbiota a of 18 wild chimpanzees and 28 wild gorillas. They also collected fecal samples from 81 humans that live just outside the national parks (in the Republic of the Congo) where the animals lived.  These were all compared to samples from 18 chimps and 15 gorillas living in zoos within the USA.   Then all these samples were compared to other published data on hunter-gatherers, rural agriculturalists, urban humans from a wide variety of countries, including the United States.

Their results:  “These results indicate that captive ape microbiomes from the USA were more similar to that of the Congolese humans than to the wild apes …the gut bacteria of apes in zoos in the United States are more similar to people who eat a ‘non-western’ diet than they are to their wild ape cousins.”  That is, the animals’ in zoos, eating a heavily plant-based diet (but not a wild diet), have gut microbiomes that resemble humans, whether in the USA or the Republic of the Congo, who also eat a similar plant-based diet.  Geography did not matter and species (i.e. human or animal) did not matter:  diet does.

They point out that wild chimps and gorillas eat natural plants, very high in fiber, very low in animal protein, while captive animals “…consume human agricultural products.”  Another major difference between the captive and the wild animals:  the latter have never been exposed to antibiotics.

What strikes me as extremely interesting is that captive animals have a higher abundance of Prevotella (including P. copri), which as you know from reading my posts these past few weeks (for example, here), is associated with a high fiber (i.e. non-western) diet.  In fact, the Congolese humans tested, who eat a non-western diet, showed the same high levels of Prevotella. The researchers postulate that this difference, between captive and wild animals, is due to the actual composition of the fibers they each eat.

Another type of bacteria, one I am not familiar with,  Treponema, was also found in captive animals and non-Western-diet humans.  This commensal bacteria is mostly absent from humans living in industrialized countries, but “…have been found in abundance in human populations with non-Westernized lifestyles, including Hadza hunter-gatherers…”  Because of this, it is thought to be an “ancestral” species, suggesting that perhaps some of these kinds of bacterial, lost to us in the industrialized world, can still be (thankfully) found in other kinds of animals and the rare human.  (We don’t yet know, of course, how important some of these “ancestral” species may turn out to be, but I for one find it comforting to know there are still repositories for them, should future research prove them to be useful for our health.)

The researchers conclude that, “Our findings indicate that the microbiome of closely related host species may be molded by changes in diet and the degree of antibiotic exposure despite their geographic location.”  Reading this, I immediately thought about a post I wrote in November of 2018, The Negative (Biome) Side of Moving the USA: “Researchers looked at people from Southeast Asia and found that there was a significant reduction in the diversity of gut microbes with each subsequent generation, culminating with their microbiota resembling those of Americans of European origin.”  When these immigrants came to the USA, their microbiomes showed high levels of Prevotella but as they, and then each subsequent generation, began to eat a typical western diet, this very rapidly shifted:  ““Even a short period of residence in the United States was sufficient to induce pronounced increases, in some cases over 10-fold, in the ratio of Bacteroides to Prevotella.”

I think this must be about the 100th time I’ve concluded a post with a reminder to eat your vegetables!    🙂

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[i] Campbell TP, Sun X, Patel VH, Sanz C, Morgan D, Dantas G. The microbiome and resistome of chimpanzees, gorillas, and humans across host lifestyle and geography. The ISME Journal. March 20, 2020. DOI: 10.1038/s41396-020-0634-2

Since Things Already Stink in This COVID-Ridden World, We Might as Well Talk Gas

I posted this story up on Facebook a few weeks ago, but have decided – since the issue is so endemic – it’s worth a blog post, for those of you who missed it.  When I was working as a nutritionist, the single most common complaints I got heard were constipation and gas/bloating.  I was glad, then, to read the following study.

Most gas is caused by the fermentation of fibers by the gut bacteria.  So while we’d all like to eat a really healthy plant-based diet, many struggle with it, from a digestive point-of-view.  (I should mention that I would always tell clients looking to improve their diet to go slowly, as they added more fiber.  It does take time for the bacteria to shift to those that can help you digest it better.  And don’t forget to drink plenty of water, which also helps.)

In this study, 63 healthy adults received 3 days of a high fiber (residue) diet including legumes (beans, as you know, tend to cause gas); vegetables; whole grains; fruit…and then, were given 28 days of a fermented milk product which included lactic acid bacteria and particular species of Bifidobacterium animalis.[i]

To be eligible for the trial (as 63 people were), during the initial phase participants had have achieved at least 50% adherence to the flatulogenic diet and had a specifically measurable increase in flatulent expulsions.  If they met criteria, they drank the fermented milk product twice per day for the aforementioned 28 days.  (Previous research using this same product showed the same, but in that case, gas production was measured by breath test.)  The results showed that the product reduced the feeling of needing to evacuate gas, the actual number of gas evacuations, and improved overall digestive wellness.  It did not increase fecal microbiota diversity but it did increase the relative abundance of certain gut bacteria, which was measured in fecal samples given throughout the course of the study.

The lessening of flatulent evacuations was associated in an increase in the abundance of Mogibacterium and Parvimonas and a decrease in Desulfobibrionaceae.  An increase in Succinivibrio and a decrease in Methanobrevibacter species led to a reduction in the feeling of needing to evacuate gas.  (In case you are wondering (and I’ll admit, I was), gas was collected using something called a rectal balloon catheter, which we can all visually imagine.  ‘nough said about that.)

As I am always looking for products to help with GI issues, I was encouraged by the study.  As these authors write:  “Our data may have also practical applications: high-residue diets have beneficial effects but are poorly tolerated and probiotics may enhance compliance to these healthy diets; conversely, probiotics may be indicated to reduce the side effects of dietary transgressions.”  While I wouldn’t call eating a high fiber meal a “transgression,” I get their point!

For those interested, it took me awhile to track down the fermented milk product they specifically used.  I found all kinds or research showing its beneficial effects, but in all these studies, it’s never actually named: it’s referred to as a “marketed” product, and that’s it.  After doing my best Sherlock Holmes imitation, I was able to figure it out:  it’s Activia, which is produced by Danone.  As they say on their website:  “Activia yogurt with Bifidobacterium lactis DN-173 010/CNCM I-2494, our exclusive probiotic culture, has been studied and shown to provide a specific digestive health benefit. Activia may help reduce the frequency of minor digestive discomfort.”  I haven’t tried it myself so can’t attest to its taste but will give it a whirl once I can safely get into the supermarket!

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[i] Le Nevé B, Martinez de la Torre A, Tap J, et al. A fermented milk product with B. lactis CNCM I-2494 and lactic acid bacteria improves gastrointestinal comfort in response to a challenge diet rich in fermentable residues in healthy subjects. Nutrients. 2020; 12(2), 320. doi: 10.3390/nu12020320.

The Maternal Microbiome and Risk for Food Allergy in Babies

The big (biome) buzz of the last couple of weeks:  research just published out of Australia shows that the presence of a certain species of gut bacteria, Prevotella copri, in pregnant women protects babies from developing food allergies  – at least within their first year.[i]

I have mentioned Prevotella bacteria in many posts over the last couple of months (for example, here and here).  As a fermenter of fiber, it is present at higher levels in those who eat a plant-based diet…and thus, is found at lower levels in those who consume a typical “western” type diet, high in fat and sugar.  It’s found at higher levels in the guts of most people living in ‘traditional communities”; and is non-existent or at very low levels in the vast minority of people living in developed nations.  (Australia, by the way, has the highest rates of food allergy in the world.)  The maternal microbiome has been shown in rodents to influence the rate of allergy in pups, particularly low levels of Prevotella.[ii]

In fermenting fiber, Prevotella increases levels of those short-chain fatty acids I write about all the time.  In proper amounts, these are highly anti-inflammatory and play a big role in boosting levels of regulatory cytokines (which modulate inflammation).  These scientists hypothesized  that, “…it is plausible that low maternal carriage of Prevotella during pregnancy may be causally related to dysregulated immune development and high rates of allergic disease among children in westernized populations.”

The researchers analyzed data collected between 2010 and 2015 which looked at fecal samples from mothers at 36 weeks of pregnancy and then from their babies, at 1, 6 and 12 months of age.  Children who had developed food allergy (58 in the cohort) were compared to those without (258 in the cohort).

They found that 20% of the babies that did not develop allergies had P.copri in their stool samples versus only 8% of babies with allergies: the presence of P.copri in the mom’s stool sample meant less risk of developing allergy for their baby.  Only 1 mother with higher levels of the bacteria in her stool had a baby diagnosed with food allergy.  Doubling the amount of P.copri in the stool meant an 8% drop in risk for the baby:  “…maternal carriage of Prevotella copri during pregnancy strongly predicts the absence of food allergy in the offspring.”  Remarkably, over 80% of the mothers in the whole database (over 1000 women) had no detectible P.copri in their stools.

While diet is the biggest factor in determining the composition of the gut bacteria, other environmental factors also play a role including antibiotic use and household size:  as David Strachan, the father of the “hygiene hypothesis” predicted in 1989, more people in the house are thought to increase bacterial diversity within the family.

These scientists are now working to figure out whether or not it is safe to administer P.corpi as a probiotic during pregnancy to protect babies.  Like everything having to do with the human biome, this is NOT a cut and dried kind of thing.  The authors point out that 1 study has shown an association between P.copri and rheumatoid arthritis and another, in animals, showed that it may exacerbate colitis.  Much of this may be dependent on the particular strain of the bacteria used.   (Nothing is ever easy.) We’ll find out, I’m sure, as the research progresses.

This is pretty important work though as their findings would suggest that the absence of P.copri in the mother raises the risk of developing food allergy in the baby by more than 50%.  That is just a remarkable finding.

I’ll conclude this post as they conclude their paper, as it sums up what we can do now perfectly:  “In the meantime, our findings support the importance of antibiotic stewardship during pregnancy as well as a diet that optimizes the health of the maternal gut microbiome.”

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[i] Vuillermin, P. et al. Maternal Carriage of Prevotella During Pregnancy Associates with Protection Against Food Allergy in the Offspring. Nature Community. 2020;11:1452. https://www.nature.com/articles/s41467-020-14552-1

[ii] https://www.news-medical.net/news/20200325/Presence-of-certain-gut-bacterium-in-mothers-could-protect-babies-from-food-allergies.aspx