Depression and the Microbiome: A Brief Update

A few days ago, the website Psychiatry Advisor, had a very nice review article[i] of our current understanding of probiotics’ effects on depression. I’ve written about this before, obviously, but want to always keep you updated on all the latest.  Besides, this is also a good lead in for my  next post, which I am devoting to leaky gut.

An overall summary:  we continue to be faced with the usual situation in medical science.   Preliminary results look very promising but way more research is need before definitive conclusions can be drawn.

What we do know right now:

      1. Major depressive disorder (MDD) is associated with chronic low-grade inflammation.
      2. A 2017 meta-analysis of 82 studies found that those with MDD have increased levels of pro-inflammatory cytokines.  Also, those with MDD also have higher rates of co-morbid inflammatory disorders like rheumatoid arthritis and heart disease.[ii]
      3. Anti-inflammatory drugs like NSAIDS (i.e. ibuprofen, etc.), for example, have proven to be anti-depressive as well.
      4. Depression is highly associated with alterations of the bacterial microbiota.
      5. Studies have shown that the probiotic Bifidobacterium infantis can normalize inflammation that is the result of stress.  (Not many probiotics contain this particular strain, but I did find this one: Align Probiotic Supplement.)
      6. The increase in pro-inflammatory cytokines from stress is known to increase intestinal barrier permeability (i.e. leaky gut). This, in turn, leads to increased levels of toxic bacterial byproducts in the blood, which is also highly inflammatory.  Several probiotics have been shown to normalize this intestinal permeability.  This past week, a study was published that looked at potential treatment for leaky gut, and among the non-pharmaceutical options presented are probiotics (like VSL 3 ) that contain Bifidobacteria and Lactobacilli; prebiotics (that contain FOS and GOS (I use this Jarrow product myself); melatonin (there are several good ones on the market like this NOW product); and NAC (n-acetyl cysteine, like this Jarrow product, which is a powerful antioxidant).[iii]
      7. I mentioned this study in that previous post mentioned above,  but it’s worth repeating. In an 8-week long randomized, double-blind trial of 40 people diagnosed with MDD, half were given the placebo and half were given a fairly low-potentcy probiotic formulation consisting of 2 billion units each of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum. Those who received the probiotic had “significantly” decreased depressive scores, and also, improved inflammatory markers and glucose metabolism (lower insulin levels, for example).  The researchers also noted significantly higher blood glutathione levels.  Glutathione is one of the major antioxidants in our bodies, as well as being crucial to normal detoxification.[iv] 
      8. There have been several other clinical trials that have shown similar excellent results.
      1. While a few other studies have not shown benefits, this review article correctly  points out that those studies were measuring mood improvement in people not diagnosed with depression.
      1. So, while there is most certainly no medical consensus on dosing, species of bacteria, and so forth, trying probiotics (along with prebiotics and other biome restoring supplements) for depression makes perfect sense.
      2. __________________________________________________
      3. [i] https://www.psychiatryadvisor.com/depression-advisor/probiotics-depression-and-the-role-of-inflammation/article/807994/
      4. [ii] Köhler CA, Freitas TH, Maes M, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand. 2017;135(5):373-387.
      5. [iii] Morris, G, Fernandex, BS, Puri, BK, Walker, AJ, Carvalho, AF, Berk, M. Leaky brain in neurological and psychiatric disorders: drivers and consequences.  The Australian and New Zealand Journal of Psychiatry. 2018;52(10):924-948.  doi: 10.1177/0004867418796955.
      6. [iv] Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M, et al. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial. Nutrition. 2016;32(3):315-320.

 

 

The Potential Anti-Cancer Power of “Parasites”

I have read the vast majority of papers ever written on the subject of therapeutic helminths, and cannot, for the life of me, remember reading one that specifically addresses their potential anti-cancer effects.  I knew that helminths’ inflammation-modulating effect should theoretically be highly beneficial in terms of lowering cancer risk, but today, for the first time, I read a whole paper[i] devoted to all the mechanisms by which “parasites” may be effective.

A few caveats:

Let me start by saying that unfortunately, none of the organisms currently used for helminthic therapy were mentioned in this paper.  Currently, then, there is only research on several organisms that are very unappealing, in that they are both unavailable commercially and have (often terrible) negative side effects.  Still, the paper provides amazing insight into the potential of such organisms to both prevent and treat cancers.

Secondly, some parasitic organisms may actually be carcinogenic. For example, Schistosoma (which has so many negative effects on people that it will never be used in helminthic therapy) is associated with bladder cancer, and certain blood-borne flukes (again, these are really dangerous), are associated with liver cancer.  Likewise, there are bacteria – for example, H.pylori, which are associated with gastric cancers.  To sum up:  there are good and bad of every kind of organism.

Third caveat:  this research is definitely in its infancy.  But what we do know so far is so promising that it’s worth reading and writing about even at this early stage.

Now a short summary of some of the paper’s highlights:

  1. Immune surveillance means that your immune system is constantly on the lookout for abnormal cells, which it then (ideally) destroys.  When things go wrong, for example, the immune system is compromised, cancer cells may avoid detection.  One example:  Trypanosoma cruzi (cruzi), a protozoa (single-celled organism) associated with disease in humans, has antitumor effects.  Epidemiological studies show that infection with this is associated with lower incidence of colon cancer, but more than that, in experimental models of breast and colon cancers, the organism is preventative.  Antibodies to T.cruzi “…were able to specifically recognize human breast and colon cancer cell lines. Interestingly these antibodies also recognized 68% of tumor biopsies from breast and colon cancer patients.”  That is, antibodies that target certain pathogenic protozoa can also target tumor cells and can help the immune system recognize them before they become problematic.
  2. Since the beginning of the 19th century, we have known that inflammation is associated with the development of cancer. For example, it’s accepted fact that chronic inflammation plays a major role in the development of colon cancer.  Thus, patients with ulcerative colitis have a greatly increased risk of developing this.  The current experimental model used for colitis involves exposing rodents to chemicals that induce inflammation.  The larval stage of an organism called Taenia crassiceps, which is closely related the beef tapeworm, dramatically down-regulates inflammation in such a model, and was “…able to inhibit the development of carcinogenesis in colon associated with inflammation.”  It reduced 60% of the total number of tumors, and more than that, 50% of the mice infected with this tapeworm did not develop tumors at all.
  3. A chemical derived from the above mentioned T.cruzi seems to prevent the formation of blood (and thus, nutrient) supply to breast tumors in both in vitro and in vivo experiments. T.cruzi also seems to induce tumor cell death (apoptosis).

This is the opening sentence of the paper’s conclusion:  “In this review we have gathered information about the different antitumor mechanisms triggered by some helminth and protozoan parasites, together they may target around 50% of the hallmarks of cancer….parasites can interfere in the growth and proliferation of a variety of transformed cell lines in vitro, but also, and more importantly, parasites and their products can modulate cancer development in vivo from melanoma to colon cancer.”

So once again, we are faced with a situation where currently available science hints at amazingly exciting potential treatments, but far too much is still unknown.  One encouraging final bit of news for you though: the commercially available organisms used for helminthic therapy all have proven anti-inflammatory effect.  Just last month, in fact, when this cancer paper was published, so was one entitled, “The Benign Helminth Hymenolepis diminuta Ameliorates Chemically Induced Colitis in a Rat Model System.”[ii]  Rats that are colonized with H.diminuta, and then exposed to a chemical that ordinarily induces colitis, have lower inflammation and less severe colitis symptoms – perhaps lowering colon cancer risk???

We can only hope that in the near future, the  helminths currently used therapeutically are looked at for their anti-cancer potential.

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[i] Callejas, BE, Martinez-Saucedo, D, Terrazas, LI. Parasites as negative regulators of cancer.  Bioscience Reports. 2018. DOI: 10.1042/BSR20180935

[ii] Jirku Pomajbikova, K, Jirku, M, Leva, J, Sobotkova, K, Morien, E, Parfrey, LW. The benign helminth Hymenolepis diminuta ameliorates chemically induced colitis in a rat model system.  Parasitology. 2018;145(10):1324-1335.

Boosting Levels of Akkermansia to Improve Glucose Metabolism

After my last blog post about microbiome changes in Alzheimer’s, including a depletion of the bacteria, Akkermansia, I became curious.  It is not as yet included in any commercial probiotic so I got to wondering if there were any known ways of boosting levels.

I found an article[i] from just last year, a commentary actually, published in Frontiers in Immunology, that states that certain dietary components will increase Akkermansia.  In animal studies, both grape polyphenols (for example, a product like this Grape Seed Capsules) and cranberry extract (a product like this Organic Cranberry Extract) both dramatically boosted Akkermansia,  while also reducing body weight and insulin levels.  Capsaicin, the chemical that makes hot peppers hot, also did the same. The article states, “Several studies have shown an increase in Akkermansia in diet-induced obesity studies and correlates with the reduction of weight gain, adiposity, and improved glucose tolerance.  Administration of live A. muciniphila reversed the symptoms of obesity and metabolic syndrome in HFD [high fat diet] mice by reducing adiposity, inflammatory markers, insulin resistance, and improved gut barrier.”  (Capsaicin can be bought encapsulated, in a product like this Cayenne Capsules)

Anyway, further snooping around led me to another great discovery.  Helminths also appear to increase levels of the bacteria.  Researchers looked at the gut microbiota of volunteers in Sri Lanka, and compared the microbiota of those with and without helminths.  Akkermansia was one of the species that was increased in the group who  had helminths.[ii]

Then, in one of those coincidences that you know I love…Yesterday morning, I came across an article on Medical News Today about how exercise affects the gut bacteria.[iii]  It describes a small study done on 17 woman who were overweight but in good health.  For 6 weeks, they were put on a bicycle endurance training program 3X per week.  Their gut microbiota was analyzed before and after.  Imagine my surprise when I read this:  “Overall, at the end of the program, the researchers found a decrease in so-called proteobacteria — that is, gut bacteria that have the potential of causing inflammation — and an increase in beneficial bacteria called Akkermansia, which have links with a better metabolism.”

So, while we all wait for our Akkamansia probiotic to hit the shelves in stores, there are still things we can do now (my favorite thing to write about, as you know)!

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[i] Anonye, BO.  Commentary: Dietary polyphenols promote growth of the gut bacterium Akkermansia muciniphila and Attenuate High-Fat Diet-Induced Metabolic Syndrome.  Frontiers in Immunology. 2017;8(850).   doi:  10.3389/fimmu.2017.00850

[ii] Jenkins, TP, et. al.  Infections by human gastrointestinal helminths are associated with changes in faecal  microbiota diversity and composition.  PlosOne. 2017. doi.org/10.1371/journal.pone.0184719

[iii] https://www.medicalnewstoday.com/articles/323351.php

Bacterial Alterations in Alzheimer’s Disease: A Case of the Missing Akkermansia?

Yesterday, I read a study[i] done on 55 people which showed substantial and distinct alterations of the gut bacteria in people with Alzheimer’s disease versus healthy controls.  More than that: the blood of those affected showed higher levels of bacterial toxins, meaning that their gut lining is inflamed and leaky, these toxins are able to get into the blood stream, cross the blood-brain barrier and cause an inflammatory response in the brain.

In those with Alzheimer’s, Bifidobacterium, Blautia, Dialister, Subdoligranum, and Citrobacter were all more abundant while, Prevotella, Roseburia, Parasutterella, Oxalobacter, and Akkermansia were less abundant when compared to those without the disease.  These gut profiles remained consistent at the 2 and then 4 month check-ups.

 I am not familiar with all these species of bacteria, but have certainly read about several of them.  Akkermansia that one I’ve been reading about a lot lately, in relation to glucose metabolism.  Abnormal glucose metabolism is associated with many negative health effects including obesity, cancer…and Alzheimer’s. In fact, it’s believed that increasing Akkermansia is one of the ways metformin works to improve blood glucose levels and that, conversely, Akkermansia mediates the action of metformin. I’ve written about this medicine before here. [ii]

A 2016 paper on Alzheimer’s and glucose states, “The impaired glucose metabolism in the brain of subject with AD is a widely recognised early feature of the disease…The link between diabetes and neurodegeneration is widely recognized and offer a target for novel therapeutic strategies.”[iii]

By the way, Akkermansia is also very beneficial to the integrity of the intestinal barrier.

I found an article about research going on at California State University into Akkermansia which confirmed that while it’s not yet available commercially, it may be “next hot” probiotic.  In animal studies, not only does it keep mice from gaining weight or suffering health issues from a high fat diet, but, says one of the researchers, “In one recent study, people who had cancer and responded more favorably to biologic treatments, which recruit your immune system to fight the cancer, had a higher abundance of Akkermansia than people who did not respond as well.”[iv]

I’ll be watching this one and will keep you updated, as always.

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[i] https://www.medscape.com/viewarticle/903302#vp_1

[ii] Naito, Y, Uchiyama, K, Takagi, T.  A next-generation beneficial microbe:  Akkermansia muciniphila.  Journal of Clinical Biochemistry and Nutrition.  2018;63(1):33-35.

[iii] Calsolaro, V, Edison, P. Alterations in Glucose Metabolism in Alzheimer’s Disease.  Recent Patents on Endocrine, Metabolic & Immune Drug Discovery. 2016;10(1):31-39.

[iv] https://www.newswise.com/articles/is-akkermansia-the-next-hot-probiotic%3F

Probiotics as Antibiotics? What a Great Idea!

My regular readers know that I often quote my original guru, the famous functional medicine doctor, Sidney Baker.  Another of his truisms:  when looking at a patient, consider whether or not the patient has too much of something, or too little of something.  Yes, it’s a very simple concept – and I can’t tell you how much it helped me successfully work with my nutrition clients.  After all, too little of something can cause disease just as much as too much of something.

Since the development of penicillin, antibiotics have been the go-to treatment for ridding us of bad bacteria.  Doctors regarded patients as having too much of something, never considering that too little of something else might be the underlying issue.

This concept was just proven true once again, in some really amazing research[i] out of the National Institute of Health.  Working with researchers in Thailand, these scientists showed that supplementing with the probiotic species, Bacillus, eradicated the pathogenic bacteria Staphylococcus aureus (S. aureus), the bacteria that causes potentially deadly staph infections.  In fact, “Methicillin-resistant Staphylococcus aureus” is the full name for the commonly recognized acronym, MRSA, the antibiotic-resistant infection that kills tens of thousands every year.

S. aureus can live in the nose and the gut. 200 volunteers in rural Thailand had their stool  analyzed for bacterial correlations with the absence of S. aureus. The scientists found 101 people had Bacillus bacteria (especially Bacillus subtilis, which is commonly found in probiotics – for example, this one) and none of these 101 people had S. aureus.  Of those without Bacillus, 25 had S. aureus in their guts and 26 had it in their noses.

Apparently, Bacillus produces a substance, something called fengycins, which inhibits the growth of staph – including the incredibly virulent strain that causes MRSA infection. To further test this correlation, the scientists colonized the guts of mice with S. aureus, and then fed them B. subtilis.  Giving the probiotic every 2 days eliminated the S. aureus.  When they gave mice Bacillus engineered to not produce fengycin, S. aureus proliferated.

“Probiotics frequently are recommended as dietary supplements to improve digestive health…This is one of the first studies to describe precisely how they may work to provide health benefits. The possibility that oral Bacillus might be an effective alternative to antibiotic treatment for some conditions is scientifically intriguing and definitely worthy of further exploration.”[ii]

This research is being pursued now in people. Imagine if all it takes to stop MRSA in its tracks is a simple probiotic!

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[i] Pipat Piewngam et al, Pathogen elimination by probiotic Bacillus via signalling interference, Nature (2018). DOI: 10.1038/s41586-018-0616-y

[ii] https://www.sciencedaily.com/releases/2018/10/181010135010.htm

Bovine Immunoglobulins…Who Knew?! (Or should that be, who moo?)

As you all know, I’m always on the lookout for natural products that can improve immunity and the health of the biome.  Today I devoted myself to reading about bovine IgG and was truly amazed at how much research has been done on it.  There’s a lot unknown at this point (like the best kind, dosages, etc.) but what is not in contention is that this stuff really, really works.

The article I read today is from this past June, and was a summary of the clinical studies (both animal and human) that have been done thus far.[i]  The results are more than encouraging.  And by the way:  for those of you who, like me, are looking for more effective ways of combating flu as the season gets underway (than the uninspiring flu shots that have been exceptionally bad these last couple of years)  – pay particular attention to this post.

First, a quick explanation.  IgG (immunoglobulin G) is one type of antibody humans and animals produce – the main one circulating in our blood. Just as humans pass on antibodies to their infants when they breast feed, providing immune protection to babies who have undeveloped immune systems, so do other milk-producing animals.  It turns out that the antibodies purified from cow milk not only successfully pass through the stomach acid, but provide excellent immune benefit to people:  “…bovine IgG can be functionally active throughout the gastrointestinal tract.  Indeed, a large number of studies in infants and adults have shown that bovine IgG (or colostrum as a rich source thereof) can prevent gastrointestinal tract infections, upper respiratory tract infections, and LPS [toxins from bad bacteria]-induced inflammation …Mechanistically, bovine IgG binds to many human pathogens and allergens, can neutralize experimental infection of human cells, and limits gastrointestinal inflammation.”

I have heard of these products, which can be bought commercially, but have not as yet given them a try.   I currently am in a flare up of my IBS, and yesterday, my doctor told me to try one for the next few months.  His recommendation was Igg Protect by Ortho Molecular Products .

You all know me though – before starting anything, I want to know more about it.

The article I read has so many high points, I am going to struggle to make a top-10 list but…here goes!  (These are not in any particular order. Sorry this is so long but – I didn’t want to leave out anything that really floored me!)

  1. “Bovine IgG can not only bind to a wide range of pathogenic bacteria and viruses, but also to many allergens.”  Studies have shown it to be effective against bacteria ranging from rotavirus to E.coli, to Klebsiella pneumoniae, to Samonella, to Streptococcus, to H.pylori.
  2. Studies also show it to be effect against allergens like rye grass pollen, house dust mites, and even wheat allergies.
  3. In some of the studies, “hyperimmune colostrum” was used. This special product is obtained by vaccinating the cows to a specific pathogen, so that the IgG product will be especially rich in those antibodies.  In an uncontrolled human trial against Clostridium difficile (C.diff), just such a product was used.  It did prevent relapse after antibiotic treatment.  A double-blind study was also done testing the effectiveness of bovine IgG versus the antibiotic, metronidazole.  The colostrum IgG was as effective in preventing C.diff-associated diarrhea as treatment with the antibiotic.  A hyperimmune IgG product rich in antibodies to H.pylori also showed, (in a double-blind trial) effective clearance of this pathogen.
  4. Some studies have been done looking at whether or not bovine IgG can infer prophylactic protection. This was tested in healthy volunteers who were given E.coli. (They’d have to pay me a lot to volunteer for this study!) None of those who received the hyperimmune colostrum against E.coli developed diarrhea while 9 out of 10 of those in the control group did.
  5. Studies done in immune-compromised patients with HIV are incredibly promising. Bovine IgG not only protected them against a variety of infections but also decreased fatigue, helped them gain weight, and improved T-cell counts.
  6. “…bovine immunoglobulins from non-immunized cows [not hyperimmune IgG] have been shown to be able to bind to…influenza virus.” One study showed reduced “…severity of influenza infection, by reducing viral load…”
  7. “Five studies have shown a reduced incidence or severity of upper respiratory tract infections in children that received colostrum from non-immunized cows.”
  8. Bovine IgG improves intestinal barrier function, thus reducing leaky gut.
  9. It is highly anti-inflammatory and has been tested in models of diseases including irritable bowel and inflammatory bowel diseases. For example, in a mouse model of colitis, those receiving bovine colostrum had reduced weight loss, better blood test results and increased levels of IL-10 and T-regulatory cells.  In humans, it’s been shown to improve symptom score in those with irritable bowel with recurrent diarrhea.
  10. In fact, that ability to boost the regulatory system (the off-switch to inflammation), also seems to prevent excessive immune response to commensal bacteria, such as is seen in inflammatory bowel disease: “Oral IgG enhanced the expression of IL-10 producing Treg, decreasing Th1 and Th2 cytokines…These studies indicate that oral immunoglobulins may help to regulate immune response to the microbiota as well as allergens – on the one hand promoting immune exclusion of pathogens, and on the other hand preventing excessive immune responses to commensal bacteria.”

So not to make a really bad pun…but HOLY COW!

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[i] Ulfman, LH, Leusen, JHW, Savelkoul, HFJ, Warner, JO, Joost van Neerven, RJ. Effects of Bovine Immunoglobulins on Immune Function, Allergy, and Infection. Frontiers in Nutrition. 2018;5(52). https://doi.org/10.3389/fnut.2018.00052

Rectifying My Own Ignorance: The Gut Biome and Spondylitis

Even knowing that so many illnesses that seem so far removed from the gut actually start there (autism, Parkinson’s, depression, etc.), I am constantly amazed when I come across yet another one.  Today, I’m writing about an article I just finished reading on Ankylosing Spondylitis.

According to the Spondylitis Association of America, “Common features of spondyloarthritis include inflammatory back pain, as well as pain and inflammation in the pelvis, neck, intestine, eyes, heels, and various larger joints….Common features of spondyloarthritis include inflammatory back pain, as well as pain and inflammation in the pelvis, neck, intestine, eyes, heels, and various larger joints.”[i]

I had heard of the illness, but knew nothing about it, and you know me…never content to remain in ignorance.  I learned that it is a member of a family of rheumatic diseases that includes enteropathic arthritis, reactive arthritis, undifferentiated spondyloarthritis, juvenile spondyloarthritis, and psoriatic arthritis. (I’d heard of the last one as the famous golfer, Phil Michelson, suffers from it.)  I have learned that there is really no doubt that it starts in the gut.  And maybe most remarkable of all:  I learned that about 2.7 million people suffer from spondylitis in the USA, which is almost 3X the number of people with Parkinson’s.  (According to of the Parkinson’s Foundation, “Nearly one million will be living with Parkinson’s disease (PD) in the U.S. by 2020, which is more than the combined number of people diagnosed with multiple sclerosis, muscular dystrophy and Lou Gehrig’s disease (or Amyotrophic Lateral Sclerosis).”[ii]

So spondylitis sufferers vastly outnumber all those well-known illnesses…and yet virtually no one has heard of it.

As Biome Buzz readers, you are like me, and want to know.  🙂

A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis[iii] was a fascinating read.  Here are 6 highlights:

  1. There is a genetic predisposition to developing Ankylosing Spondylitis (AS). 90-95% of people diagnosed with it are positive for the genetic marker HLA-B27.  Amazingly, in animal studies, rats with this genetic marker do not develop AS if they are raised in a germ-free environment.  “However, the arthritis develops when commensal bacteria, such as Bacteroides vulgalus, are introduced into these germfree models.”
  2. There are specific pathogenic bacteria that may play a role in the development of the disease, including Klebsiella pneumoniae. While not yet proven, there is almost certainly an association.
  3. “Almost 70 percent of patients with AS have subclinical gut inflammation, which indicates that the two diseases may be similar entities with a common origin, that is gut dysbiosis.” In fact, the enteropathic arthritis I mentioned above is arthritis associated with inflammatory bowel disease.
  4. A 2007 study: patients with AS were given Moxifloxacin, an antibiotic that works against both Gram-positive and negative bacteria. The results “…have shown that AS patients treated with Moxifloxacin resulted in a significant and sustained improvement…”  Serum inflammatory markers were greatly reduced after 12 weeks.
  5. The paper cites two interesting studies on specific probiotic strains that may be helpful. Lactobacillus casei, “…has potent anti-inflammatory and antiarthritic effect.”  In this study they found that it has, “…significant preventative effect on collagen-induced arthritis rat model.”  In the second study, the species, Lactobacillus rhamnosus, seemed to partially prevent relapse of colitis in rats with the HLA-B27 genetic marker.  Also, prebiotics (specifically inulin and FOS) also decreased colitis in these rats, as well as increased levels of good bacteria and decreased pro-inflammatory cytokines.
  6. A low starch diet, like the Specific Carbohydrate Diet for example, may be beneficial. The few studies done have shown relief of symptoms, and a significant drop in blood inflammatory markers.  What’s also really interesting is that in vitro, sugars like glucose, sucrose and lactose (substrates) cause a 10-fold increase in Klebsiella microbes per gram of   substrate, “…showing that carbohydrates are highly necessary for growth and replications of Klebsiella or even other related enteropathics [gut pathogens].”

The take-away message is pertinent to anyone suffering from any kind of autoimmune and/or inflammatory disease.  Genes certainly play a role in terms of increasing susceptibility to specific illnesses, but it takes an environmental insult – a disruption of the gut flora – to invoke disease.  Most people with the HLA-B27 will not develop AS…and conversely, not everyone with AS has that particular genetic marker.  If we could just learn to support and protect our biomes, starting at birth, the number of people suffering from these horrendous life-long illnesses would undoubtedly drop dramatically.

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[i] https://www.spondylitis.org/Overview

[ii] http://parkinson.org/Understanding-Parkinsons/Causes-and-Statistics/Statistics

[iii] Yang, L, Wang, L, Wang, X, Xian, CJ, Lu, H. A possible role of intestinal microbiota in the pathogenesis of Ankylosing Spondylitis.  International Journal of Molecular Sciences. 2016;17(12).  doi: 10.3390/ijms17122126.

More On the Parkinson’s/Gut Bug Connection

This past Thursday I promised you the 2nd big story of last week:

We’ve known for a while that Parkinson’s seems to start with an “infection”  in the gut.  I’ve talked about this several times on this blog.  Well, it looks like there is a very close association between Parkinson’s and Helicobacter pylori (H.pylori), the bacteria that causes stomach ulcers.  A review article in the Journal of Parkinson’s Disease compiled all current information on the link and found 4 major findings:

Firstly, people with PD are 1.5 to 3 times more likely to have H.pylori infections than those without the disease.  Secondly, those with PD and H.pylori have worse motor function than those with PD but without H.pylori infection.  Thirdly, eradicating H.pylori improves motor function…and fourth, eradication also improves absorption of L-dopa, the medication used to replace the lost dopamine in the brain.[i]

Holy smokes, right?!

Scientists do not yet know if H.pylori infection predisposes people to getting PD, if it is responsible for the progression of the disease (and if so, will treating it alter disease progression) or if it’s even a direct cause of PD.  So, as of right now, they are 4 main hypotheses that need to be tested:

  1. Toxins produced by pylori may damage neurons
  2. The infection causes a huge inflammatory response, which, in turn, damages the brain
  3. H.pylori disrupts the normal gut flora and this dysbiosis is the ultimate culprit
  4. H.pylori interferes with the absorption of L-dopa

From the conclusion of the paper:

“The gut is being increasingly considered as a critical focal point in the pathology of PD. This gut pathology may be multifactorial, involving H. pylori, intestinal microflora, inflammation, misfolding of alpha-synuclein in the gut and brain, cholesterol and other metabolites, and potential neurotoxins from bacteria or dietary sources.  Eradication of H. pylori or return of the gut microflora to the proper balance in PD patients may ameliorate gut symptoms, L-dopa absorption and motor functions.”[ii]

What I am puzzled about is this:  about 50% of the population of the world is thought to carry H.pylori, with higher rates in the industrialized world.[iii]  (In fact, I’ve always wondered, knowing how common it is, why the bacteria cause ulcers only a small percentage of people.)  What are the factors that might make it become toxic in some?  As of now, no one knows but…I suspect this work will be aggressively pursued in the near future and of course, I will follow it closely.

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[i] https://www.sciencedaily.com/releases/2018/09/180924105749.htm

[ii] David J. McGee, Xiao-Hong Lu, Elizabeth A. Disbrow. Stomaching the Possibility of a Pathogenic Role for Helicobacter pylori in Parkinson’s Disease. Journal of Parkinson’s Disease, 2018; 8 (3): 367 DOI: 10.3233/JPD-181327

[iii] Brown, LM. Helicobacter pylori: epidemiology and routes of transmission.  Epidemiologic Review. 2000. 22(2):283097.

Bacteriophages: A Clinical Study

There are a lot of great biome stories this week.  Tough choice, what to write about today!  There are two items that came out on top of the list so you get one today and one early next week.

Today’s top story is about a huge step in using phages therapeutically.  You all know how excited I am about the promise of bacteriophages! (You can read just one of my previous posts about it here.  This is the only product I have found – Florassist – to use phages in a probiotic mix.) Having suffered terrible side effects from antibiotics in my life, I am watching this field with hawk eyes.  I reckon there will come a day soon when phage technology will be advanced enough to make dysbiosis a thing of the past, on top of  reducing the need for antibiotics enormously.

So how’s this for exciting?!  The first official USA clinical study, conducted at Colorado State University, was published last month.[i]  In this randomized, double-blind, placebo cross-over pilot study 36 people with GI issues, including diarrhea, gas, bloating and/or abdominal pain, were assigned to either a placebo group or a treatment group for the first 4 weeks. After a 2 week washout period, the groups were switched.  The treatment consisted of 4 kinds of bacteriophages that target E.coli, which can cause GI issues, sometimes severe.

The phages “significantly decreased circulating interleukin 4, a protein often associated with allergic response and inflammatory disorders including dermatitis and rheumatoid arthritis.”  More than that, the gut flora remained stable – which would not have been the case had antibiotics been used, obviously – while levels of E.coli were greatly reduced.  And the treatment was associated with zero side effects.[ii]

I loved this quote by one of the researchers:  “”If you told someone to go eat viruses for a month, they’d probably say you’re crazy…”  Well – yeah, in the not-very-distant-past, if you’d told someone to eat yogurt as it is swarming with bacteria (thus, the reason for the euphemism  “active yogurt cultures” listed on the containers) they’d have called you crazy.  But with every passing day, I think, more and more people are coming to understand the concept of the human ecosystem and its variety of life forms.

I genuinely believe that the times, they are a’changin’.

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[i] Melinda Gindin et al. Bacteriophage for Gastrointestinal Health (PHAGE) Study: Evaluating the Safety and Tolerability of Supplemental Bacteriophage Consumption, Journal of the American College of Nutrition (2018). DOI: 10.1080/07315724.2018.1483783

[ii] https://medicalxpress.com/news/2018-09-bacteria-fighting-viruses-approach-gut-health.html

When Your Gut Talks, Your Brain Listens or…The REAL Sixth Sense

Two papers just came out, each showing – in different ways – how the gut is directly connected to the brain.  My gut feeling  2018-09-25_16-13-28is that this is going to be critically important research in the future.

We already knew that the gut lining contained over 100 million nerve cells, and that the gut talks indirectly to the brain via hormones.  This is why, for example, it takes about 10 minutes for your belly to tell your brain that you are full.  The feeling of satiety is hormone-driven.  (All those of you who have dieted know these rules:  eat slowly, to give your brain time to register the food intake; drink a glass of water 10  minutes before you eat, so you feel less hungry, etc.)  Hormones work (relatively) slowly.

Remember: over a year ago, in June 2017, I wrote about research in Parkinson’s out of Duke University that showed that the immune protein, alpha-synuclein, which was known to become damaged (folded) in the disorder, seems to originate in the endocrine cells of the gut and then makes its way into the brain via gut nerve cells.  (The current belief is that copious amounts of alpha-synuclein are released by the gut in order to fight some kind of gut infection.  The nature of that infection is currently unknown.)  These scientists were actually able to video the gut endocrine cells moving toward the neuron fibers and establishing a connection. Take a few seconds to watch that video here – it’s seriously cool.  “With the new finding of alpha-synuclein in endocrine cells, Liddle and colleagues now have a working explanation of how malformed proteins can spread from the inside of the intestines to the nervous system, using a non-nerve cell that acts like a nerve.”[i]

In this latest experiment, scientists (also from Duke University) injected a fluorescent rabies virus (which is transmitted through nerves) into the colons of mice and “…waited for the enteroendocrine cells and their partners to light up.  Those partners turned out to be vagal neurons…”[ii]  The endocrine cells released the excitatory neurotransmitter, glutamate, to communicate directly with brain and nervous system.[iii]  “By synapsing with the vagus nerve, neuropod cells connect the gut lumen to the brainstem. Neuropod cells transduce sensory stimuli from sugars in milliseconds by using glutamate as a neurotransmitter. The neural circuit they form gives the gut the rapidity to tell the brain of all the occurrences of the day, so that he, too, can make sense of what we eat.”

In a separate study, also just published, scientists used lasers to stimulate nerves in the gut and were not only able to induce a sense of reward (which led to the mice repeating behaviors) but also measured increases in dopamine in the brain, which enhances mood and motivation.  In fact, the vagus nerve connection from the gut led to stimulation of, and dopamine-release in, the Substantia nigra, the particular part of the brain affected in Parkinson’s.  “Specifically, right, but not left, vagal sensory ganglion activation sustained self-stimulation behavior, conditioned both flavor and place preferences, and induced dopamine release from Substantia nigra.”[iv]

Says Dr. Bohorquez, lead author of the first study, “”We think these findings are going to be the biological basis of a new sense…One that serves as the entry point for how the brain knows when the stomach is full of food and calories. It brings legitimacy to [the] idea of the ‘gut feeling’ as a sixth sense.”[v]

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[i] https://www.sciencedaily.com/releases/2017/06/170615100616.htm

[ii] https://www.sciencemag.org/news/2018/09/your-gut-directly-connected-your-brain-newly-discovered-neuron-circuit

[iii] Kaelberer, MM, et. al. A gut-brain neural circuit for nutrient sensory transduction. Science. 2018. 361(6408). DOI: 10.1126/science.aat5236

[iv] Han, W, et. al. A neural circuit for gut-induced reward. Cell. 2018.  doi.org/10.1016/j.cell.2018.08.049

[v] Op cit., sciencemag.org/news

Early Life Exposure to Gut Bacteria: The Timing Matters

I’ve read before that there is a possibility that the timing and order of exposure to various bacteria at birth will ultimately make a huge difference in the final makeup of the microbiota. I just finished reading a pretty telling paper[i] on this that is definitely worth sharing.

These researchers, from the University of Alberta, inoculated genetically identical infant mice in sequence with two “seed communities” (bacteria from adult mice), “A” first and then “B,” or vice versa. In a second experiment, they inoculated the pups with a cocktail of 4 bacterial strains and a seed community.  In summary, they discovered that, “…colonization order influenced both the outcome of community assembly and the ecological success of individual colonizers.”  Whatever was introduced first had the strongest influence on the ultimate composition of the bacterial microbiome when the pups reached adulthood.

At this time, scientists believe that genetics, diet, environment, lifestyle and psychological are responsible for only 30% of the variation found in the microbiomes of humans.  How this was determined, I don’t know but…if true, that leaves a gaping hole in our knowledge of how individual microbiomes develop.

We already know that disruption of the early, developing microbiota is associated with chronic disease.  I wrote about this just last week, in regards to autism, for example.  It is pretty scary how many things can go wrong  in the creation of the biome, leading to a life time of health issues. Research like this is proving more and more that what we come in contact with starting at birth is permanent.  Looking at the bright side though for a moment, says the lead researcher on this study, “Having long-term persistence of microbes when they colonize in the gut early in life means that a health-promoting biome could potentially be established by introducing beneficial bacteria straight after birth.”[ii]

But what about those who were not fortunate enough to be introduced to the good stuff very early in life?  In my last blog post, I wrote about those Israeli studies on probiotics, one of which suggests that they may not colonize some people well, as some microbiomes appear more resistant to change than others.

From the conclusion of the paper:

“Given the importance of historical contingency for gut microbiota assembly, clinical and medical interventions early in life (e.g. antibiotics, C-sections, formula feeding) are likely to have longer lasting consequences, driving not only inter-individual differences but potentially also aberrant patterns of colonization that could potentially be prevented by an adjustment of clinical practices to avoid priority effects….As the understanding of the health-promoting attributes of gut bacteria continues, it will be important to evaluate how they can be established more permanently. Once assembled, the gut microbiota is extremely resilient to therapeutic modulations, dietary changes and moderate doses of antibiotics, and colonization resistance constitutes a major barrier to introducing beneficial microbes….More permanent persistence can be achieved if microbes are introduced early in life. In addition, the findings demonstrated that early introduction of just a few species can divert the entire trajectory of the microbiota. If such shifts can be introduced reproducibly, then early colonizers could be selected to deliberately control microbiome assembly to obtain predictable outcomes….priority effects will favor bacteria that are introduced first, thereby providing an opportunity to potentially prevent aberrant microbiomes, and by doing so, dysbiosis-related diseases.”

My mentor, the functional medicine guru, Dr. Sidney Baker, used to tell me that, “The hardest thing in the world to fix is bad gut flora.”  He most certainly hit the nail on the head there.  Still, considering that I have seen diet work, helminths work, high dose probiotics work, etc., I have to believe that we have at least SOME control – some ability to heal the microbiota.

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[i] Inés Martínez, Maria X Maldonado-Gomez, João Carlos Gomes-Neto, Hatem Kittana, Hua Ding, Robert Schmaltz, Payal Joglekar, Roberto Jiménez Cardona, Nathan L Marsteller, Steven W Kembel, Andrew K Benson, Daniel A Peterson, Amanda E Ramer-Tait, Jens Walter. Experimental evaluation of the importance of colonization history in early-life gut microbiota assembly. eLife, 2018; 7 DOI: 10.7554/eLife.36521

[ii] https://www.sciencedaily.com/releases/2018/09/180918114441.htm

Yet More Anti-Probiotic Hype

Over the last two weeks or so, there’s been a lot of negative press about probiotics.  We’ve been through this before though, you and I…and I’m sure we’ll go through it again.  Some study or another makes a controversial claim and the media jumps all over it because it grabs people’s attention. I’ve waffled about covering this whole hoopla but finally decided I should since Biome Buzz readers are always the most up-to-date on all the biome happenings!

So here is a brief overview of the two papers that have caused such an uproar:

A team at  the Weizmann Institute in Israel (which, actually, produces some of the best biome research in recent years) did a 4 week study on 15 people – so a tiny sample size, short time frame – and found that in some people probiotics thrive while others seem to be resistant to colonization.[i]  They concluded that not everyone may benefit from standard probiotic treatment.  Since we all have different gut bacteria already – as individual as our fingerprints – it only makes sense that people will respond differently.

My thoughts upon looking at the study:  it was not long.  How do we know that other formulations of probiotics, given for longer periods of time, won’t change the results?  As the authors state, “Patterns of colonization resistance upon use of other probiotics strains, or by population subsets not included in our studies, such as children, the elderly and individuals with existing medical conditions merit further prospective human studies.”

In a second study  researchers looked at whether or not probiotics colonize the gut after antibiotic use.[ii]  There were only 21 people in the treatment group of the study, and these were then randomly divided into 3 groups:  7 people allowed their microbiomes to recover on their own; 8 people were given a probiotic for 4 weeks; the final 6 were treated with fecal microbiota transplant (FMT) which was made up of their own bacteria, cultured before the antibiotics were given.  They found, not surprisingly, that antibiotics cleared the way for colonization with the probiotics but – in what naturally stoked the media frenzy – they found that this wasn’t beneficial in that, the probiotics seemed to prevent the microbiome from returning to normal for several months afterwards.  (Those treated with FMT returned to normal within days.)

The conclusion, that probiotics may keep the gut bacteria from normalizing following antibiotics,  is literally based on results in only 8 people.  The authors acknowledge that their study has several “important limitations.” For example, they tested only 1 probiotic product.  Before any definitive conclusions can be drawn, many more larger and more robust studies would need to be done.

The first thought that occurred to me when I read about this latter study was “And what about clostridia?”  FMT is not approved in the USA for anything other than resistant clostridia infection, so suggesting that doctors harvest people’s microbiota before antibiotics and then do a fecal transplant isn’t happening in this country anytime soon.  We are left then – along with most of the rest of the world – with a choice of taking a probiotic or not taking a probiotic when given an antibiotic.  If you chose to not take one, do you increase your risk for developing a C.diff infection?

I don’t know the answer and these researchers do not address it at all. However, a very quick search led me straight to a Cochrane review study done just last year that summarized the findings of 39 randomized trials covering a total of 9955 participants.  “Thirty-one studies (8672 participants) assessed the effectiveness of probiotics for preventing CDAD [C.diff infection] among participants taking antibiotics. Our results suggest that when probiotics are given with antibiotics the risk of developing CDAD is reduced by 60% on average.”  It goes on to say, “Side effects were assessed in 32 studies (8305 participants) and our results suggest that taking probiotics does not increase the risk of developing side effects….The short-term use of probiotics appears to be safe and effective…”[iii]

This then, of course, begs the question, not addressed by this Israeli study:  what does the lack of “return to normal” of the gut flora actually mean for human health?  Does it actually matter?  And/or does it matter enough to forsake the protection afforded by probiotics?

Based on what the data suggest as of today then:  I’ll risk it and take probiotics if I need to take an antibiotic…call me crazy.

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[i] Zmora, N, et. al. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell. 2018. 174L6):1388-1405.

[ii] Suez, J, et. al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 2018. 174(6):1406-1423.

[iii] https://www.cochrane.org/CD006095/IBD_use-probiotics-prevent-clostridium-difficile-diarrhea-associated-antibiotic-use