Your Brain and Your Microbiota…Which Forms Which?

This is a great follow up to my post on Tuesday about the relationship of personality to the gut bacteria.   Today I’m covering a new study from UCLA which looks at how the gut bacteria affect the actual structure and function of the brain.[i] Our understanding of the gut-brain axis continues to grow; it really is fascinating watching the slow but steady progress!

40 healthy women provided stool samples, and were then divided into two groups, based upon the composition of their gut flora.  33 of them had higher levels of Bacteroides than Prevotella; the other 7 had the opposite profile, with Prevotella-family bacteria predominating.

It turns out that their bacterial profiles were predictors of both the amount of gray matter in various parts of the brain as well as their reactions to different stimuli.

In terms of structure, “…white and gray matter imaging discriminated the two clusters, with accuracy of 66.7% and 87.2% respectively.” That is, there was statistically significant correlation between the make-up of the gut bacteria and the structure of the brain. Women with higher levels of Bacteroides (versus Prevotella) had thicker gray matter in their cerebellum and frontal region which are “…involved in the complex processing of information” and more brain matter in the hippocampus, which is a big player in memory processing.  The Prevotella group had less brain matter in several regions including “functional and structural differences in the hippocampus” (which is the brain region involved in emotion regulation), as well as differences in areas involved with attentional and sensory processing.

This latter group of women, when viewing negative images, showed less activity in their hippocampus, and greater levels of anxiety and irritability than the Bacteroides group.

Of course, we still face a chicken-or-the-egg scenario in that it is currently unknown whether or not it is the brain dictating the gut flora or the gut flora dictating the structure/function of the brain. The authors point out that while “…some aspects of the microbiota’s influence on the CNS are likely to be established early as traits, other aspects may be malleable and are vulnerable to environmental factors…”  Timing too may matter:  what you eat long term, or during early years of life while the brain is still developing, may have lasting influence.  It does appear that diet is a major factor.  In fact, these researchers have already published work demonstrating that in healthy women, 4 weeks of ingestion of “…a fermented milk product with probiotics can shift functional brain responses to an emotional attention task…providing more direct evidence in humans that brain function can be affected by modulation of gut microbiota.”

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, which is associated with a plant-based diet.  With so few women fitting into the Prevotella group then, the authors advise caution in interpreting their results.  Much larger studies are needed to confirm whether this “…propensity towards developing a more negative affect during this paradigm is a marker of personality traits, a risk factor for developing clinically relevant negative moods states, or just a healthy variant.”

The interpretation that a plant-based diet (which leads to higher amounts of Prevotella than Bacteroides but also, a more negative emotional state under these laboratory conditions) is therefore less desirable is fallacious.  Someone’s emotional state may, in fact, dictate their diet.  I, for example, thought about a healthy diet a lot less when I was younger and hadn’t yet faced my son’s autism diagnosis.  Yes, I am under a great deal more stress but we also eat way healthier.  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.  (Wouldn’t it be interesting if they followed these women over the next 20 years to see how they fare, health-wise?!)  In fact, the structure of the brain in these women may not actually be caused by their gut bacteria, or these particular gut bacteria.  This is a correlation study, not a causation one.

As always, I will watch and wait to see further research on this.

_______________________________________________

[i] Tillisch K, Mayer E, Gupta A, et al.  T, Zeevi D, Zmora N, et al. Brain structure and response to emotional stimuli as related to gut microbial profiles in healthy womenPsychosomatic Medicine. 2017. DOI: 10.1097/PSY.0000000000000493

Your Personality and Your Gut Bacteria: Mirror Reflections?

I posted the news last week on the Biome Buzz’ Facebook page, about research out of Oxford University in the UK[i] which connected personality type to specific microbiome patterns.  The story has gotten huge coverage in the world of the biome, so I reckon I better write about it in greater detail.  After all, you come here to get the latest news in detail, hot off the presses, right?

The study involved fecal samples from 655 adults (71% female, 29% male).  They all filled out a questionnaire which asked about lifestyle, health, behavior, and so forth.  The paper’s author, Katerina Johnson (from the Department of Experimental Psychology), then associated personality type (for example, sociability and neuroticism) to the gut bacteria in the samples.

The questionnaire used, the International Personality Item Pool, uses 50 items to group people into 5 personality types:

  • “extraversion, or the “propensity to seek and enjoy others’ company”
  • agreeableness, defined as “trust and cooperation in social interactions”
  • conscientiousness, or the “attention to detail and focus”
  • neuroticism, i.e., the “tendency to feel negative emotions”
  • openness, which researchers have described as “creativity, intellectual curiosity, and willingness to seek new experiences”[ii]

After adjusting the data for variables that might influence the composition of the bacteria (sex, age, BMI, birth delivery mode, infant feeding method, antibiotic use in the last 6 months, probiotic use), she was left with a pool of 261 qualifying participants.

The results were pretty remarkable:  “…both gut microbiome composition and diversity were found to be related to differences in personality.”

Those types of bacteria now associated with autism spectrum disorders proved consistent in that, in the general population, they were also found in less social people.  Those individuals with extensive social networks had more diverse microbiota, suggesting that social behavior is important for microbiome health. (We are social animals, after all, so this didn’t shock me.)  For example, Akkermansia (whose health benefits I have covered several times before, including here), Lactococcus and Oscillospira were “…found to be more abundant in individuals with a higher sociability score.”  This coincides with prior research which has shown that those with autism have a reduction in Lactococcus and Oscillospira, and 1 study thus far has found lower levels of Akkermansia as well.  In animal studies, Oscillospira has already been associated with social behavior, and both this species and Akkermansia, “…are associated with good health; Akkermansia has anti-inflammatory properties and there is some evidence it may be protective against metabolic disorders while lower levels of Oscillospira are linked to inflammatory disease.”

Also really interesting:  those who were less social behavior had higher levels of Desulfovibrio and Sutterella, the former of which I have covered in relation to autism in the past (see here):  “…in fact, it has been hypothesized that Desulfovibrio species may play an important role in the pathophysiology of autism.”

Another not-surprise: stress and anxiety reduced microbiota diversity.  And, as I have talked about in the past (see here), poor sleep quality also appeared to lead to a loss of diversity.

A few other important points:

  1. People who ate more foods with naturally occurring pro- and prebiotics had significantly lower levels of stress, anxiety and neuroticism, and proved less likely to develop a mental illness:  “Diversity of the gut microbiome was also related to the amount of food people consumed containing natural probiotics and prebiotics.”
  2. Remarkably, the research did not show the same for pro- and prebiotics in supplement form. This latter finding, however, may be because those who have been on antibiotics or who have gut issues – thus already likely having dysbiosis issues – are more likely to use supplements.
  3. This one is not a surprise. Those who were formula fed as babies had less diverse microbiota.

The author points out that the relationship of the gut microbiota and behavior is bidirectional and thus, “…the gut microbiome can affect the stress response and stress also disrupts the gut microbiome.”  We can assume then that improving one’s social behavior may have long-term health benefits.

I want to share Dr. Johnson’s concluding remarks as they are definitely worth your time to read:

“…it is pertinent to reflect on the ways in which our modern-day living may provide a perfect storm for dysbiosis of the gut. We lead stressful lives with fewer social interactions and less time spent with nature, our diets are typically deficient in fibre, we inhabit oversanitized environments and are dependent on antibiotic treatments. All these factors can influence the gut microbiome and so may be affecting our behaviour and psychological well-being in currently unknown ways.”

I couldn’t have said it better myself!

_______________________________________________________

[i] Johnson, KV-A. Gut microbiome composition and diversity are related to human personality traits. Human Microbiome Journal. 2020;15.  https://doi.org/10.1016/j.humic.2019.100069

[ii] https://www.medicalnewstoday.com/articles/can-your-gut-bacteria-predict-your-personality#More-friends-may-promote-gut-health

Coming Soon: Sports-Specific Probiotics?

Last September, the big news in the wonderful world of the biome was that Harvard was taking on designing probiotics to improve athletic performance: “The Wyss Institute for Biologically Inspired Engineering at Harvard University has announced that its athlete microbiome-based technology will be commercialized by Fitbiomics Inc., a recently formed startup company, to develop highly validated probiotics based on elite athletes’ microbiomes, which could improve athletic performance and, conceivably, even overall health.”[i]  (For all you major stud muffins out there, you can actually sign up now to beta test their product.)  I am really intrigued by this whole field of research.  After all, we have known for several years that elite athletes have biomes different from the rest of us mere mortals…and that exercise improves the quality of the bacterial microbiome.  You don’t have to be going to the next Olympics to reap the benefits of regular exercise.

I found some new research today that takes this all a step further.[ii]  Scientists in Ireland took a look at how different kinds of exercise impact the microbiome. They sampled feces and urine from 37 elite Irish athletes who competed in 16 different sports.  The sports were grouped by high muscle contraction/high oxygen consumption (i.e. cycling type exercise); high muscle contraction/low oxygen consumption (i.e. judo); low muscle contraction/high oxygen consumption (i.e. field hockey).[iii]

It turns out that highly dynamic (moving) forms of exercise, like field hockey, versus moderately dynamic (like fencing), versus mixed dynamic/static sports, like rowing, all lead to different microbiome profiles.  For example, high dynamic sports led to higher levels of Bifidobacterium animalis, Lactobacilllus acidophilus (25x greater than in the other groups of athletes), Prevotella intermedia, etc.  On the other hand, athletes involved in moderate dynamic sports had greater levels of Streptococcus suis and Clostridum bolteae, among others.

They also found significant differences in how the biome functions.  Middle distance running and swimming were found to have the biggest differences here.  As one example:  in the mixed high dynamic and static group (i.e. rowers), “…pathways involved with folate and amino acid biosynthesis…were found to be 1.5 times greater…” when compared to other groups.

What I found particularly interesting was that this effect was determined to be independent of foods eaten:  “The difference in  microbiomes and metabolome across groupings, in the absence of significant dietary differences, suggest a role for exercise type as a contributing factor.”

This study did not look at the reason for these differences but I will keep an eye out for future work in this field.  After all, there may very soon come a day when you can choose the probiotic that is exactly right for your sport of choice.  (2024 USA Olympic swim team, here I come!)

____________________________________________________

[i] https://otd.harvard.edu/news/harvards-athlete-based-next-generation-probiotics-technology-licensed-to-fi/

[ii] O’Donovan CM, Madigan SM, Garcia-Perez I, et al. Distinct microbiome composition and metabolome exists across subgroups of elite Irish athletes. J Sci Med Sport. 2020; 23(1):63-8. doi: 10.1016/j.jsams.2019.08.290.

[iii] https://www.gutmicrobiotaforhealth.com/en/who-would-have-guessed-that-sport-is-impacting-our-gut-microbiota/

The Promise of Helminths for Multiple Sclerosis

Today I get to write about something other than the bacterial microbiome!  Woopa! I was very happy to find a new paper on the possibilities of using helminths (helminth immunotherapy (HIT), as these authors call it) to prevent and alleviate multiple sclerosis (MS).[i]   The article gives a great overall picture of where we currently stand, research- wise, and what work needs to be done going forward.  More than that, I also learned some new tidbits which I think are very worth sharing with you.

I’ve written before about helminths and MS.  As these authors acknowledge, what we currently know holds great hope, although it is a fraction of what we need to know.  Still, the majority of the current studies (20 of 23), “…reported a protective effect of HIT…especially when the helminth or helminth-derived product was provided prophylactically…”  Few studies currently exist on using HIT for those already affected – but I’ll come back to that in a moment as those studies too, hold promise.

One of the main issues in the field is lack of “technical” consistency.  The existing studies have used many different species of helminth and those organisms were used in many different ways.  In spite of this though, there is an overall remarkable consistency in findings.  For example, there is great consistency in all these varied experiments in the way the immune system responds to the presence of helminths:  they stimulate the Th2 family of cytokines, which includes regulatory ones, leading to lower levels of inflammation.  Another interesting, and consistent, finding has to do with the B cells of the immune system.  Generally speaking, depleting these kinds of immune cells via pharmaceutical works well for ameliorating the symptoms of MS, and thus are considered “major players in MS pathogenesis.”

Very little work (2 studies so far) has been done looking at helminths’ effects on B cells, but what we do know is that when an organism has helminths, B cells are implicated in promoting the Th2 response.  In one study, the researchers transferred B cells from helminth-infected mice with the MS-like syndrome into mice who were also afflicted, but who did not have helminths.  These B cells diminished the MS-like symptoms in the latter mice.  In a human study, B cells from helminth-infected MS patients were shown to suppress inflammatory cytokine production and to stimulate regulatory cytokines:  “Altogether, these observations suggest that HIT may modulate B cell function and contribute to the beneficial outcomes in…MS.”

Of the studies done thus far (in animal models, in which an MS-like syndrome is induced), only two have shown no protective effect from helminths.  However, results of these must be interpreted with caution.  In one of them, the helminths were cleared before MS was induced, “…which could explain the lack of an effect.”  In the other, a helminth-derived product was used – not a living organism.  The paper states that “…the majority of animal studies support the hypothesis that pre-existing helminth infection can limit the onset of MS-like symptoms in experimental models.”

The article points out that most people turn to helminths after diagnosis, and thus, studies looking at the effects helminths may have on alleviating symptoms are particularly useful.  Unfortunately, there are very few of these.  One unsuccessful one again used a product derived from Schistosoma eggs, not the actual organism.  Products derived from other helminths were more successful.  In one study, using the actual organism H. Polygyrus, partial remission was noted at only 3 weeks post inoculation.  The best human study, covering a period of 5 years, I have discussed before in that  earlier post.  Those with MS who had helminths fared way better than those without, with no worsening of symptoms or new brain lesions.

Thus far, there have been 4 human clinical trials which have reported results.  They all used Trichuris suis ova, TSO (which is a porcine-native whipworm), and varied greatly in length, from 3 to 10 months.  The only one which saw no improving trends was the 3 months one.  It appears, based upon these studies, that the longer the patient has had helminths, they better they continue to do (i.e. an uphill trend).

I feel like a broken record writing this, but we may as well get used to it because there is always more to be learned.  In this case, we really, really need more science before we know how to best to dose helminths, which ones are the best organisms (which will likely vary from disease to disease), and so forth.  Still, as this paper concludes, “…although there are only a limited number of studies that have tested whether HIT can have therapeutic effects once disease is established, there are indication of beneficial effect using some HIT regimes…”

________________________________________

[i] Charabati, M, Donkers, SJ, Kirkland,  MC, Osborne, LC. A critical analysis of helminth immunotherapy in multiple sclerosis. Multiple Sclerosis Journal. 2020. doi: 10.1177/1352458519899040

Breast Cancer: A Little Bit of Yogurt Seems to Go a Long Way

This past October, I wrote about probiotic use in breast cancer.  If you remember, that paper concluded that what few in vitro and in vivo studies we have look promising.  One piece of research mentioned in that paper is particularly pertinent to today’s post:  “One Japanese study asked 306 women with BC, and 662 women without, about their diets, lifestyles and other risk factors and found that regular and long-term consumption of L. casei Shirota (found in Yakult yogurt, and which I have written about before – for example,  here ) was ‘…significantly associated with decreased BC risk in Japanese women.’”

One of the big biome stories of the week:  another paper just came out that once again, points out the fact that eating yogurt is highly associated with a decrease in breast cancer risk.[i] This paper, out of Lancaster University in the UK, suggests the following hypothesis:  “…the mechanism proposed in this article is that the bacteria which cause cancer induce inflammation which leads to the destruction of the stem cells…”  This leads to “genetic instability” and mutations within the breast cell DNA.

The authors point out that breast ducts are far from sterile.  Pregnancy and lactation are known to decrease the risk of breast cancer fairly dramatically:  “Following pregnancy and lactation, they will have a flora which is dominated by lactose fermenting bacteria.  This appears to be protective against the development of cancer.”  However, bacteria from other areas of the body, where pathogenic bacteria may be present, can travel via the blood stream and can cause dysbiosis in a wide variety of other tissues.  For example, periodontitis, which is inflammation of the gums caused by bad bacteria, is highly associated with a wide variety of other illnesses including senility, atherosclerosis, rheumatoid arthritis and cancer (including of the gastrointestinal tract, breast, prostate and pancreas).  It is likely that “…organisms of the mouth are carried through the blood to distant sites and cause direct tissue destruction and inflammation.  In the breast we envisage that the pathogenic bacteria directly damage epithelial cells…”

The good news:  eating daily yogurt seems to make a very statistically significant difference in breast cancer risk.  One meta-analysis (which has been replicated), which looked at thousands and thousands of cases, showed that “…high and modest dairy consumption significantly reduce the risk of breast cancer compared with low diary consumption.”  Further analysis showed that the effect forms of dairy were low fat dairy and yogurt – not other forms, like fluid milk.  And the amount:  about 2-3 cups of these forms of dairy per day (400-600 grams).

In a press release about the study, one of the authors states, “…The stem cells which divide to replenish the lining of the breast ducts are influenced by the microflora, and certain components of the microflora have been shown in other organs, such as the colon and stomach, to increase the risk of cancer development. Therefore, a similar scenario is likely to be occurring in the breast, whereby resident microflora impact on stem cell division and influence cancer risk.”[ii]

The conclusion:  “…there is a simple, inexpensive potential preventive remedy; which is for women to consume natural yogurt on a daily basis…”

A little bit of good news, on the things-you-can-do-now front!

____________________________________________________

[i] Marwaha, AK, Morris, JA, Rigby, RJ. Hypothesis: bacterial induced inflammation disrupts the orderly progression of the stem cell hierarchy and has a role in the pathogenesis of breast cancer. Medical Hypothesis. 2020; 136:109530. doi:10.1016/j.mehy.2019.109530.

[ii] https://medicalnewsbulletin.com/can-eating-yogurt-prevent-breast-cancer/

Fiber: And You Thought This Was Simple (ha!)

Many times over the years I’ve written about prebiotic fibers and gut health.  What seems so simple at first glance (i.e. “eat more fiber”) turns out to be anything but…just like everything else having to do with the gut biome!  I just finished reading a really interesting little article that was published in the proceedings of the Nutrition Society, from a conference held at the Royal Society of Medicine in the UK.[i]  It is a great follow up to my post of a few weeks ago, which talked about how too much of a good thing is just as bad as too little.  (As my old mentor, Dr. Sidney Baker, used to say (summarizing basically all of medicine):  does this patient have too much of something or too little?)

Dr. Rhodes summarizes some recent work looking at dietary fibers and to summarize in just a few words – they are not all the same. Historically, starting in the 1990s or so, we were all told to get at least 5 servings per day of fruit and vegetables, excluding starchy vegetables like potatoes, yams and plantains which didn’t “count.”  This, according to Dr. Rhodes, had very little evidence supporting it and in fact, there is “…some evidence that plantains for example might be particularly beneficial.”

The research on simply adding more fiber to the diet to stave off colorectal cancer has been contradictory at best.  Dr. Rhodes suggests that this might be an issue of over generalization:  “One possible conclusion from these contradictions is that it may not be helpful to generalize about health impacts of large food groups.” After all, fruit and vegetables, for example, contain many, many different nutritional components and too much of one or too little of another can have major health implications.

Looking then at colorectal cancer as an example, he points out that bacteria of the gut has come under great suspicion as playing a major role in its development:  “…cancer is so relatively rare in the small intestine (.4% life-time incidence) compared with the colon and rectum (6% life-time incidence in western countries) and bacteria re approximately 104 more numerous in the colon.” Research has shown some highly suspect bacteria include Fusobacterium and E. coli, among others.  E. coli has been found to adhere to the mucosal lining of the gut in both colon cancer and in Crohn’s disease, and promotes inflammation. In places where the diet includes high amounts of fiber (I’ve written about this before here), colon cancer and inflammatory bowel diseases are extremely rare.  Therefore, “…we investigated the possibility that soluble dietary fibres and other complex carbohydrates might be able to inhibit E. coli adherence to the epithelium.”  It turned out that fiber from plantains and broccoli, but not from apples or leeks, have a profoundly positive effect on protecting these bacteria from invading the mucosal lining.  And this applied to not just E.coli, but also other pathogenic bacteria including C. difficile.  Dr. Rhodes calls these inhibitory fibers contrabiotics.

You’ll remember that  bacteria eat these fibers and in fermenting them, produce short chain fatty acids (SCFA).  SCFAs are very, very beneficial to health, generally speaking, as you know, but…as I mentioned in the first paragraph of this post, too much of anything is NOT GOOD.  Studies on different soluble fibers have shown that higher doses of citrus pectin tend to be beneficial whereas inulin may be harmful.   Animal studies have shown that in mice in whom the anti-inflammatory cytokine, IL-10, is blocked, inducing inflammatory bowel disease, a diet rich in citrus peel pectin ameliorated the disease whereas a diet containing a similar amount of inulin exacerbated the colitis.

Why?  Inulin was correlated with high amounts of the short chain fatty acid, butyrate.  Now, butyrate, of course, is usually very good.  But that is the key phrase – in the right amount:  “Although butyrate is widely regarded as beneficial to the colonic epithelium, it is perhaps insufficiently recognized that this benefit is very much dose-related.”  Remember my article on propionic acid where I talked about research stating exactly the same thing?  High doses of butyrate, “…have been known for a long time to be toxic to colon epithelial cells in vitro…”

The ecosystem of the biome is unbelievably convoluted and science has barely begun to pick apart how each element affects others.  There are trillions of organisms interacting with each other, secreting an unbelievable array of metabolites (most of which are still unknown).  Throw food into the mix and – well, I reckon it will be decades and decades before we have even an inkling of how this all works. The question of fiber alone is not even vaguely simple:  “The impacts of fibre on microbiota are complex and also depend on the existing microbiota.”

Dr. Rhodes mentions other components of fruit and vegetables (like lectins – which I may write about soon) and also briefly addresses the question of emulsifiers in processed foods.  To summarize the latter: they are bad.  I’ve written about this before (just one example of several – here) so I won’t go into any detail now.  Just avoid them as much as you can.

So to conclude, two major points from this article:

  1. Some sound advice: “Dietary advice to the general public should therefore address factors that reduce the risk of a range of conditions, not just one, and should ideally impact beneficially on all-cause mortality….There is, for example, evidence that adherence to a Mediterranean diet, and its components; low meat, high fruit and vegetable, nuts, and olive oil impacts beneficially on all-cause mortality.”
  2. “If you are searching for a single dietary component that might prolong life there is arguably nothing that has a stronger case. Regular coffee drinking has been associated with reduced risk of type 2 diabetes, cardiovascular mortality, cancer, cirrhosis and most importantly, with a reduction in all-cause mortality.”

Waahooo! (Judy wrote, swallowing another mouthful of java…)

____________________________________________

[i] Rhodes, J.M. Conference on ‘Diet and Digestive Disease’ Plenary Lecture 1: Nutrition and gut health: the impact of specific dietary components – it’s not just five-a-day.  Proceedings of the Nutrition Society. 2019.  doi:10.1017/S0029665120000026

Another Step Forward: Ankylosing Spondylitis and the Microbiome

The evidence continues to mount pointing to microbiome alterations as being (one of?) the underlying cause of ankylosing spondylitis (AS).  Just a few weeks ago, I wrote about a long-term study on 150 patients with AS which showed distinct alterations in the biome.  A second major paper (out of China) appeared in the Journal of Autoimmunity within the last few weeks which moved the research forward once again.[i]

I’ve pointed out in previous posts about AS that “…at least 2.7 MILLION people suffer from these diseases in the USA alone, which is almost 3X the number of people that suffer from the way better known Parkinson’s disease alone…”  This is an illness that affects millions of people at yet, remains relatively unknown and unstudied.  Worse still, it typically takes years to be diagnosed, leaving many people untreated and suffering.  I am always really happy when I see some new information about it.

In this recent paper, the scientists looked at the fecal microbiome of 108 people with AS, 85 of whom were untreated, the other 23 of whom were undergoing treatment.  They also had feces from 62 healthy controls.

They did multiple tests which provided a great deal of new data:

  1.  They confirmed that specific bacterial species are at higher levels in those with untreated AS when compared to healthy controls.  These species include Bacteroides coprophilus, Parabacteroides distasonis, Eubacterium siraeum, Acidaminococcus fermentans and Prevotella copri.  Levels of other bacteria were lower than controls, including Enterococcus faecium.
  2. When patients with AS are treated, levels of some bacteria began to resemble those of healthy controls: Prevotella levels decreased and Enterococcus faecium increased:  “…the facts  above indicate a possible causal relationship between Prevotella copri and AS pathogenesis.”  The shift in this bacterial species toward control levels was more marked with immune-suppressant medicines than with just NSAIDS (non-steroidal anti-inflammatories, like ibuprofen).
  3. Several pathways associated with the microbiome are altered in those with AS, including one that may lead to bone destruction and compromise gut wall integrity.
  4. The pattern of bacterial alterations in those with AS is distinct enough that it looks like it will be able to be used diagnostically. This is really good news, in that, as mentioned above, diagnosis of the condition typically takes YEARS, leaving people untreated, or inappropriately treated, which of course leads to further bone deterioration.
  5. A quick definition for anyone unfamiliar:  molecular mimicry encompasses the idea that foreign proteins may look an awful lot like our bodies’ own and thus, we form autoantibodies to both, leading to autoimmune disease.  These researchers found 3 peptides (which are just short proteins) “…among bacterial species enriched in AS patients that are similar to auto-antigens with a known role in AS.”  In fact, one of these peptides “…stimulated secretion of the pro-inflammatory molecule IFN-gamma by immune cells in AS patients, but not in controls.”[ii]  This peptide mimics one found in collagen, which is the main component of cartilage.  As the body attempts to destroy the foreign invader, it ends up attacking its own cartilage.

The conclusion remains that “Despite the fact that several gut microbiota studies have been performed in AS patients, we are still far from a clear causality between gut dysbiosis and AS pathogenesis. Unlike other inflammatory diseases such as RA whose development have been proven to partially attribute to gut dysbiosis, the exact relationship between any specific microbial taxa and AS pathogenesis has not been reported yet.”  So way more still needs to be done.

Still, this year already we’ve seen two major steps forward in research.  And that is, at least, of some comfort.

___________________________________________

[i] Zhou, C, et. al. Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis. Journal of Autoimmunity. 2019. DOI: 10.1016/j.jaut.2019.102360

[ii] https://ankylosingspondylitisnews.com/2020/01/23/gut-microbiome-in-ankylosing-spondylitis-patients-is-imbalanced-and-contributes-to-inflammation/

Early Life Stress, the Microbiome and Children’s Behavior

Well, this will come as a complete shock to most of you.  (NOT)  The bacterial contents of children’s guts affects their behavior.

One of the big biome stories of the last few days is that research out of Oregon State University and the University of Oregon has shown that school-age children with behavioral issues have different bacteria in their guts than the normally behaved controls.[i]  Of course, this does not prove that the gut bacteria are determining behavior.  It may well turn out that the opposite is true:  behavior determines the gut bacteria.  What these scientists actually did was zero in on children who faced “…a range of adverse experiences and caregiver stressors and relationships…” to see if they had alterations to the microbiome.  Their “…results indicated that the taxonomic and functional composition of the gut microbiome correlates with behavior during a critical period of child development.”

That is, “caregiving behaviors” modified the gut microbiome.

Now, as the mother of a child with autism, let me say that, like the rest of you in my shoes, I tend to be pretty hypersensitive about anything that smacks of “refrigerator mother” syndrome.  In this case though, please remember that these researchers do state that this proves nothing more than a correlation, not a causation.  This research is not a blame game.  It is a study of how stress of any kind alters the gut biome which, in turn, may alter a child’s behavior.  And this is really important to know.

To summarize, the scientists stat that “While we cannot infer causality within this study, these findings suggest that caregivers may moderate the gut microbiome’s link to environment and behaviors beyond the first few years of life.”

So let’s all take a deep breath and talk about the science.

  1.   “Ongoing research seeks to characterize the underlying mechanisms by which adverse environments and caregiving behaviors (both positive and negative) influence a child’s behavioral development. Such research demonstrates that these environments and caregiving behaviors can alter the developmental trajectory of central, autonomic, and peripheral nervous systems function.”  Well, that makes perfect sense, right?  Stress in a family would of course tend to lead to stress in a child.
  2. We all know that stress has profound physiological effects. We all know, too, that stress – both physiological and emotional – impacts the microbiome.  I’ve written about this before, for example, here and here.
  3. We Biome Buzzers are pretty comfortable with the idea that our gut bugs influence our behavior, and vice versa. Here are a couple of posts on that topic:  here and here.

So following that trail of logic, it makes perfect sense that caregiving behaviors influence a child’s microbiome which, in turn, may influence a child’s behavior.

In this study, the researchers looked at 40 children 5 to 7 years of age.  Their parents filled out questionnaires that asked about socioeconomic risk, behavioral dysregulation, caregiver behavior, demography and gut history (like antibiotic use).  The parents were also asked to journal the child’s diet for 1 week.  Fecal samples were then collected from the children.

A quick summary of their findings:  “…our study reveals supportive evidence that the psychosocial environment continues to shape not only the taxonomic composition, but also the functional potential of the microbiome…”

It turns out that economic and social forms of adversity lead to different microbial profiles.  For example, poor economic status may lead to greater toxic exposures, which alters the microbiome and intestinal permeability.  This, of course, leads to alterations in the immune system.  The quality of the child-parent relationship were indicative of altered functionality of the gut microbiome, and subsequent depression and impulsivity issues in the children.  (By functionality, they mean how the microbiome performs.  For example, are vitamins produced normally?  How are amino acids synthesized into neurotransmitters, etc.)?

The authors conclude:  “…we discovered that not only are there significant associations between metrics of socioeconomic risk and behavioral dysregulation with the microbiome, but that the quality of the parent-child relationship (here parentally reported) and parental stress statistically moderated these relationships.”

I don’t think there’s anything revolutionary here, but still, it is an interesting little paper.  It’s yet another confirmation of the critical importance of the gut-brain axis,  and the fact that external factors ranging from diet to lifestyle affect that biome and ultimately, human behavior. The lead researchers, Thomas Sharpton, believes that “… if large studies confirm these findings, it might be possible to figure out a way to use microbiome information to predict how a child’s behavior might develop. Having that information might lead to earlier — and possibly more successful — interventions.”[ii]   And everyone likes interventions!

____________________________________________

[i] Flannery, JE, Stagaman, K, Burns, AR, Hickey, RJ, Roos, LE, Glultiano, RJ, Fisher, PA, Sharpton, TJ. Gut feelings being in childhood: the gut metagenome correlates with early environment, caregiving, and behavior.  mBio. 2020; 11(1).   doi: 10.1128/mBio.02780-19

[ii] https://www.webmd.com/children/news/20200121/could-a-kids-microbiome-alter-their-behavior#1

Lupus and Helminths: Preventive Promise?

I continue to monitor the macrobiome space, watching as the evidence (very) slowly but surely continues to mount in support of helminths’ ability to alleviate, or even prevent, the development of autoimmune diseases.  The latest news is that, in an animal model, Japanese researchers have found that a species of helminth (intestinal worms native to all mammals), Hymenolepis microstoma (HM), a species of tapeworm, native to rodents,  can stop lupus in its tracks.[i]

First, a little about lupus, in case you’re not familiar.  According to the Mayo Clinic, it is a systemic autoimmune disease that can affect many systems including your joints, skin, kidneys, blood cells, brain, heart and lungs.[ii]  The National Center on Lupus states on their website that at least 1.5 million Americans have the disease, 90% of whom are women.  It is potentially an extremely serious disease:  it is among the top 20 leading causes of death in females, aged 5-64.[iii]

As is the case with all autoimmune diseases, no one knows either the cause or the cure for lupus, and like many others, is treated with an array of immune-suppressants and biological agents.

I have described the known immune-modulatory effect of helminths many times on this blog (2 quick examples of many here and here), so won’t go into details in this post.  For those unfamiliar, a very brief explanation:  in order to survive, helminths have evolved to modulate the inflammatory response of their hosts to keep from being killed off.  They are potent activators of the regulatory system (the off switch to the inflammatory one).  Improved sanitation (toilets, shoes, purified drinking water, etc.) has led to the eradication of  our native macrobiomes in the industrialized world, leaving us with lower levels of regulatory cytokines and thus, the tendency to have excessive and perpetual inflammation.

While many studies now exist in animal models, and some in humans, showing helminths’ benefits in treating diseases like allergy, multiple sclerosis,  and even autism, etc., prior to this paper, none really existed looking at their efficacy in treating lupus.  Apparently, this is because of a lack of a good animal model of the disease.  In this experiment, the researchers used mice that have been bred to spontaneously develop a lupus-like syndrome.

Three different helminths were tested in germ-free mice: Trichuris muris (a roundworm native to rodents); Heligmosomoides polygyrous (another roundworm native to rodents); and Hymenolepis microstoma, which, as I mentioned above, is a different kind of helminth  –  a flatworm (tapeworm).  Only the tapeworm was able to successfully colonize the lupus-prone mice, and thus, it was the only one which ended up being used for this experiment.

The lupus-prone mice, after colonization, were monitored via blood draws, looking for the production of autoantibodies.  Uninfected mice gradually began to produce the autoantibodies, peaking at 8-9 months of age.  However, the mice with the helminths on board never produced autoantibodies.

The kidneys are primary targets for lupus autoantibodies, and the degree of damage can be measured by protein in the urine (proteninuria).  The uninfected mice developed proteninuria around 9 months of age; the  mice with the helminths never developed it.  The mice were autopsied and indeed, in the mice with the helminths, the kidneys were completely normal as opposed to those of the uninfected mice, which showed major pathology.

An interesting note:  if the mice were given an anti-helminth agent after only a month of infection, these protective effects were not seen.  It is the long-term presence of the helminths which provided protection from the development of lupus.

The authors conclude, “Helminthic infections are known to induce immune regulatory cells to modulate immunity.  We found that perivascular inflammatory responses…were suppressed, suggesting that the immune suppression induced in Hm-infected mice attenuates inflammation through activation of regulatory T cells (Tregs).”  This is exactly what so many other studies have found.

This study is significant in that,  “…the suppressive effects of Hm on inflammatory diseases have never been reported. Thus, our report includes two novel findings: the suppression of the natural onset of SLE in a helminthic infection, and the protective ability of Hm against inflammatory diseases.”  The Hymenolepis family of tapeworms are not well-studied in terms of their inflammation suppressing effects in diseases. (It is not completely unstudied though.  I talked about a couple of new papers looking at Hymenolepis dimimuta about a year ago, here.   This paper is a big step forward in providing among the first such studies on these helminths. And lupus is, as I mentioned above, way understudied in terms of helminths.

To end on a really interesting final note:

“Infection with Hm improved all symptoms and signs of SLE and prevented death.”

That is, 70% of the mice with helminths lived until the end of the experimental period, far longer than those uninfected:  “Hm prevents natural development of SLE and prolonged survival of NZBWF1 mice.”

So there you have it.  Yet another feather in the cap for our macrobiotic old friends.

__________________________________________

[i] Olia, A, Shimokawa, C, Imai, T, Kazutomo, S, Hisaeda, H. Suppresion of systemic lupus erythematosus in NZBWFI mice infected with Hymenolepis microstoma.  Parasitology International.  2020. https://doi.org/10.1016/j.parint.2020.102057

[ii] https://www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789

[iii] https://www.lupus.org/resources/lupus-facts-and-statistics

Bile Acids and Your Microbiome (It May Not Sound Sexy but…They are a Huge Factor in Health)

Ok, it’s time for me to tackle a topic that is totally new to me. Today’s subject:  bile acids.  It may not sound exciting but it turns out, bile acids have a huge part to play in your health, and that effect is based upon the contents of your microbiome.

Several months ago, I first stumbled across the topic when I came upon a 2014 article out of the University of California, Davis, relating bile acid dysregulation to gut dysbiosis and gastrointestinal (GI) cancer.[i]  Before I describe this, and then some new research, let’s start with a definition.  Bile acids (BA) are made by your liver to break down fat that you eat.  They are derived from cholesterol.  Primary bile acids, secreted by the liver into your GI tract, are then converted into secondary bile acids by enzymes secreted by your gut bacteria.

According to that 2014 article, our modern diet, which is high in (unhealthy) fat and sugar (along with other factors, including lack of physical exercise, etc.) has led to the current epidemic of obesity and diabetes, both of which are linked to an increased risk for cancer.  Both diabetes and obesity have also been linked to dysregulation of bile acids and also, dysbiosis of the microbiome.  Subsequent elevated levels of secondary bile acids, along with a pro-inflammatory shift in the bacterial microbiome, have been linked to cancer:  “…recent findings have implicated a detrimental interplay between BA dysregulation and intestinal dysbiosis that promotes carcinogenesis along the gut-liver axis.”

The exact mechanisms are, of course, not as yet understood…which brings me to two new pieces of research out of Harvard.[ii]  Just as too much is not good, neither is too little.  To boot, BA have a direct major effect upon the immune system.

It turns out that bile acids “…promote the differentiation and activity of several types of T cells involved in regulating inflammation and linked inflammatory conditions.”  And as the bacteria of the gut are critical in converting bile acids into secondary bile acids, and immune-signaling molecules, they are also critical in this immunological process.

The first study showed, in an animal model, that bile acids, once converted into these immune-regulatory molecules by gut bacteria, activate two kinds of immune cells:  Treg (T regulatory cells, which are the off-switch to the inflammatory system) and T helper (effector) cells, Th17, which are proinflammatory.  Of course, to remain healthy, you need an inflammatory response to fight pathogens, and you equally need a regulatory system to turn that inflammation off when it’s no longer needed.  There is a crucial balance between the two.  These researchers found that two particular bile acid molecules affected Treg and Th17, and these two molecules are indeed found in human stool, which suggests that this research also applies to us.  Says the lead researcher on this study, “Our findings identify an important regulatory mechanism in gut immunity, showing that microbes in our intestines can modify bile acids and turn them into regulators of inflammation.”

If these findings are confirmed in humans, these natural molecules can be used to modulate inflammation in diseases affecting the gut, like inflammatory bowel diseases (IBD).

The second  Harvard study showed that gut microbes and diet “…work in concert to modify bile acids, which in turn affect the levels of colonic Tregs in mice.”  Low levels of Treg cells, from low levels of bile acids, make the mice prone to developing inflammatory conditions, like IBD.  This study is a bit more complicated, and involved populating mice with gut bacteria in which genes which are responsible for BA conversion (into these immune-signaling molecules) are silenced.  They then put these bacteria, or normal bacteria, back into germ-free mice.  Those animals who were given the modified bacteria had markedly lower levels of Treg cells (and therefore, higher inflammation).  In other words, gut microbes which convert BA are critical for gut health.

They then tested the effects of diet.  Animals fed minimal diets had low levels of BA and thus, low levels of Treg, which of course makes senses.  Fat in the diet is what stimulates the body to produce BA after all.  However, animals with germ-free guts who received rich diets also had low levels of Treg, proving that gut microbes are crucial in producing those immune-signaling molecules from BA.

In a second part of their experiment, the scientists broke up the mice into 3 groups.  The first was fed a minimal diet.  The second was fed a nutrient-free diet and the third group was fed minimal food, but was also supplemented with bile acid signaling molecules.  All three groups were then given a substance that induces colitis.  Not surprisingly, only the animals fed a minimal diet who were not supplemented with the BA molecules actually went on to develop the disease.

Back then to that first 2014 article:  it concludes with a section which suggests that there are potential treatments for BA dysregulation, which include probiotics and prebiotics (to improve the quality of the microbiome), as well as dietary changes.  For example, vitamin B6 has been shown to improve colon health.  Other natural substances include burdock root (from a plant in the daisy family) powder and genistein (an isoflavone derived from plants like soy), which have shown, “…moderate efficacy in normalizing BA homeostasis and the gut microbiome in animal models.”

If you think about it, diet is crucial in more ways than one.  That is, a healthy diet, rich in nutrients, is crucial for the stimulation of BA, as shown by the above studies.  Diet is crucial for maintaining a healthy weight and thus, avoiding the inflammation discussed in the 2014 article.  And diet also modulates the health of the microbiome, thereby indirectly affecting inflammation by affecting the bacteria responsible for converting BA into the immune-signaling molecules necessary to maintain health.

So your take home message is, yet again, eat a health diet!

_________________________________________________________

[i] Tsuei, J, Chau, T, Mills, D, Wan, YJY. Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer.  Experimental Biology and Medicine. 2014; 239(11): 1489–1504.   doi:10.1177/1535370214538743.

[ii] https://medicalxpress.com/news/2020-01-fat-dissolving-bile-acids-gut-immunity.html