Multiple Sclerosis and Propionic Acid: A Potential Treatment?

I’ve illustrated this post with a picture of Janus, the Roman god of, among other things, duality.  Every time I read about short chain fatty acids (SCFAs), I think of him.

Over the years, I’ve written about the benefits of SCFAs many times. (Here’s just one of many such examples.) I’ve also written about the massive amount of research that suggests that too much of a good thing, including SCFAs, are neurotoxic and extremely detrimental to health.  (For example, here.)

I’ve commented before about how I find this idea of balance particularly interesting.  SCFAs are critically important for good health as long as you have the right amount; and to make this even more complex, the timing is critical:  they are good in the right amount at the right time.  Just as excess levels are associated with disease, so are low levels. Since SCFAs are produced by gut bacteria, it’s easy to imagine how alterations in the microbiota can alter levels of these metabolites to influence the development of various illnesses.

The human biome is insanely complex.

A week ago or so, a paper was published in the journal, Cell, which explored how propionate (also called propionic acid, or PPA) “shapes” the course of multiple sclerosis (MS) by influencing the immune system.[i]

Like other autoimmune diseases, MS involves an increase in inflammatory immune cells and a decrease in regulatory ones (Treg, which modulate inflammation).  This hyper inflammatory response leads the body to mistakenly attack the myelin sheaths of nerve fibers, which is a protective layer surrounding the nerves.  This hampers the ability of nerves to send and receive signals properly.

In this study, the blood and stool of almost 300 people with MS were examined:  the results showed low levels of PPA, no matter what type of MS the person had (i.e. relapsing-remitting, progressive, etc.)  The bacterial species which produce PPA were  found at lower levels; bacterial species associated with disease, like Shigella, were found to be at higher levels.  The microbiome composition of the MS patients also varied according to the course of their disease, and this paralleled the fact that those newly diagnosed had the lowest levels of PPA, “…indicating that alterations in the gut microbiome might affect the severity of MS and that successful interventions might involve restoration of gut homeostasis.”

Thus, these scientists hypothesized that supplementing PPA, with its anti-inflammatory capabilities, might have a beneficial effect on those with MS, the hope being that the metabolite could boost levels of regulatory cytokines.  91 patients and 24 controls were given 1000 mg of PPA daily for 14 days.  After these 2 weeks, Treg (including IL-10, one of the most important) rose by 25% in the control group and by 30% in the MS patients.  52 patients continued to take the PPA after the study concluded, and the improvement in Treg remained.  This experiment was repeated in a 2nd group of patients and the results were the same.  To boot, high levels of pro-inflammatory immune cells dropped significantly.

Long-term PPA supplement use was also studied.  41.2% of those on PPA had a lower  annual relapse rate; 47.4% had a stable relapse rate; 11.3% had an increased rate of relapse.  And one more interesting finding:  22 patients, who remained on the PPA for a year and a half, underwent brain MRIs: “…the striatum, a region known to shrink (brain atrophy) in MS, actually increased in volume compare to scans taken before starting this treatment.”[ii]   This correlated with an improvement in clinical symptoms:  “This improved Treg cell function correlates with alleviation of clinical symptoms in MS patients. In a retrospective setting, we observed a decrease in relapse rate and stabilization of disability during long-term [propionic acid] supplementation.”

By the way, no adverse effects to the PPA supplementation were reported.

The researchers conclude that their study saying that it “…provides further evidence of the hypothesis that SCFAs are reduced in autoimmune diseases, such as MS, as a consequence of an altered gut microbiome.… [PPA] supplementation had a beneficial effect on immunological, neurodegenerative, and clinical parameters in MS patients, including relapse rate and disability progression.”

This is very preliminary research, so rest assured, I will follow it.  This this may well apply to other autoimmune diseases and help many people.

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[i] Duscha, A, et. al. Propionic acid shapes the multiple sclerosis disease course by an immunomodulatory mechanism.  Cell. 2020;180(6):1067-1080.  https://doi.org/10.1016/j.cell.2020.02.035

[ii] https://multiplesclerosisnewstoday.com/news-posts/2020/03/11/diet-has-an-impact-on-the-multiple-sclerosis-disease-course

Gut Bacteria and Diabetes: Progress on Several Fronts

Several new studies have recently been published examining the relationship between gut bacteria and diabetes.  With one in ten people in the United States suffering from diabetes (which doesn’t include those with metabolic syndrome/insulin resistance, which would greatly inflate that number), we desperately need research in this area.

The first study was a meta analysis out of Oregon State University, published in the Lancet’s journal, EBioMedicine.[i] Scientists analyzed 42 studies on humans, and found that while there was no definitive consensus among them, there were some fairly consistent trends.  Firstly, Bacteroides and Bifidobacterium appear to be protective against type 2 diabetes (TD2): in all but one study, Bifido were found to be high in healthy controls and low in those with TD2.  The results regarding Lactobacillus species were very mixed:  L. acidophilus, L. gasseri and L. salivarius seem to be high in those with TD2, while other species in the family were low.  I found this an interesting concept:  11 studies showed that Lactobacillus have positive effect when combined with other bacteria, like Bifidobacterium.  Thus, researchers suspect that different families of bacteria work together in a synergistic way, protecting humans from developing diabetes.  Overall, they state, “Among the commonly and consistently reported findings, the genera of Bifidobacterium, Bacteroides, Faecalibacterium, Akkermansia and Roseburia were negatively associated with T2D, while the genera of Ruminococcus, Fusobacterium, and Blautia were positively associated with T2D.”

The second study looked at 40 people with severe obesity, half of whom had T2D, the other half of whom had normal blood glucose levels.[ii]  The researchers looked at samples of their blood, liver and 3 different kinds of fat tissue.  There were distinct differences between those with diabetes and those without.  In the liver and some fat tissues (the fat connecting the colon and stomach) from those with TD2, high levels of bacteria and bacterial fragments were found.  The thinking is that the increased inflammation from obesity causes leaky gut, allowing these out of the intestines.  This inflammatory process, in turn, prevents insulin from being able to do its job and remove glucose from the blood.  In fact, the bacteria found in those with TD2 are often from environmental sources:

“Our results find support in previous studies that report bacterial colonisation in blood and tissues in healthy and disease states, and further suggest that environmental bacteria, which are likely to be present in food and water, may cross the gut barrier to accumulate in the blood and organs. Most environmental bacteria that are increasingly found to be present in patients with T2D can be linked to …infections that are often distributed via hospital water supplies.  Because patients with diabetes are usually more frequently hospitalised than their counterparts without diabetes, they are at greater risk of contracting infections and therefore may acquire part of their tissue microbiota during such visits.”

They conclude that more research is needed, obviously, but that “These findings support the hypothesis that environmental bacteria can reach specific niches at various body sites and potentially influence glycaemic control.”

The third study was conducted collaboratively between McGill University in Canada, Kyoto University in Japan, and INSERM/University of Paris, in France.[iii]  These scientists looked at blood samples from 148 people and found one particular bacterial metabolite, 4-Cresol, appears to be a potential biomarker for resistance to developing diabetes: it is consistenly found in lower levels in the blood of those with diabetes. In animal studies, low doses of it cause an increase in pancreatic beta cells that produce insulin and reducing obesity.

4-Cresol is produced by a variety of gut bacteria, and is also a product of the fermentation of the amino acids, tyrosine and phenylalanine.  It’s also found at low levels in certain foods, including tomatoes, asparagus, wine, dairy, coffee and tea, and even ground water.  It appears to downregulate proinflammatory cytokines and to upregulate regulatory (anti-inflammatory) cytokines.

The lead researcher in this last study is quoted as saying, “Our goal is to develop therapeutic approaches that allow fine modulation of the intestinal flora, by promoting the proliferation of ‘good’ bacteria whose function is well understood and thus the production of bacterial metabolites at therapeutic doses…”[iv]

Sounds good to me.

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[i] Gurung, M, et. Al.  Role of gut microbiota in type 2  diabetes pathology. EBioMedicine. 2020;51:102590. OI:https://doi.org/10.1016/j.ebiom.2019.11.051

 

[ii] Anhê, F.F., Jensen, B.A.H., Varin, T.V. et al. Type 2 diabetes influences bacterial tissue compartmentalisation in human obesity. Nat Metab 2, 233–242 (2020). https://doi.org/10.1038/s42255-020-0178-9

 

[iii] Brial, F, et. Al. The natural metabolite 4-cresol improves glucose homeostasis and enhances B-cell function. Cell Reports. 2020;30(7):2306-2320. DOI:https://doi.org/10.1016/j.celrep.2020.01.066

[iv] https://newatlas.com/science/gut-microbiome-bacteria-diabetes-metastudy-metabolism/

A Metabolite Direct Link Between the Gut and the Brain: Think Autism, Parkinson’s, etc….

Today’s post describes what may be a critical finding in defining at least one mechanism whereby gut microbes directly affect the brain.  Those interested in developmental disorders, like autism; Parkinson’s; Alzheimer’s; chronic fatigue; etc. should pay particular attention as, according this article, this information is likely applicable to those illnesses, and many  more.

The relationship of neurological disorders to the gut bacteria is well established, as you know. This includes the developmental disorders and diseases mentioned above, as well as the development of anxiety, depression, etc. However, “…evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive.”  Thus, it’s a major step forward that scientists at the University of Glasgow have discovered two new molecules that are produced by gut bacteria and that can travel directly to the brain, crossing the blood-brain barrier.[i]  These molecules structurally greatly resemble carnitine, a compound derived from amino acids, which is critical in transporting fatty acids into the mitochondria of cells, where the fats are “burned” to produce energy.  In looking like carnitine, these molecules essentially take the place of the real compound, thereby preventing real carnitine from performing its essential functions, “…leading to inhibition of brain cell function.”

These 2 molecules appear to be made by certain members of the Clostridiales family (C. clostridioforme and C. symbiosum).  The authors of this paper theorize that these bacteria produce these “fake carnitine” molecules to give themselves a competitive advantage against species that do poorly in the presence of carnitine.  Not much is known about these two species, except that their presence “…in the gut microbiome is associated with low microbial diversity, while C. symbiosum presence could further distinguish obese from lean participants.”  We also know that these 2 strains are increased in the guts of those with autism, and completely absent in controls in studies comparing the two populations.

Mitochondrial dysfunction is well established in autism, as well as in Parkinson’s and Alzheimer’s.  In autism, carnitine has been looked at as a potential treatment for a subgroup of those on the spectrum.  A 2019 paper states, “Autism onset can be connected with various factors such as metabolic disorders: including carnitine deficiency….Some people with autism (less than 20%) seem to have L-carnitine metabolism disorders and for these patients, a dietary supplementation with L-carnitine is beneficial.”[ii]  Another 2019 review describes the few clinical trials yet done on the population, which, while small, also showed consistency in results:  there was improvement, often significant improvement, in the symptoms of autism.  (The doses and duration of treatment varied greatly in these trials, so the fact that there was general consensus as to the benefits of carnitine treatment, I’d think, make the results that much more significant.)[iii]

In digging around, I also found that some evidence of carnitine’s protective role in Parkinson’s, heart disease, type 2 diabetes, etc.  I also found studies linking low levels of carnitine with depression and anxiety.

Back to autism for one last thought:  as you know, from reading my many posts (two of many examples, here and here) on the work of Dr. Derrick MacFabe and others in the field, the short-chain fatty acid, propionate (PPA) is now generally accepted to play a significant role in the development of many cases of autism.  Abnormal gut bacteria, which includes high levels of clostridia (PPA producers, as well as the producers of these carnitine-like molecules), in the population – possibly combined with food sources (PPA is a common preservative) are likely to blame.  High levels of PPA cause a reduction in carnitine levels:  “PPA is thought to affect mitochondrial fatty acid metabolism by sequestering carnitine.”[iv]  So now we are faced, thanks to this altered gut microbiota, with both a reduction of carnitine levels and these carnitine-analogs which replace what little carnitine is available, further destroying normal mitochondrial function.  This, in turn, affects the way energy is produced in the cell and thus, the way the brain develops and functions.

Animal (dairy, meat, fish) products contain carnitine.  If you tend to avoid these in your diet, and are among the susceptible population, you may want to consider supplementation. (Of course, talk to your health care practitioner first.) Carnitine (best taken in the form acetyl-l-carnitine) is a very low risk supplement.  Only in high doses, 3000 mg per day or more, can it have side effects including nausea and vomiting. Strikes me that this may be another can’t-hurt-could-help kind of thing.

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[i] Heather Hulme et al. Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication, Science Advances (2020). DOI: 10.1126/sciadv.aax6328

[ii] Demarquoy, C and Demarquoy, J. Autism and Carnitine: A possible link.  World Journal of Biological Chemistry. 2019;10(1):7-16.  doi: 10.4331/wjbc.v10.i1.7

[iii] Malaguarnera, M, and Cauli, O. Effects of l-carnitine in patients with autism spectrum disorders: review of clinical studies. Molecules. 2019;24(23):4262.  10.3390/molecules24234262

[iv] Thomas, RH, Foley, KA, Mepham, JR, Tichenoff, LR, Possmayer, F, MacFabe, DF. Altered brain phospholipid and acylcarnitine profiles in propionic acid infused rodents: further development of a potential model of autism spectrum disorders. Journal of Neurochemistry. 2010;113:515-529.  oi: 10.1111/j.1471-4159.2010.06614.x

Response to Prebiotics Depends on Your Existing Gut Bacteria

This is a small, but I thought really interesting, study and I guess I’m not alone in finding it significant:  it was published in a premier medical journal, Gut.[i]  It’s a great illustration of the complexity of gut biome optimization because of the individuality of every person.  We don’t even yet know what a “healthy” microbiome looks like, let alone how each component affects each other and our response to diet and supplements.

These researchers’ results show that the composition of the gut bacteria changes the way the person responds to the addition of prebiotics (in this case, inulin) to the diet.  They took the fecal microbiota from  4 people with obesity and used it to inoculate mice (who’d been treated with antibiotics to wipe out much of their gut bacteria).  The mice were fed a high fat diet which was supplemented with the prebiotic, inulin.  The response to the inulin completely depended upon which person’s bacteria the mouse was given. Two donors’ (donor 2 and 3) microbiota led to no response to the inulin; the other two mice, with donations from 2 other people (donors 1 and 4), showed metabolic improvement, particularly in the mouse with donor 4’s microbiota.

The presence of certain genera of bacteria predicted response: “Barnesiella, Bilophila, Butyricimonas, Victivallis, Clostridium XIVa, Akkermansia, Raoultella and Blautia correlated with the observed metabolic outcomes…,” such as a decrease in adiposity.

A group of obese individuals, including the 4 people involved in the mouse study,  were then supplemented with 16 grams per day of inulin for 3 months.  Metabolic and microbiota changes, similar to what was seen in the mice, were seen in donors 1, 2 and 3.  Globally, responders to the inulin involved in the study showed “…an increase in Bifidobacterium species and Butyricicoccus and a decrease in Collinsella, Barnesiella, Akkermansia and Bilophila.”[ii]

The conclusion that can be drawn:  “These findings support that characterising the gut microbiota prior to nutritional intervention with prebiotics is important to increase the positive outcome in the context of obesity and metabolic disorders.”  That is, a certain profile of gut bacteria may mediate the metabolic benefits of prebiotics on those with obesity – and of course, you can reasonably extrapolate that it’s likely that a similar patterns would be seen in everyone, obese or not.  Different people will respond differently to dietary changes:  the interactions between diet and gut bacteria are highly personalized.

It has already been established in prior research that in healthy adults, eating a high fiber diet will determine the benefits of supplementing with an inulin-type prebiotic.  This, of course, once again hammers home the point I’ve stated about a billion times on this blog:  eat your fruit and vegetables!

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[i] Rodriguez J, Hiel S, Neyrinck AM, et al. Discovery of the gut microbial signature driving the efficacy of prebiotic intervention in obese patients. Gut. 2020; doi: 10.1136/gutjnl-2019-319726.

[ii] https://www.gutmicrobiotaforhealth.com/baseline-gut-microbiota-may-determine-inulin-effects-on-weight-loss/

Inflammatory Arthritis and the Gut

I’ve been keeping an eye out for anything new and interesting in the realm of the biome and arthritis – any kind of arthritis.  Following are some highlights from a recent article on the two way communication between the gut immune system and the resident bacteria, and its association to rheumatoid arthritis (RA), osteoarthritis (OA), and inflammatory spondylitis (SpA) conditions like psoriatic arthritis and ankylosing spondylitis.[i]

The authors start by emphasizing that while exact mechanisms of action are as yet unknown, evidences continues to mount that these illnesses are directly related to alterations in the gut bacteria, and that those alterations are may well be causative.

  1. 70% of the immune system is located in the gut.  And there is sufficient data to establish that communication between that immune system and the microbiota, “…promotes intestinal barrier integrity, supports the functional capacity of the gut epithelium, protests from pathogens and maintains the immune homeostasis in the gut.”
  2. Rheumatoid arthritis: Recent research has shown that years before arthritic changes become evident, dysbiosis has been found to be present, “…suggesting an important role of microbiota in the transition from the preclinical to the clinical stage of RA.”  The most accepted current hypothesis is molecular mimicry, meaning that the antibodies created by the immune system to fight off a pathogenic bacteria mistakenly mark body tissue for destruction.  Programmed cell death (apoptosis) of infected colon cells is known to create antibodies to both the pathogenic bacteria, Citrobacter rodentium, and autoreactive antibodies, and concurrent inflammation.  P. corpi is a bacteria of particular interest in that two RA-specific autoantibodies are very similar to those formed to battle this bacteria. The same with a particular yeast, Collinsella aerofaciens.
  3. Notable differences are found in the composition of the gut flora between those with RA and SpA.
  4. Here are some remarkable SpA statisics: as many as 10-15% of those with SpA go on to develop inflammatory bowel disease (IBD), and conversely, 30% of IBD patients will develop SpA.  That astounds me.  50% of those with SpA who do not have GI symptoms still test positive for microscopic intestinal inflammation. As mentioned in #4, those with SpA have major differences in gut microbiome composition: for example, Akkermansia and Ruminococcous, which are important in gut health, are almost non-existent in these patients.
  5. While not firmly established, there is a growing belief in a causal relationship between these alterations and SpA-family disease. Rodents genetically predisposed to spontaneously develop SpA do not do so when kept in a germ-free environment, so they have no gut bacteria.  Give them some of the altered gut flora though from the same type of mouse with SpA…and they rapidly develop the disease.
  6. Chronic, low-grade inflammation and obesity are already recognized causes of osteoarthritis. Several pieces of evidence show that the gut bacteria play a pivotal role in causing and maintaining this systemic and gut inflammation.
  7. Probiotics: we’re not there yet.  In an animal model, Lactobacillus casei showed clear anti-arthritic activity.  However, the human clinical studies have been too small and short-term to produce any kind of consistent or meaningful results in treating either RA or SpA.  In osteoarthritis, however, some success has also been seen in rodents.
  8. Prebiotics: again, we are plagued with inconsistent results in trying to treat any of these arthritis diseases in humans.  In rodents, supplementing obese mice with OA with oligofructose led to higher levels of Bifodobacteria, which in turn led to improved gut health, and a reduction of inflammation, including in the joints of the animals. These results were consistent with some of the things seen in overweight humans (in a double-blind, placebo controlled study) when treated with the same:  they lost weight and had lower levels of toxic bacterial byproducts in their blood, demonstrating improved intestinal barrier function.

These authors conclude that it is now clear that “…unfavorable dysbiosis-mediated immune alterations precede the development of these disorders, suggesting causal relationships in this link [between the microbiota and the immune system].” This is exactly the same  phenomenon I described on Tuesday, seen in those with Parkinson’s.

We have to hope that soon there will be regular testing of our biomes.  Perhaps if we can catch these changes early on, someday soon we’ll be able to prevent all these diseases from developing in the first place.

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[i] Kalinkovich, A, and Livshits, G.  A cross talk between dysbiosis and gut-associated immune system governs the development of inflammatory arthropaties.  Seminars in Arthrisi and Rheumatism. 2019; 49 (3), 474-484.   DOI: 10.1016/j.semarthrit.2019.05.007

Parkison’s and the Gut: An Update

I haven’t given you a Parkinson’s-and-the-biome update in several months now, and as yesterday I read a great review of the current status of our knowledge on the connection between the two, I figured it was time.[i]

I am sure that most of you are very familiar with Parkinson’s Disease (PD), which is the 2nd most common neurodegenerative disorder after Alzheimer’s.  We have known for several years now, that it appears that the disease starts in the gut, although the exact mechanism of action is still unknown.  It seems, reading this paper, that the generally accepted (simplified) scenario right now is the following:

An unknown pathogen damages the nerves of the GI tract, resulting in the mis-folding (distortion) of a protein called α-synuclein (also known as Lewy bodies or Lewy neurites).  These Lewy bodies first accumulate in the gut.  Through various mechanisms, including the vagus nerve (which connects the brain to the gut’s nervous system), they move into the brain, including the substantia nigra, destroying the dopamine-producing cells there, resulting in the symptoms of the disease.

There is a large body of research now supporting this model:

  1. Lewy bodies have been found in the intestinal wall, including in the earliest stages of the disease. When serious research into PD started, about 40 years ago, these were “…quickly recognize in the GI tract of PD subjects as a clinical implication and pathological hallmark of PD.”  The presence of α-synuclein pathology, in fact, allows the progression of PD to be divided into stages. Early on, the patients display gastrointestinal symptoms like constipation, insomnia, the impairment of the sense of smell, with α-synuclein pathology evident in the olfactory bulb and the vagus nerve.  In the next stages, movement-related symptoms appear, such as tremor, rigidity, and postural instability (balance issues), and the substantia nigra may be positive for α-synuclein.  In the last stages, the patient will have severe motor issues, as well as potentially neuropsychiatric disturbances, and the Lewy bodies will reach other parts of the brain, like the cerebral cortex.
  2. α-synuclein is a normal protein in humans, but its exact purpose is unknown. I have read in other papers that it is thought to be a part of the immune system. In this paper, they suggest that it  “…plays a role in modulating the supply and release of dopamine to regulate neurotransmission.”  In PD, a folded (distorted) form of the protein accumulates in different parts of neurons.
  3. The “unknown pathogen” well, yeah – it’s unknown right now. Its effects though can be seen in damage to the nervous system of the gut, which is also thought to be the cause of the GI symptoms seen early on in PD.  80% or more of PD patients have gastrointestinal symptoms related to the disease.  By the way, the pesticide, rotenone, when given to animals orally, can “…induce PD-like neuropathological changes…”  So environmental causes are most certainly a possibility.  In fact, as I was reading the paper, I remembered reading this little article a couple of years ago, on research looking into the pesticides/PD connection. You can also read more about the relationship of diseases, including PD, to other toxins in the environment here.
  4. We know that severing the connection of the vagus nerve to the brain protects against the development of PD, which adds to the accumulating evidence of the gut being the origin.
  5. This paper briefly describes other fascinating research which, in different ways, shows the same: the gut origin of the disease.  For example,  researchers found that 62 patients with PD “…displayed α-synuclein accumulation in gastric, duodenal, and colonic biopsies more than 8 years prior to the onset of the motor symptoms of PD.”  Holy cow, right?
  6. The vagus nerve pathway is not the only one that is suspect: leaky gut has been found to be a major factor in those with PD as well, which allows toxins from the gut easy access to the blood stream and brain.  Researchers have found inflammation in the central nervous system in those with PD, associated with altered gut bacteria:  all these factors demonstrate that the gut microbiome “…is associated with and involved in gut permeability and the inflammatory response in PD patients…these findings are consistent with observations that the GM may be directly or indirectly involved in gut permeability and inflammatory responses in the GI and CNS  in PD and hence may affect PD pathology.”  (I’ve written about leaky gut and PD here.)
  7. Currently, a growing body of research shows that these “gut-initiated pathological processes” are the result of disturbances of the gut bacteria. (This does not, of course, preclude pesticides, which absolutely can affect the gut bacteria.)  The article lists many changes in specific species of gut bacteria. For the sake of brevity,  I will mention only a few especially interesting ones.  Those with PD have been found to have low levels of Prevotellaceae, which produces beneficial short-chain fatty acids as well as thiamine and folate, all of which are found at low levels in those with PD.  As I have mentioned before on this blog, Prevotella is known to improve gut barrier integrity.  And one more example for you:  levels of Enterobacteriacceae is positively correlated with the severity of postural instability  and gait difficulty found  in those with PD.
  8. Interventions to improve the quality of the gut bacteria (prebiotics, probiotics, diet, exercise, stress reduction, etc.) are “…supported by the fact that enzymes involved in dopamine synthesis in the brain are controlled by the GM [gut microbiome] and the GMBA [gut microbiota-brain axis].” Species like Bacillus are actually dopamine producers, believe it or not.  I wrote about the status of the research on this back last November, here.  We’re not there yet, but as you know I always say, if it can’t hurt and it could help, do it.
  9. Conclusion: “PD pathogenesis may be caused or exacerbated by GM disorder and microbiota-induced inflammatory responses.”  We don’t know for sure, but the weight of evidence suggests (more so every day) that PD is initially a gut-microbiome disorder.

If this subject particularly interests you, as it does me (seeing as I have multiple friends who have developed the damn disease in their 40s and 50s – INSANE), take some time to check out some of my other posts on the subject.   There are a lot!

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[i] Yang, D, et. al. The role of the gut microbiota in the pathogenesis of Parkinson’s Disease. Frontiers in Neurology. 2019.  DOI: 10.3389/fneur.2019.01155.

Diabetes and Metabolic Disorders: Are Helminths a Solution?

According to the CDC, about 10% of the United States’ population now has diabetes, and 90-95% of those have type 2.[i]  That is tens of millions of people in this country alone, let alone world-wide.  I need you to be sitting when I tell you the world-wide rate, according to the World Health Organization: “The number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014.”[ii]  And that is the most recent number, and it was from 6 years ago.

I’m brooding this morning about it because  yesterday I read a paper about the mechanism of action of helminths in alleviating diabetes symptoms:  “We postulated that helminth infections act by modulating the pro-inflammatory cytokine and chemokine milieu that is characteristic of T2DM [type 2 diabetes mellitus (official name)].”[iii]  To test their hypothesis they measured blood levels of pro-inflammatory chemicals in 60 people with diabetes who already had helminths (Strongyloides stercoralis) on board…and then measured these same chemicals 6 months after giving them anti-helminth drugs. They compared them to 58 helminth-free individuals who did not have helminths.

Those with helminths had “significantly diminished levels” of all pro-inflammatory chemicals measured, and to no one’s surprise, killing off their helminths resulted in vastly increased levels.

3 key points from their discussion section:

  1. The authors point that helminths’ anti-inflammatory effect (boosting of regulatory cytokines, which modulate inflammation) is already well-established in metabolic diseases:  “…regulatory pathways induced by chronic helminth infections have been associated with reduced insulin resistance and a lower prevalence of metabolic syndrome and T2DM, suggesting that helminth-mediated immunomodulation affords a protective effect against metabolic diseases.”
  2. Infection with this particular helminth, Schistosoma, is inversely related to the development of metabolic syndrome and diabetes (that is, as infection rates go up, the rates of the diseases go down…and vice versa), treating people with anti-helminth medicines causes the reverse: kill the helminths and rates of these metabolic disorders go up.
  3. Interestingly, while rates of the inflammatory chemicals rose dramatically once helminths were killed, they did not go as high as seen in those individuals who did not have helminths. The authors postulate that this because the  6 months  of the study may not have been enough time for inflammatory levels to fully get back to their disastrous normal.  This is a really important point:  it takes months to a year (or more) for helminths to reach their full anti-inflammatory effect, as research has shown and likely then, it takes months for the system to return to its pro-inflammatory state once the helminths are gone.

The conclusion:  “…our study offers novel insights into the immunological interactions between helminth infections and metabolic disorders…” and that helminth infection, “…could offer novel therapeutic approaches to treating inflammatory metabolic diseases.”

By the way, you’ll note that helminths did not cure the Type 2 diabetes.  Obviously, other steps are still necessary, like weight-loss and a healthy diet.  Also, the number and type of helminths were not controlled in this study.  These people were colonized, yes, but who knows by  how many organisms, how long they’d had the organisms, and perhaps most importantly – whether this particular kind of helminth is optimal in treating the disease.

You do have to wonder, do you not:  how much worse must things get before the medical community acknowledges that we desperately need more research into the optimal ways of using an apparently benign treatment that already exists in nature, to help the millions and millions of people suffering in the world?

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[i] https://www.cdc.gov/diabetes/basics/type2.html

[ii] https://www.who.int/news-room/fact-sheets/detail/diabetes

[iii] Rajamanickam A, Munisankar S, Dolla C, Menon PA, Thiruvengadam K, Nutman TB, et al. (2020) Helminth infection modulates systemic proinflammatory cytokines and chemokines implicated in type 2 diabetes mellitus pathogenesis. PLoS Negl Trop Dis 14(3): e0008101. https://doi.org/10.1371/journal.pntd.0008101

Inflammatory Bowel Disease, the Microbiome and…(ahhhh!) Mango

My regular readers know that I am always on the lookout for “things you can do now,” and that I get very excited when I find something that actually makes sense, even if it’s not entirely proven or the mechanism of action fully understood.  Yesterday, I came across research out of the University of Texas looking at the effects of eating mango on inflammatory bowel disease.[i]

Besides, it is one of my all-time favorite foods, so it’s a pleasure to wax lyrical on the delight that is a ripe mango.

Believe it or not, something as simple as eating 200-400 grams (approximately 7-14 ounces) per day of mango appears to make a measurable difference in alleviating  the symptoms of inflammatory bowel disease (IBD). These researchers conducted a small pilot study on 10 volunteers (3 with Crohn’s disease and 7 with ulcerative colitis, all currently on drugs for their illnesses) with mild to moderate IBD, and had them eat mango daily for 8 weeks.

Their justification for the research: mango contains polyphenols, natural plant compounds that act as antioxidants, and have been shown in many studies to protect against cancer and other diseases.  Some of the polyphenols you may be familiar with include flavonoids and phenolic acids.  Their presence is one of the reasons a plant-based diet is so healthy.  Previous studies have shown that mango polyphenols “…possess anti-inflammatory, anti-obesogenic [obesity] and anti-cancer activities, indicating their potential in modulating risk factors for intestinal disease.”  In animal studies, in which colitis has been chemically induced in rodents, a mango-based beverage attenuated inflammation.

Results of this study:

  1. Scores of an assessment of disease activity (bowel frequency, stool consistency, abdominal pain, nausea/vomiting, etc.) improved: “…findings in this study indicated that 8 weeks of mango intake exert beneficial effects in slowing the progression and reducing the severity of IBD…”
  2. Levels of blood inflammatory markers associated with IBD significantly improved.
  3. Stool analysis showed marked improvement in the quality of the bacterial microbiome, with significant increases in Lactobacillus species, including plantarum, reuteri and lactis.  These species “…are known to possess anti-inflammatory activity in the treatment of colitis by down-regulating the secretion of TNF…and up-regulating IL-10.”  (TNF-alpha is a major player in the pro-inflammatory system; IL-10, as I have talked about many times on this blog, is a major player in the regulatory system, which turns off the inflammatory response when no longer needed.)
  4. The short-chain fatty acid, butyrate, significantly increased. This SCFA is associated with improved intestinal barrier function (i.e. improved leaky gut).
  5. One phenomena was noted, unrelated to IBD: “…daily mango intake seemed to have been associated with a slightly decreased calorie and fat intake.”  Now this may not seem all that interesting…except that it’s not the first time this has been noted in a study.  Several studies have shown the same, including one that noted a decreased trend in caloric intake in obese people.

Obviously, this was a tiny study (it was only a proof-of-concept, after all), so the results should be interpreted with caution. Still, it is nice to report some good news. I don’t have IBD, but what the hell?!  It’s not like you have to twist my arm to convince me to eat my mango daily.

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[i] H. Kim, V.P. Venancio, C. Fang, et al., Mango (Mangifera indica

L.) polyphenols reduce IL-8, GRO, and GM-SCF plasma levels and increase Lactobacillus species in a pilot study in patients with inflammatory bowel disease, Nutrition Research(2020), https://doi.org/10.1016/j.nutres.2020.01.002

Bile Acids, Inflammatory Bowel Disease, and the Microbiome: A Rapidly Developing Story

Back in January, I wrote about how bile acids are regulators of inflammation and thus, when dysregulated (either too high or too low), this dysregulation can lead to disease.  Bile is produced by the liver and excreted into the intestines to digest fat.  Gut bacteria convert these primary bile acids into secondary bile acids, which are, in turn, immune signaling molecules, and I described research out of Harvard looking at the exact mechanism of action.  In that post, I also wrote about a second paper, also from Harvard, that looked at how diet and the gut bacteria work together to modify these immune-mediating bile acids.  I mention that “…low levels of bile acids make the mice prone to developing inflammatory conditions, like IBD.”

Well, new research out of Stamford University has zeroed in on a particular kind of bacteria missing from those with ulcerative colitis (UC) which may be responsible for the development of the disease.[i]  The study consisted of 2 groups of patients, 17 with UC who had undergone surgery to remove the colon and rectum.  The surgeons then reposition the lower end of the small intestine to create a pouch that acts as a rectum. Unfortunately, half of these UC patients develop a condition called pouchitis, which is inflammation of this pouch similar to the UC itself.  The second group of patients had a rare genetic condition which leads to that same surgery but almost  never develop pouchitis.  In comparing the two groups, they noted that those with UC had markedly lower levels of  both microbial diversity and secondary bile acids, including the two most prominent, deoxycholic acid and lithocholic acid, mirroring the Harvard research.  They noted too that the family of bacteria called Ruminoccoccaceae was significantly low in the UC patients versus the others.  These bacteria, along with several other kinds, carry the genes to create secondary bile acids.  Ruminococcaceae are a family of bacteria within the class of Clostridia.[ii]

In fact, when primary bile acids were incubated in stool samples from the patients with the genetic condition, secondary bile acids were created.  This did not happen with the same procedure using stool samples from the UC patients.  And in 3 different animal studies, when mice with IBD were supplemented with these 2 bile acids, markers for inflammation  markedly improved.

There is a phase 2 clinical trial happening at Stamford right now on 15 patients with UC who have had this pouch surgery; they are being given a naturally occurring secondary bile acid which is already approved by the FDA for other conditions.  I will absolutely keep an eye out for those results.  However, looking at Clinical Trials.gov, it looks like the primary completion date of the study isn’t until December 2025.  (I wish that there were a trial ongoing for those who have not as yet lost the bottom of their colon/rectum.  It would be great to see if this treatment could help prevent that horrible surgery in the first place.)

A postscript:  as I was getting ready to post this, I spotted breaking news about a brand new study out of Michigan State University about the discovery of brand new bile acids that are produced only by our gut microbes, not by our own bodies.[iii]  The discovery has apparently rocked the scientific world in that, no new bile acids have been found since their initial discovery in 1848:  “This discovery will change how medical textbooks address digestion, and it contributes to an ever-growing body of knowledge supporting the importance of the microbiome…”  And these new bile acids are “…particularly abundant in the guts of people suffering with gastrointestinal diseases, such as Crohn’s…”

This is really a developing story: the recognition of a completely altered bile acid composition in those with diseases involving intestinal inflammation.  Definitely stay tuned!

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[i] Sidhartha R. Sinha, Yeneneh Haileselassie, Linh P. Nguyen, Carolina Tropini, Min Wang, Laren S. Becker, Davis Sim, Karolin Jarr, Estelle T. Spear, Gulshan Singh, Hong Namkoong, Kyle Bittinger, Michael A. Fischbach, Justin L. Sonnenburg, Aida Habtezion. Dysbiosis-Induced Secondary Bile Acid Deficiency Promotes Intestinal Inflammation. Cell Host & Microbe, 2020; DOI: 10.1016/j.chom.2020.01.021

[ii] https://en.wikipedia.org/wiki/Ruminococcaceae

[iii] https://www.sciencedaily.com/releases/2020/02/200226131321.htm

Babies, Anxiety and the Gut Biome

Remember last Thursday, when I wrote about the relationship of the gut bacteria to the structure and function of the brain?    I mentioned in that post that, “In Western populations, Bacteroides and Prevotella species tend to dominate, with the former outnumbering the latter –as they did in this sample of women. A diet high in fat and animal protein (i.e. a standard Western diet) is more associated with higher Bacteroides species than Prevotella…”  I went on to point out that, “Prevotella levels are markedly higher in non-Westernized societies, which consume plant-based diets, where people are actually less prone to ‘mental’ illnesses like depression or anxiety. And don’t forget, low levels of Prevotella  have also been associated with leaky gut and also, Parkinson’s disease.  So the likelihood is that higher Prevotella amounts are better for health.”

With that fresh in mind, yesterday morning I spotted an article[i] that looked at the composition of the bacterial microbiome in infancy and its relationship to the development of anxiety issues in toddlers, and the findings should come as no surprise:  “…we found a clear association between decreased normalised abundance of Prevotella in faecal samples collected at 12 months of age and increased behavioural problems at 2 years…”

This finding held even when other variables were accounted for, like mode of birth, pet ownership, maternal smoking, breast feeding, and so forth.

The test group tested consisted of 201 infants, selected from an Australian birth cohort of over 1000 babies.  Stool samples were collected at 1, 6 and 12 months, and when the babies reached 2 years of age, their parents filled out extensive questionnaires.  No association was found in behavioral differences based upon the first 2 stool collections, but the 12-month sample found significant associations.  Believe it or not, Prevotella was found in only 4% of the children who went on to have anxiety issues versus 44% of the children without any problems.  (Lacnospiraceae species were also altered in the behavior group, although when other factors as mentioned above were accounted for, this was somewhat less significant.)

The main factor leading to lower levels of Prevotella? You guessed it: antibiotic use.  However, the behavior group’s antibiotic use was not different from the non-behavioral group with low levels of Prevotella, so this was not considered significant in terms of predicting behavior.

The mechanisms are still unknown but there are numerous possibilities:  stimulation of the vagus nerve, various enzymes or cytokines, tryptophan metabolism, the immune system, and so forth.  Studies are already underway to replicate these findings and to delve into causality.  The implications of this work may be huge:  as these authors state, this work “…adds support to evidence that the human gut microbiota may have long-term neurodevelopmental consequences, conferring protection or vulnerability to behavioural and mental health outcomes in later life…”  This work, therefore, may have tremendous relevance not only to anxiety disorders (which are on the increase in industrialized nations) and other mental health issues, but also autism (remember the fecal microbiota transplant study – FMT led to higher levels of good bacteria, including Prevotella, which is low in those with autism), and potentially illnesses that tend to hit in later life, like Parkinson’s disease.  It’s looking more and more like eating right from the moment of birth is crucial for long-term physical and mental health.

Hopefully there will be more to report to you in the near future.  In the meantime, eat that plant-based diet!

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[i] Loughman, A, et. al. Gut microbiotia composition during infancy and subsequent behavioural outcomes. EBioMedicine. 2020. DOI:https://doi.org/10.1016/j.ebiom.2020.102640