Probiotics, Omega 3s and Chronic Inflammation: Part 2

In part 2 of this look at what we currently know about the benefits of probiotic and omega supplementation on chronic, low-grade inflammation, we’ll be looking at the most common and best studied probiotics, alone and in combination.[i]

 As I mentioned in Tuesday’s Part I post ,  Lactobacilli and Bifidobacteria are very widely studied.  They have been shown, for example, to improve the health of the intestinal barrier via a variety of mechanisms including the production of the short-chain fatty acid (SCFA), butyrate, which I have discussed in many prior posts (like here).  Low butyrate is associated with intestinal barrier dysfunction, among other health issues.

A quick note:  I have included in this summary the exact strains used in the studies listed.  I’m not sure how completely relevant they are to efficacy, but for the sake of completeness, you’ll have them in front of you.

Let’s look at Lactobacillus first.   This is a review of a few of the clinical studies we currently have:

  1. L.acidophilus NCFM and L.paracasei Lpc-27, as well as other strains of Lactobacillus, are known to adhere to intestinal cells blocking the adherence of a variety of pathogens.
  2. Regular use of Lactobacillus delbrucckii Bulgaricus 8481 prevents cytomegalovirus reactivation in the elderly and could counteract some “…hallmarks of immunosenescence.” (I’ve talked about this in previous posts like here.)
  3. Lactobacillus rhamnosus GG reduces proinflammatory cytokines, as shown in a study of healthy subjects, and a combination of paracasei DSM 13434, L. plantarum DSM 15312, and L. plantarum DSM 15313 reduces them in the digestive systems of people with neuroinflammation, which may be extremely important for people as they age.
  4. L.plantarum has been shown to improve cognitive performance (especially attention) in older people with mild cognitive issues.

Bifidobacterium:

  1. B.lactis B1-04 can enhance immunity of mucosal surfaces, like the gut lining, and seems to provide benefits for healthy adults in reducing the risk for upper respiratory tract infections.
  2. B.longum subsp. Infantis decreases LPS concentrations, reducing inflammation, and B. infantis 35624 may also reduce inflammatory cytokines. This likely leads to improved intestinal barrier function, and relieves gut issues like IBS.
  3. IBS patients show a 1.5-fold decrease in Bifidobacteria.

Lactobacillus and Bifido Combinations:  “Combining probiotic strains may produce synergistic effects, conferring additive benefits…”  A couple of examples, for your reading pleasure:

  1. Combining L.paracasei Lpc-37 with L.acidophilus 74-2 and B. animalis subsp. lactis 420 reduced the symptoms of adult atopic dermatitis and overall health.
  2. A combination of helvetics R0052 and B. longum R0175 has been shown to reduce psychological stress.
  3. lactis Bi-07 combined with L. acidophilus NCFM has been shown to improve digestive health and to reduce bloating.
  4. lactis Bi-07 combined with L. acidophilus NCFM benefits the immune system of children thereby reducing illness, need for antibiotics and missed days of school.
  5. One last one: a combination of Bifidobacterium and Lactobacillus, along with thermophiles DSM 24731 may reduce chronic low-grade inflammation in older adults, as well as reducing homocysteine levels – which could, in turn, reduce the risk of age-related conditions including neurological ones.

We know that fatty acids have a highly beneficial effect on inflammation, and recent research shows that it may take markedly higher levels than previously recognized to make a physiological difference – as high as 2000 mg (or more) per day.  On their own, omega 3s potentially can have a positive effect on inflammation-related conditions like Alzheimer’s and diabetes, and other diseases of aging.  In combination though with probiotics, there may be a highly significant beneficial effect:  omega 3s “…can act as prebiotics in the gut…”  The mechanism is not yet fully understood, but it seems to increase the levels of LPS-suppressing bacteria (like Bifidobacteria) and decrease LPS-producing gram-negative bacteria (like Enterobacteria).  Omega 3s’ interaction with probiotics also seems to promote the growth of bacteria which produce SCFAs, like butyrate, which improve the health of the epithelial barrier, while also promoting the growth of bacteria that are associated with leanness.

A randomized, controlled trial of 60 overweight adults, given a combination of omega 3s and the probiotic, VSL-3, resulted in “…greater improvement in insulin sensitivity than probiotic administration alone.”   In fact, evidence is rapidly mounting that shows that “…combining probiotics and omega-3 fatty acid supplements may be a particularly beneficial strategy as they seem to promote health in various areas through synergistic effects.”

To conclude then this marathon discussion of some of the latest research findings:  “Hypothetically, combining omega-3 fatty acids with probiotics offers a promising strategy to prevent the development of low-grade inflammation as well as offering non-pharmaceutical treatment modalities, which might be especially relevant in patient groups that suffer from increased systemic inflammation, such as aged and obese individuals. However, this research field is still in need of well-conducted and properly controlled clinical trials to further support this hypothesis.” While of course more research is desperately needed, seems to me that this is one of those “can’t hurt, could help” kind of scenarios!

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[i] Hutchinson, A.N.; Tingö, L.; Brummer, R.J. The Potential Effects of Probiotics and ω-3 Fatty Acids on Chronic Low-Grade Inflammation. Nutrients 2020, 12, 2402.

Probiotics, Omega 3s and Chronic Inflammation: Part 1

As I am always on the lookout for things we can do now, I was particularly interested in reading a new paper just published in the journal Nutrients which reviewed what we know about using probiotics together with omega-3 fatty acids to reduce chronic low-grade inflammation – the bane of modern industrialized societies.[i]  My regular readers know only-too-well that such inflammation is associated with an enormous variety of chronic illnesses ranging from heart disease to cancer to autoimmune diseases to depression to obesity to Parkinson’s disease, and so many more.  This paper was so rich in information that I’m going to split up my summary into two parts, so that I can fit everything in.

We know, of course, that inflammation has been linked to alterations in the bacterial microbiome by a variety of mechanisms including the release of lipopolysaccharides (LPS), which are toxins produced by gram-negative bacteria and are linked to the development of everything from impaired epithelial barrier function (i.e. leaky gut) to obesity to diabetes.  In a vicious cycle, LPS causes an increase in immune activation as it makes its way through the leaky gut, leading to a continual proinflammatory state, which further impairs gut barrier function.  This increase in circulating proinflammatory molecules is observed in a many chronically ill patient groups, as well as those with obesity and in the aging (inflammaging, which I’ve written about before as well, like here).

What can be done?  Well, of course, diet is key:  avoiding proinflammatory foods (i.e. foods high in unhealthy saturated fats, sugar, salt, etc.) and eating more anti-inflammatory foods (fruit and veggies, whole grains, etc.) is mandatory.  In fact, “…dietary changes have been estimated to explain as much as half of the structural variations in microbiota composition.”  But, as this article states, there are certain nutritional factors that are important to normal immune functioning and could greatly benefit immune regulation:  “In particular, probiotic bacteria, prebiotic fiber, and omega -3 fatty acids have been suggested to serve as positive modulators of this nutrition-inflammation coalition. These dietary components interact with bacterial organisms in the gut, modulating the release of metabolites that signal to a variety of bodily systems (e.g., the immune system).”

So what does the research tell us as of today?  (I’m trying to hit all the high points in this post and the next!)

The Gut-Brain Axis and Health:

  1. Psychological stress is a “…potent modifier of inflammation in the gut by increasing intestinal epithelial permeability, adversely affecting immune regulation and influencing the enteric microflora.” (That’s a big UH OH for me.)   Chronic stress causes a decrease in Bacteroides and Clostridum, which leads in turn to increased inflammation.
  2. “Several studies have observed a relationship between dysbiosis and increased susceptibility to psychiatric and neurologic pathologies…including Alzheimer’s disease, Parkinson’s disease, and stroke, and psychiatric disease such as anxiety disorders, depression, and autism.”
  3. Bacteria getting out of the gut through an impaired intestinal barrier has been shown to contribute to the development of major depressive disorders. Dysbiosis is linked to alterations in tryptophan (an amino acid, the precursor to serotonin) metabolism. The subsequent reduction in serotonin levels is observed in those with depression. There is now a “robust body of evidence” that probiotics have a positive effect on depression, driven by an increased availability of serotonin as well as a reduction in inflammation.

The bacterial microbiome and Immune Modulation via Probiotics, Prebiotics and Omega 3s:

  1. In a randomized controlled study (RCA), healthy women were given Bifidobacterium animalis Lactis, Streptoccocus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp. Lactis twice daily for 4 weeks.  They showed positive changes in brain activity and emotional regulation.
  2. “Another RCT conducted in adults with major depressive disorder reported that 8 weeks of administering Lactobacillus acidophilus and Lactobacillus casei combined with Bifidobacterium bifidum significantly reduced depressive symptoms in relation to placebo.” This combination of probiotics also significantly reduced metabolic, inflammatory, and oxidative stress biomarkers in the blood.
  3. Diets high in prebiotics are linked to increased microbiota diversity. And how’s this for interesting:  how quickly a particular prebiotic fiber is metabolized affects where in the colon it has its beneficial effect.  Thus, different fibers may be more or less important for people depending on what their guts/health issues look like.
  4. Omega 3 fatty acids are also anti-inflammatory and can make their way into the brain, especially the frontal, parietal and occipital lobes. This is very dose dependent:  it takes higher doses to get into the brain.

In my next post on this article, specific details about Lactobacillus, Bifidobacterium, combinations of  them…and combining them with omega 3s.

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[i] Hutchinson, A.N.; Tingö, L.; Brummer, R.J. The Potential Effects of Probiotics and ω-3 Fatty Acids on Chronic Low-Grade Inflammation. Nutrients 2020, 12, 2402.

The Microbiome and Major Ligament Injuries

A brand new topic today for The Biome Buzz, but after hearing the sports news earlier  this week, this really struck me as interesting and odd, so here goes…

This past Sunday, September 20th, 7 players in the National Football League here in the USA tore their anterior cruciate ligaments (ACL).  7 in one day!   What on earth is going on though that make this injury so unbelievably common these days?!  As a big fan of sports, this has been a real bee in my bonnet these last few years.

Another anecdote, this one back in time:  10 years ago or so, one of my dogs tore his doggie version of an ACL just running outside to play.  When I met with the surgeon who was to repair Apollo’s leg, he told me flat out that veterinarians have been talking for the past few years about how much more common the injury has become and they have no idea why.  “He’ll likely tear the other hind leg at some point too,” he warned me, “Once one goes, so does the other.”  Sure enough, 3 or 4 years later leg #2 popped, with my poor dog doing nothing but walking across the lawn.

Why these injuries are becoming more common is unknown but a new article really got me to thinking after reading this new research.[i]   According to the paper, it’s important to know that 50% of patients who tear an ACL will develop osteoarthritis in the injured limb, called post-traumatic osteoarthritis (PTOA).  The veterinarian surgeon warned me about this too, by the way.  Anyway, I find it fascinating that in this newly published paper, researchers found that giving rodents oral antibiotics before such an injury reduces inflammation in the injured joint and slows down the progression of PTOA.

We already know that changes to the bacterial microbiome may reduce osteoarthritis inflammation, but next-to-nothing is known about changes to that biome prior to an injury.

The scientists gave antibiotics (an ampicillin/neomycin cocktail) to the animals for 6 weeks prior to the ACL rupture.  A microscopic examination 6 weeks after the injury showed that the animals  treated with antibiotics had less loss of cartilage at the injury site than did the untreated controls.  There was less inflammation in the treated animals, and present at the wound site were more macrophages, which are immune cells associated with healing.  What I think is actually the most interesting part of this research is that the antibiotics led to less inflammation in UNINJURED joints as well.

A summary of the research, which appears on Medical Express, points out that antibiotics are often prescribed for teens and young adults, who actively participate in sports, at the rate of 790 prescriptions per 1000 people.  I admit to being shocked by this sentence: “…therefore, gut dysbiosis (a microbial imbalance) may be more common than expected in young athletes suffering an articular injury. In this scenario, the gut dysbiosis may provide a benefit to these young people, if they suffer a joint injury.”[ii]  Wait…what?!

The overuse of antibiotics is already a major issue in this country and biome depletion is a known leading cause of many health issues, as you all know.  Call me crazy but doesn’t this seem an odd way of assessing this new data!  Bearing in mind, as I said above, that , “The results show that this particular antibiotic regime had a beneficial effect on the health of injured and uninjured joints…”  – would that not imply that there is some component of the microbiome that is causing joint inflammation, which may LEAD to the increase in these severe injuries?  We know these ligament tears are increasing in prevalence; in this study, giving antibiotics leads to better outcomes after surgically creating an injury, i.e. giving antibiotics reduces join inflammation.  To me this implies that the next step to study (apart from the obvious question: will giving antibiotics after the injury help speed healing, which the scientists say they will look at in future work) is can antibiotics prevent the injuries in the first place?  Or better still:  what bacteria are being shifted in giving the antibiotic that cause improve joint health?  But what do I know.

I’m really interested in these answers so stay tuned:  I’m watching this space to see where this research leads.

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[i] Melanie E. Mendez et al. Antibiotic Treatment Prior to Injury Improves Post-Traumatic Osteoarthritis Outcomes in Mice, International Journal of Molecular Sciences (2020). DOI: 10.3390/ijms21176424

[ii] https://medicalxpress.com/news/2020-09-antibiotic-pre-treatment-joint-inflammation.html

Disrupted Sleep: Bad for the Health of You and Your Microbiome

Researchers at the University of Illinois, Chicago, have recently published research demonstrating that disrupted sleep leads to elevated blood pressure and alterations to the bacterial microbiome.[i]  I’ve been covering this subject for a while as I myself am a terrible sleeper, and have a life long history of irritable bowel…and sleep and IBS go hand-in-hand all too often.  I’ve pointed out in past posts (like this one, for example) that research shows that alterations to the bacterial microbiome lead to disrupted sleep, and disrupted sleep leads to higher levels of inflammation which adversely affect the gut flora.   In this study, the scientists looked at long term (28 day) sleep disruption in an animal model.  The rats had their sleep disrupted while having their brain activity, blood pressure and heart rates monitored.  The researchers also analyzed their fecal microbial content.  There was a control group of animals used for comparison.

They noted that the rats had an increase in blood pressure which lasted (for an as yet unspecified period of time) even after the animals were permitted to return to normal sleep.  Likewise, they noted that the disrupted sleep led to adverse microbiome alterations, as has been shown in previous research.  (ugh) The microbiome shift, however, did not take place immediately:  it took a week for these alterations to start.  And when they did, the scientists noted an increase in species associated with higher levels of inflammation, as per prior findings.  (double ugh)

Some specifics:  they noted that in the intervention group, short chain fatty acid (SCFA) production was altered, there was less bacterial diversity, there was a lower ratio of  Firmicutes  to Bacterioidetes species, and there were higher levels of Proteobacteria, as compared to the controls.  There were also certain fecal metabolites that are significantly correlated with high blood pressure.

Previous research has shown that metabolites produced by gut bacteria, like SCFAs and something called succinate, can increase blood pressure.  It’s also known that sleep fragmentation (SF) is linked to adverse cardiovascular changes in both rodents and humans, and in rodents, it’s also documented that disrupted sleep leads to changes in the endothelial lining of the gut.  In humans, disrupted sleep is specifically associated with cardiovascular issues like arterial stiffness, hypertension and as well as metabolic syndrome and more.

There are 3 novel findings in this research:  1. The degree of arterial pressure is directly linked with the amount of sleep that is lost (the more sleep lost, the higher the blood pressure); 2. After a week of fragmented sleep, changes in the gut microbiota are apparent including a reduction in diversity, altered ratios of bacteria (as noted above), an increase in the abundance of Proteobacteria, and the relative abundance of butyrate-producing bacteria.  3.  The relative abundance of certain bacteria (those that produce acetate and succinate) as well as several fecal metabolites are correlated with arterial pressure.

To sum up: sleep fragmentation seems to affect blood pressure without microbiome influence at first, but the gut microbiome is “clearly impacted” by extended periods of fragmented sleep.  Understanding these changes is really important because it provides a means, hopefully, of preventing cardiovascular disease, etc. in both night-shift workers as well as those with sleep disorders including sleep apnea (untreated, sleep apnea is well known to lead to potentially fatal cardiovascular events).  This is a really interesting point, from the conclusion of this paper:  this research, “…provides insights indicating that changes to the gut microbiota from SF are not unidirectional, and alterations in specific metabolite producing bacterial populations are dependent on the ‘dose’ of SF and blood pressure elevation.”  That is, the severity of the sleep fragmentation matters. The less sleep you get, the worse off you are.

Says one of the authors of the paper, “We hope to find an intervention that can help people who are at risk for cardiovascular disease because of their work and sleep schedules. People will always have responsibilities that interrupt their sleep. We want to be able to reduce their risk by targeting the microbiome with new therapies or dietary changes…”[ii]

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[i] Katherine A. Maki et al, Sleep fragmentation increases blood pressure and is associated with alterations in the gut microbiome and fecal metabolome in rats, Physiological Genomics (2020). DOI: 10.1152/physiolgenomics.00039.2020

[ii] https://medicalxpress.com/news/2020-09-links-poor-high-blood-pressure.html

Yogurt and Maintenance of the Epithelial Gut Barrier

When I was a kid, there was a commercial on TV that I’ve never forgotten, for Dannon Yogurt. It showed a bunch of people from Soviet held Georgia who were all around 100 years old, looking like they were in their 60s, actively running around doing farming, chopping wood, etc.  The voice over pointed out that yogurt was a huge part of their diet.  Take 30 seconds to watch it here – I just found it on You Tube!

Anyway, it made a huge impression on me, probably because we started eating yogurt around then, having NO idea what “active yogurt cultures” meant. (You’ll notice there is no mention of probiotics, bacteria, etc. in the commercial.)  I loved yogurt as soon as I tasted it, and have been a big eater of it since.  On that note, I came across an article definitely worth sharing with you on the health benefits of yogurt.  Yogurt is “…a rich source of high-quality protein, calcium, phosphorus, and folate.  Moreover, yogurt serves as an important source of probiotic bacteria that may also confer a benefit on gut barrier function by stimulating the diversity and function of the gastrointestinal microbiota, reducing intestinal transit time, and enhancing gastrointestinal innate and adaptive immune responses.”[i]

A cross-sectional study of 1076 men and women (from 2 different cohorts) was conducted at Harvard’s TH Chan School of Public Health looking at specific health outcomes from eating yogurt.  The scientists wanted to see how yogurt affects a blood marker for gut barrier dysfunction (CD14), i.e. leaky gut.  CD14 is a molecule released by certain immune cells as a response to lipopolysaccharides, which are toxic metabolites produced by some types of gut bacteria.  An immune response to these toxins, seen in the blood, means that they are making their way out of the gut – thus, it is a marker for issues with the gut barrier.

The researchers found that the consumption of two cups of yogurt per week makes a statistically significant improvement in CD14 concentrations (especially in men) indicating that it makes a meaningful difference in improving epithelial barrier function:  “Our findings suggest the strengthening of gut barrier function as a plausible mechanism for the observed inverse associations of yogurt consumption with gastrointestinal diseases and disorders involving other systems.”

By the way, we know from past research that diet is a major factor in gut health and barrier function, as you know.  (Read this post, for example, from October 2018.) And we know from other studies that fermented milk products affect the immune system positively and protects against the risk factors for type 2 diabetes,[ii]  as well as obesity, cardiovascular disease, certain cancers, and intestinal disorders.

So there you have it:  high quality yogurt should certainly be a part of everyone’s diet!

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[i] Luo, X., Sui, J., Birmann, B.M. et al. Association between yogurt consumption and plasma soluble CD14 in two prospective cohorts of US adults. Eur J Nutr (2020). https://doi.org/10.1007/s00394-020-02303-3

[ii] https://www.gutmicrobiotaforhealth.com/health-benefits-linked-to-yogurt-consumption-could-be-explained-as-a-result-of-improvements-in-gut-barrier-function/

A New “FMT” Probiotic to Treat Ulcerative Colitis: A Clinical Trial

The results of a stage 1 clinical trial of a novel probiotic (created from purified human stool) in treating mild to moderate ulcerative colitis (UC) were just published in the journal, Gastroenterology.[i]  I didn’t pay a huge amount of attention last week when I first spotted it, but decided to check it out this past weekend, in case there was anything useful for us.  It turned out there is, so I’m glad I took the time.

It appears that this product will be, at least at first, considered a pharmaceutical. There’s good and bad to that, of course:  the bad is that I’m afraid it will only be available via prescription and my guess is that, at least at first, it will only be covered by insurance for UC or perhaps, other inflammatory bowel diseases.  Those of us without will likely be out of luck in obtaining it.  The good is that for those who desperately need it, it will be covered by insurance and considering how expensive ordinary probiotics are, that’s not a bad thing. Still, this particular type of probiotic holds tremendous interest to, and promise, for all of us.

By the way, a quick aside:  I did find a 2019 press release stating that an upcoming late stage 2B trial was in the works and that this trial is considered pivotal in that, the Company (Seres Therapeutics) who manufactures the product, “…recently obtained feedback from the FDA indicating that the results from this study, in conjunction with data from a second pivotal study, could enable a SER-287 Biologics License Application.”[ii]

Still, as probiotic capsules or liquids created from isolated, purified bacteria from human stool will someday be par for the course (remember that just such a product was used in the very successful studies on autism.  Also, products, isolated from elite athletes, are also being created to improve athletic performance.  So even if the products are not as yet available to us mere mortals, I think we should follow along with the research as it piles up.

Back to the now published phase 1 trial to establish safety and efficacy: this was a double blind trial on 58 adults with mild to moderate UC.  They all received 6 days of either oral vancomycin (a gut antibiotic) or a placebo, and then 8 weeks of either the probiotic (SER-287) or a placebo. In total there were 4 groups:  placebo/placebo; placebo/SER-287 once per week; vancomycin/SER-287 once a week; vancomycin/SER-287 daily.

The results: “A higher proportion of patients in the vancomycin/SER-287 daily group (40%) achieved clinical remission at week 8 than patients in the placebo/placebo group (0), placebo/SER-287 weekly group (13.3%), or vancomycin/SER-287 weekly group (17.7%)…”  That’s a pretty outstanding result!  By the way, there were no differences in adverse events reported among the various groups.

It’s also important to note that they found higher levels of the species in the probiotic in stool from those on the probiotic versus those on a placebo, but in the group that did not get vancomycin first, this was not maintained after a week.  In those in the vanco groups, higher levels of SER-287 species were found in stool throughout the study compared to those who got the placebo (not vanco), and as you’d expect, the highest levels were found in those who got the probiotic daily.  In other words, the treatment did exactly as planned:  vancomycin wiped out much of the gut flora which was then successfully altered with the human-derived probiotic, which colonized the intestines leading to remission at a clinically significant rate.

Bear in mind that this was just a small, short phase 1 study too.  For all we know, the rate of remission might be higher if it had lasted longer.  Secondly, we also don’t know that optimal dosing was used yet.  (We also, of course, don’t know what the participants were eating during the trial.  Not relevant to this study.  Still, wouldn’t it be interesting to know that when comparing those 40% who achieved remission versus those 60% who did not?!) They conclude, therefore, that, “SER-287 following vancomycin was significantly more effective than placebo for induction of remission in patients with active mild-to-moderate UC.”

In case you were wondering how the probiotic was produced: the FDA approved their process for screening, and 3 stool donors were selected.  The stool was cleared of all impurities and 3 lots of SER-287 were produced, each lot from only 1 of the donors.  They basically pulled out some of the bacteria that are not spore-forming, so that each product ended up with 10-20% spores by weight, and included species like Clostridium, Gemminger, Dorea, Roseburia, Blautia, and Faecalibacterium.  After treatment, a decrease in non-spore-forming bacteria like 12 Veillonella, Streptococcus, and Bacteroides was noted.  Spore-forming bacteria tend to be quite resilient because, when in an inhospitable environment, they retreat into hardy spores, and can reactivate when circumstances improve.  (This is why C.difficile infections are so damn hard to eradicate.)

I am quite sure we are seeing the start of a trend:  treatment of disease by eradication of “faulty” bacterial microbiomes followed by replacement with healthy bacteria.  This is essentially non-invasive fecal microbiota transplant, but of course, with select species of bacteria.

I took a quick look at Seres Therapeutics website and found that they just released, in August, a press release announcing  positive results from a phase 3 trial of another product, SER-109, to treat recurring C.difficile infection (CDI), in fact.  “The study showed that SER-109 administration resulted in a highly statistically significant absolute decrease of 30.2% in the proportion of patients who experienced a recurrence in CDI within eight weeks of administration versus placebo, the study’s primary endpoint. 11.1% of patients administered SER-109 experienced a CDI recurrence, versus 41.3% of placebo patients.”  They are now applying for final product approval from the FDA.    Looks like this is a company we’ll have to keep an eye on!

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[i] as: Henn MR, O’Brien EJ, Diao L, Feagan BG, Sandborn WJ, Huttenhower C,Wortman JR, McGovern BH, Wang-Weigand S, Lichter DI, Chafee M, Ford CB, Bernardo P, Zhao P,Simmons S, Tomlinson A, Cook D, Pomerantz R, Misra BK, Auninš JG, Trucksis M, A Phase 1b safetystudy of SER-287, a spore-based microbiome therapeutic, for active mild to moderate ulcerative colitis,Gastroenterology (2020), doi: https://doi.org/10.1053/j.gastro.2020.07.048.

[ii] https://www.microbiometimes.com/seres-therapeutics-announces-initiation-of-ser-287-phase-2b-eco-reset-clinical-study-for-ulcerative-colitis/

This Week’s News on COVID and the Gut Biome

It seems like new information is coming out daily about the relationship of COVID-19 to the gut, and I’m trying to stay on top of it as best as I can for us all.  On Monday of this week, I spotted an article on Bloomberg about a new study out of a Hong Kong university, stating that the virus may linger in the gut long after it has cleared the respiratory system.[i]  The actual study was conducted last February on 73 patients, more than half of whom tested positive for the virus in their stool.  The scientists zeroed in on 15 of these positive cases to better understand what was happening, in terms of viral activity.

Interestingly, while active in the gut, the virus caused no GI symptoms in 7 of these people.  And it remained active 7 days after respiratory samples were negative; in 1 patient, in fact, they found active virus in the gut 30 days after respiratory tests were negative.  Whether or not stool is a means of transmission is being further tested.  According to the lead researcher on this paper the gut bacteria of patients with GI COVID infection show a loss of protective bacteria and a proliferation of disease-causing ones, and this was worsened in those patients who were treated with antibiotics.  He suggests that probiotics may be helpful in treating COVID.  (Remember this blog post of mine from August 6th?)

On Wednesday, I found an article on News Medical about another paper just out that presents a host of new and interesting findings.[ii]  Researchers at the Mount Sinai School of Medicine found that 60% of patients hospitalized with the virus have GI symptoms.  They looked at 44 patients in their hospital during the peak of the pandemic here in New York, and collected stool samples during the acute and the convalescent phases of the infection.[iii]  (Interestingly, re:  my previous post on COVID, half the patients were characterized as obese and 70% had high blood pressure.  There is no controversy over this:  higher levels of systemic inflammation make you more prone to more severe COVID infection.)  70% of the patients studied had GI symptoms, mainly diarrhea.  Some had nausea and vomiting.  41% of patients tested positive for the virus in their stools, and it was found more frequently in those with GI symptoms than without.  That makes sense, and the numbers look similar to the Hong Kong study.

Here is where things get wonky.  These scientists found that more patients without GI symptoms required admission to the ICU:  54% of them, versus only 19% of patients who did have GI symptoms.  Weird, right?!   It turned out that inflammatory markers were lower in those with GI symptoms, although this did not reach statistical significance.  Unlike the study out of Hong King, they found that those with negative respiratory tests did not have detectable viral RNA in their feces. They DID find, however, that those who died of COVID had much higher viral loads in their feces than did the survivors, and that inflammatory cytokines were elevated in COVID patients – as is seen in other intestinal infections and inflammatory conditions – but that these did not associate with actual GI symptoms.  Unlike the Hong Kong study, they found no specific microbiome alterations in the population. And finally, they found lower levels of regulatory cytokines (i.e. the off-switch to the inflammatory response) in the stool than of those severely infected.

So the biggest mystery, as far as I’m concerned, is why would it be that a “…significantly lower proportion of patients with GI symptoms were admitted to the ICU compared with those without GI symptoms”?  There were no significant differences in blood markers for inflammation between the two groups. (What they did find, consistent with prior research, is that the more severe the disease presentation, the higher the levels of inflammatory cytokines found in the blood.)

Their conclusion is that while there is massive systemic inflammation in those with severe COVID,   “…our data suggests that the gut can be an immunologically active organ during SARS-CoV-2 infection, as evidenced by virus-specific IgA, but there is little evidence for overt intestinal inflammation, even in patients with diarrhea or other GI symptoms.”

As soon as I finished writing this post for the first time, I found yet another article on COVID and the gut, this one on Gut Microbiota for Health[iv] , so just a couple more points.  The authors of this article reiterate that some studies have shown bacterial alterations in those with COVID, and they point to two meta-analyses (here and here) showing the efficacy of probiotics in reducing the incidence, and the duration, of viral infections.  (This, on top of the clinical trial I wrote about previously.)

The article points out that China’s National health commission and National Administration of Traditional Chinese Medicine both now recommend probiotics for the treatment of severe COVID.  This is not, however, an accepted practice yet in the Western world.  However, in light of the fact that we now know that what causes severe illness and death from COVID is actually a monster inflammatory response (cytokine storm), and at least 70% of the immune system is in the gut, the authors of this article state, “…one might argue that gut microbiome-immune system crosstalk could work as a team to normalize host immune response…”

I don’t know what to  make of it all.  Hopefully, we’ll get some more answers in the near future.

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[i] https://www.bloomberg.com/news/articles/2020-09-07/covid-19-patients-may-have-prolonged-gut-infection-study-finds

[ii] https://www.news-medical.net/news/20200908/Limited-gut-inflammation-in-COVID-19.aspx

[iii] Britton, G. J. et al. (2020). SARS-CoV-2-Specific IgA And Limited Inflammatory Cytokines Are Present In The Stool Of Select Patients With Acute COVID-19. medRxiv preprint. doi: https://doi.org/10.1101/2020.09.03.20183947. https://www.medrxiv.org/content/10.1101/2020.09.03.20183947v1

[iv] https://www.gutmicrobiotaforhealth.com/is-gut-microbiome-lung-crosstalk-worth-considering-during-the-current-covid-19-pandemic/

Baobab and Microbiome Diversity: Eat Like a Hazda!

A few days ago I received an email from a company (Dhow Nature Foods ) that is producing powdered baobab, asking if I’d consider writing a blog post about the product. I was pretty excited to hear from them. Baobab, you ask? What the hell is baobab and why was Judy excited?

Some of you may remember back in March, 2018, I wrote about research at Rutgers University which “…demonstrated that by adding a variety of fiber to the diet, a distinct group of gut bacteria are fed and produce highly anti-inflammatory short chain fatty acids which reduce inflammation and help control appetite.” In their study, two groups with type 2 diabetes ate the same healthy diets but one was given large amounts of dietary fiber, which, at the end of the 12 week study, resulted in a greater reduction of blood glucose and weight loss.  At the end of the post, I mention the work of Dr. Jeff Leach and colleagues who studied the diet and biomes of the Hadza, one of the last true hunter-gatherer tribes left on earth. I was – and still am – astounded by one of the facts pointed out in the paper I referenced: the average American eats about 15 grams of fiber a day. The Hadza, whose microbiomes boast a diversity we cannot even imagine, eat about 100 grams.

According to a 2019 paper by Dr. Leach and colleagues, the Hadza live in Tanzania and subsist on 5 groups of foraged and hunted foods:  honey, tubers, berries, meat and – you guessed it – baobab.[i]  These foods do vary in quantity based upon the seasons, i.e. dry versus wet. Their gut bacteria do vary according to season.  Baobab though is consumed year round.  And their incredibly high-fiber diet has allowed them to preserve ancestral species of bacteria that we have at very low levels in the industrialized world – or have lost completely:  “These bacterial taxa are candidates for future study toward a better understanding of the co-speciation of humans and gut microbes, and of what has been disrupted in recent times.”

Another article[ii] from 2018 states, “The study of traditional populations provides a view of human-associated microbes unperturbed by industrialization, as well as a window into the microbiota that co-evolved with humans. Here we discuss our recent work characterizing the microbiota from the Hadza hunter-gatherers of Tanzania. We found seasonal shifts in bacterial taxa, diversity, and carbohydrate utilization by the microbiota. When compared to the microbiota composition from other populations around the world, the Hadza microbiota shares bacterial families with other traditional societies that are rare or absent from microbiotas of industrialized nations.”[iii]  One of the biggest differences is in the high level of microbes in the Hazda’s gut capable of degrading plant fiber; considering the amount they eat, this is not surprising.  In comparison, the American gut is filled with microbes “…well adapted to forage on intestinal mucus,” as we tend to barely eat fiber at all.  The authors actually name those species that have been lost or have become rare in industrialized societies the VANISH (volatile and/or associated negatively with industrialized societies of humans) taxa.  Ugh.

Here’s an interesting fact:  there was no decreasing levels of diversity in elderly people among the Hadza, such as we see in our elderly population in the industrialized world. The reason is likely due to the fact that the elderly continue to live with the rest of the camp, and are not isolated.  This was found in a large study of healthy Chinese people as well, aged 30 to 100, again because traditionally, the elderly are revered and kept within the family.

So, a few facts about baobab:  it grows in Australia, the Middle East, and parts of Africa.  Really all of the tree is edible, including the bark, leaves, seeds, and fruit.. The fruit is rich in vitamin C (10x that of an orange), and is thought to have antimicrobial, antiviral, anti-oxidant and anti-inflammatory properties. In traditional societies,  it is used to relieve everything from GI issues (i.e. diarrhea and constipation) to stimulating the immune system, to hydration and skin health.  In one study at Oxford Brookes University, the baobab fruit extract, baked into bread, was found to lower glycemic response in humans. [iv]

In my eternal quest to find promising new products to try for gut health, I am very interested in this one.   Dhow foods is now shipping outside of Africa to Australia and the UK, and will shortly be available in the USA.  I will test it out once it’s available here in America. In the meantime, I checked out their recipe page which lead me to a different site, on which I found potentially wonderful recipes like this one:    Ok…yum.  If any of you in other countries where baobab is currently available do give it a try, please let us know how you fare!

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[i] Fragiadakis, Gk, et. al. Links between environment, diet, and the hunter-gatherer microbiome.  Gut Microbes. 2019;10(2):216-227.  https://doi.org/10.1080/19490976.2018.1494103

[ii] Wilson, A.S., Koller, K.R., Ramaboli, M.C. et al. Diet and the Human Gut Microbiome: An International Review. Dig Dis Sci 65, 723–740 (2020). https://doi.org/10.1007/s10620-020-06112-w

[iii] Gabriela K. Fragiadakis, Samuel A. Smits, Erica D. Sonnenburg, William Van Treuren, Gregor Reid, Rob Knight, Alphaxard Manjurano, John Changalucha, Maria Gloria Dominguez-Bello, Jeff Leach & Justin L. Sonnenburg (2019) Links between environment, diet, and the hunter-gatherer microbiome, Gut Microbes, 10:2, 216-227, DOI: 10.1080/19490976.2018.1494103

[iv] https://www.medicalnewstoday.com/articles/306445#nutrition

Losing Weight – Gaining it Back…and the Microbiome

Today, for your reading pleasure, a kind of amazing 14 month long clinical trial out of Ben-Gurion University, in Israel![i]  As I am sure you all know, after dieting and losing weight, it is incredibly difficult to keep it off.  I read, not that long ago, that the average person on The Biggest Loser regained 70% of the weight they’d lost within a few years of being on the show.  Can you imagine going through the effort of losing 200 or 300 pounds, only to gain 3/4 of it back?!  Over the years, I’ve read a lot about the potential reasons for this including lapsing back into bad eating habits, the desire of the body to return to what it believes is “homeostasis,” lowered resting metabolic rates, etc.  The fact is, no one knows for sure but the microbiome has also become a huge target for research, with good reason.  We know that those who are lean versus not have radically different microbiome profiles.

Most people reach their lowest body weight after 4-6 months of dieting, and then tend to start regaining weight even if they continue to watch what they eat.  This international team of researchers, therefore, preserved the personal microbiome (froze the bacteria isolated from fecal samples) of the participants at that 6 month point.  The participants were assigned to one of three groups.  And this is where it gets REALLY interesting.  Group one dieted using healthy dietary guidelines.  Group two was put on the Mediterranean diet while group three was put on a green Mediterranean diet.  What is a green Mediterranean diet, you ask? (So did I!)  They were given something called Mankai, which is a specific strain of the duckweed plant, which was put into a green shake with green tea and 28g of walnuts.  This green drink led to the most significant change in the gut microbiome during the 6 month weight loss phase.

After 6 months, all 90 participants provided fecal samples that were processed into purified, odorless capsules.  The participants were then given either 100 capsules of their own microbiota or a placebo, which they ingested until month 14, the conclusion of the trial.

The results are crazy!  All 90 participants lost weight: on average, about 18.2 pounds.  However, only in the non-placebo green-Mediterranean diet group  was weight-regain limited to only 17.1%.  The rest, who got the placebo, or who did the other diets, regained on average, 50% of the weight they’d lost.  That is an incredibly significant result.

In an complimentary animal study, in which Mankai was given to rodents, the scientists were able to replicate these results, also noting the improved insulin sensitivity in the animals.  The belief is that Mankai optimizes the microbiome due to its protein and fiber content:  “”The nutrition-microbiome axis has been proven in this study as high polyphenols diet, and specifically, Mankai, a protein-based plant and dietary fibers could ideally optimize the microbiome in the weight loss phase, to induce potent microbiome to recall the flora of germs related to regain attenuation and improved glycemic state after transplantation.”[ii]  They found that the green diet increased several species (Alistipes putredinis, Bacteroides vulgatus and Bacteroides uniformis) which were previously associated with leanness.

Mankai does not appear to yet be available for purchase. I found this company, Eat Mankai ,  that looks like it may soon start selling the product.  Perhaps they are undergoing some kind of regulatory process?  I don’t know.  But anyway, it really is a fascinating food:  it is the only plant source that contains all 9 essential amino acids, plus iron, folate and vitamin B12, on top of other nutrients.  I have signed up to receive their newsletters so I can stay on top of things for those of you who are interested.

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[i] Rinott, E., et al (2020) Effects of Diet-Modulated Autologous Fecal Microbiota Transplantation on Weight Regain. Gastroenterology. doi.org/10.1053/j.gastro.2020.08.041.

[ii] https://www.news-medical.net/news/20200826/Consuming-personal-fecal-microbiome-when-dieting-may-limit-weight-regain-study-shows.aspx

The Macrobiome and Mycobiome in IBD: A Look at the Role of “Dirty Old Friends”

A very recent paper, published just this past May, caught my eye because of its title:  “Inflammatory bowel diseases, the hygiene hypothesis and the other side of the microbiota: Parasites and fungi.”[i]  How often on this blog have I talked about the incredible complexity of the human biome?  This paper was a very interesting read on this topic, so I definitely want to share some highlights.

It starts with one of the best explanations of “evolutionary mismatch” I have ever read:  “According to this concept, an organism that evolved in a given environment might be maladapted to a novel, different environment.  In other  words, a mismatch in the conditions in which we live today, compared to the conditions in which our genes and bodies had been shaped by natural selection, might imply that several hereditary traits are maladapted; this, in turn could lead to overall perturbances in homeostatic equilibrium.”  It goes on to point out that, until the industrial revolution – microseconds away in evolutionary terms – we lived in conditions essentially similar to those of wild animals.

To sum up:  “Co-existence with parasites, and with a variety of other ‘almost-pathogenic’ microorganisms, is thus to be regarded as the normal condition for our ancestors…we humans evolved in a type of environment that no longer exits, and are now living in a radically different condition: we are experiencing an evolutionary mismatch.”

Dr. William Parker of Duke University, a foremost authority on the immunology of helminth colonization, talks about this concept over and over in his papers.  Read a couple of examples here and here.

Here are a few super interesting facts from today’s paper:

A.  Inflammatory bowel diseases were among the first pathologies to be associated with alterations in the microbiome.  One of the papers referenced in this section dates back to 1991 in fact, even before more modern lab techniques were developed to look at the microbiota.  Noted 30 years ago were the fact that bacteria like Desulfovibrio species (I have written about this too)  were at increased levels in those with IBD.

B.  There is now very strong evidence that the bacterial microbiota is heavily influenced by the presence (or lack of the presence) of other components of the biome, including protozoa, fungi and helminths. In turn, the bacterial components influence them right back.  And of course, ALL these critters are influenced by diet and other lifestyle factors.

C.  Some interesting facts about fungi in IBD:

    1. Studies seem to indicate that Candida albicans might “represent the true gut symbiotic fungi.” The two species Sacchromyces cervesisiae and restricta may or may not be as well – research is ongoing.
    2. Recent research shows that dysbiosis of the mycobiome, including overgrowth of Candida species, is correlated to IBD, as well as other diseases including ulcers, antibiotic-associated diarrhea, hepatitis, etc. An increase in albicans are known to be associated with inflammatory flareups in IBD.  The relationship of alterations to the mycobiome is pretty well established in IBD.  In fact, in those with Crohn’s disease, an increase in antibodies to fungal targets has been seen BEFORE the disease diagnosis!
    3. Other research has shown a positive correlation of S.cervesisiae to bacteria, including Bifidobacterium, Roseburia, etc. These kinds of bacteria are highly anti-inflammatory and are at low levels in those with IBD, especially during flare ups.
    4. Likewise, there is a positive correlation, between the abundance of the fungi, tropicalis, which is significantly increased in IBDs, and potentially pathogenic species like E.coli, and these worked together to create a protective (to themselves) biofilm. I’ve written about this before, here.
    5. Metabolites of bacteria, including short-chain fatty acids, keep C.albicans in check. (Reminiscent of  my last post on proteobiotics, right?!.)

D.  Most of the info in the paper about the macrobiome (helminths) is stuff I have covered in past posts, but a quick refresher:

    1. Helminths stimulate the Th2 family of cytokine which “…promote rapid intestinal epithelial cell turnover, mucus production and increased gut motility…” along with increased production of regulatory cytokines, which modulate the inflammatory response, promote wound healing and intestinal repair.
    2. “Numerous studies support the hypothesis that helminths are able to induce beneficial effects to modulate IBDs, both directly and/or indirectly.” The former is by suppressing the production of damaging inflammatory cells, responsible for maintaining inflammation in IBD.  The latter is by modulating the gut bacteria, thereby reducing the inflammatory response.  They reference several papers in which demonstrated this beneficial effect on the gut bacteria.  (As just one example of many on The Biome Buzz, you can read more about this here.)
    3. Different helminths appear to have somewhat different effects, likely because they excrete different metabolites; they appear to affect the levels of different probiotic bacteria. A couple of examples:  Necator americanus (hookworm), for example, seems to promote the growth of Lactobacillus and of SCFA-producing species.  An antigen produced by the helminth, Hymenolepis diminuta, seems to ameliorate colitis in a rodent model.  (You can read way more about this here.)

The authors point out, by the way, that other organisms, like protozoa, also undoubtedly play a critical role in the whole picture but were beyond the scope of this paper.  (And don’t forget archaea too!  And wait…how about the virome?! Seriously…the complexity is enough to boggle the mind.)

So, the conclusion?  “There is now convincing evidence that a correct shaping of the immune balance requires some type of contact with parasites, and with a varied microcosm of gut-dwelling microorganisms, or perhaps even with just transient, but frequent, “gut-passengers.  The so called dirty old friends.”  They authors go on to state that obviously we are not going to go backwards and live in non-hygienic circumstances. They believe it would be difficult to “…imagine an extensive use of worm therapies,” and think the way to go is pharmaceutical products made from the excretions of helminths.  I find that ironic in that, the whole paper talks about the incredible complexity of the interactions between all these native members of the human biome.  Isolating one or two chemicals is hardly a replacement for the living interactions going on between all these organisms.  It would be like saying that the droppings of birds in the woods is a replacement for their actual presence in the ecosystem of a forest, no?   They suggest the same, by the way, for fungi:  “We are still far from applications, but the prospects are encouraging, for a future in which molecules derived from parasites and fungi will vicariate the disappearance of our dirty old friends, helping us in the maintenance of a healthy gut.”

Maybe I’m wrong and “sterile” pharmaceuticals will work but…you can’t fool Mother Nature, can you?

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[i] Panelli,  S, et. al.  Inflammatory bowel diseases, the hygiene hypothesis and the other side of the microbiota: Parasites and fungi. Pharmacological Research. 2020;159. https://doi.org/10.1016/j.phrs.2020.104962