Curmudgeon’s Corner

Probiotics: Why Do They Work So Well?

By Jacob Schor, ND, FABNO

A study published last year has been nagging at the back of my mind.  In it, Faith Dickerson and colleagues report that probiotics appear useful to control mania.  They had enrolled a group of 66 patients who were hospitalized for acute mania and gave half of them probiotic supplements and the others placebos to take at home after they were discharged for the following 24 weeks. The researchers tracked which of these patients ended up being readmitted.  Of the 33 patients who took the placebo, 24 came back to the hospital.  Of those receiving the real thing (a combination of Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) only eight returned.  These numbers made the relative hazard ratio for rehospitalization in the experimental group a mere 0.26, [95% confidence interval [CI] 0.10, .69; P=0.007] a 74% decline in risk of rehospitalization. Additionally, those patients who received probiotics and were admitted back in the hospital, stayed there for fewer days than those who received placebo, 2.8 vs. 8.3 days.  In other words, taking probiotics appears to have provided a solid benefit to these patients.(1)

I am glad that these patients found such benefit.  We should all make a point of remembering this study next time we have a bipolar patient.

What’s nagging me is that I have no idea why these worked so well, or for that matter why probiotics work in any clinical trial.  Given the gazillions of bacteria in the human gut, why do a handful of capsules make such a big difference or for that matter any difference?

We should not doubt that probiotics are helpful.  A recent PubMed search for probiotics or lactobacillus yields citations for over 2,100 published clinical trials.  Probiotics have been tested in clinical trials for all sorts of health problems including gastroenteritis, vaginitis, urethritis, arthritis, radiation side effects, cancer of all sorts, fatty liver disease, heart disease, and so on.  More recently studies have begun to identify specific species of bacteria that are helpful for specific situations and conditions.  Somewhere or other I’ve got a list of what species are associated with greater benefit from the immunotherapy drug pembrolizumab.  We know which bacteria increase GABA in the brain and reduce seizures; which bacteria increase insulin sensitivity and control DM-2, and so on.  The list gets longer with every webinar.  What is not clear to me is why plain old Lactobacillus acidophilus does anything useful.

Three decades ago at National College of Naturopathic Medicine all this seemed to make sense.  Biology was simpler then.  We had yet to hear of dark biology.  The gut was inhabited by E coli, lactobacilli, bifidobacteria, and maybe a few yeast.  Any other living thing found on a stool test was probably a pathogen that ought to be eliminated.

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Our notion that lactobacilli are important to human health goes back more than a century to Élie Metchnikoff and his 1907 book, The Prolongation of Life.  He theorized that the gut microbiota produce toxic substances that damage the nervous and vascular systems, leading to aging.(2) Metchnikoff suggested that eating fermented milk products would “implant” beneficial, lactic acid-producing bacteria in the intestinal tract and would “arrest intestinal putrefaction and must at the same time postpone and ameliorate old age.”  Metchnikoff based his thinking on two observations.  First, that Bulgarian peasants, who were believed to live to very old age, ate large amounts of fermented milk products.  Second, the natural fermentation of food by lactic acid-producing microbes inhibited the growth of putrefactive organisms.  Metchnikoff concluded, “… as lactic fermentation serves so well to arrest putrefaction in general, why should it not be used for the same purpose within the digestive tube?”

Metchnikoff’s “Bulgarian bacillus” theory became popular and still remains widely believed to be fact.

This notion that the long life spans in isolated populations could be attributed to specific foods took quite a beating a decade back with the publication of the Akea study.  This study investigated longevity on Sardinia, an area then referred to as a “blue zone.”  The term ‘blue zone’ had been popularized by Dan Buettner in National Geographic in 2005 and was applied to parts of the world where people lived the longest.(3-5) Buettner identified Okinawa, Sardinia (Italy), Loma Linda (California), Nicoya (Costa Rica), and Ikaria (Greece) as blue zones.  He created a list of common lifestyle and diet traits these people shared in common and popularized them as ways to live longer.(6)

In the Akea Study, Michel Poulaina and colleagues looked carefully at the people who lived in an area of Sardinia that had an unusually high number of centenarians.  These researchers conducted a more methodical and exhaustive examination than Buettner had but were not able to identify any specific mechanism or dietary traits to explain why people living in their study area lived so long.

Instead, Poulaina et al suggested an “… interesting hypothesis … that the high rate of inbreeding determined by frequent marriages between consanguineous individuals and low immigration rates have progressively decreased the variability of the genetic pool and facilitated the emergence of genetic characteristics that protect individuals from diseases that are major causes of mortality particularly in older individuals.”(7)

In other words, the secret to long life in these ‘blue zones’ may not be yogurt, dried apricots or any other specific foods, nor good living or any of the traits Buettner would have us aspire to but instead, inbreeding.  The lifestyle trait that sets the people in these areas apart is a cultural acceptance of older men taking younger second and third wives.  Thus, genes for longevity and protection from disease were amplified in the population.

In fact, the term ‘blue zone’ might be appropriate to describe areas of high consanguinity, which means frequent inbreeding, rather than lifestyle traits that we would wish to emulate. Metchnikoff’s assumption that fermented milk would increase lifespan may have been like these blue zone areas, a misinterpretation of the facts.

Lactobacilli bacteria are the most common bacteria found in fermented foods.  They are among the easiest of any bacteria to grow.  As I write this article, I have a loaf of sourdough bread rising in my kitchen.  Despite my repeated neglect, the lactobacilli and yeast in the ‘starter’ continues to produce delicious bread. In the old days, when we isolated gut bacteria on agar plates, it also looked as if lactobacilli bacteria dominated the gut.  If there weren’t ‘enough lactobacilli in there’, it made sense for patients to supplement with lactobacilli.

There are certainly a lot of microorganisms living in the gut; early estimates suggest the population exceeds 1014.  It has often been repeated that there are about 10 times more bacteria than human cells in the body.  However, this estimate has been revised downward and currently the ratio of human-to-bacteria cells is believed to be closer to 1:1.  It turns out that these “…  ubiquitous statements regarding … bacteria residing in our body trace back to an old back-of-the-envelope calculation” from 1972.(8,9)

The idea that most of these bacteria were either E. coli or Lactobacilli species has also proven to be incorrect: “…  there has been a general and persistent assumption that a large number of Lactobacillus form stable and numerically significant populations in the human intestinal tract, especially in the small intestine, where they are presumed to form epithelial associations.  Considering how widespread and accepted this perception is, there is surprisingly little experimental evidence that supports it.”(10,11)

In fact, lactobacilli make up only a teeny-tiny portion of the total bacterial population in the human gut.  When we first learned about intestinal bacteria, the only way to identify them was to culture colonies on differing growth media, a method that has proven to be inaccurate in comparison to the newer techniques that:

… have revealed that the diversity of the gut microbiota has been greatly underestimated.  Although a complete catalogue of the members of the collective human gut microbiome is not yet available, more then 10,000 different species are estimated to be present, among which a large majority of these microbes are resilient to cultivation by currently available methodologies.[12] 

These newer technologies suggest lactobacilli are in the distinct minority, far outnumbered by a multitude of other bacteria species.  The old school techniques have given way to “culture-independent molecular measuring” techniques, the most objective being direct sequencing of the 16SrRNA genes. (13)  Such technology has also revealed a greater diversity in the gut biome than we ever dreamed possible.

This shouldn’t surprise us that much as, “… the vast majority of experimental studies conducted after 1960 clearly showed that they [lactobacilli] form marginal populations in the human gut.  When total anaerobic culturing techniques are used, lactobacilli form a very small proportion of the cultivable human fecal microbiota and can rarely be cultured at population levels exceeding 108 CFU per gram….”(14)

This should remind us how far off popular belief may be from actual fact.

Let’s do the math.  If gut lactobacilli account for only about 0.01% of the bacteria that can be grown, then only one in every 10,000 bacteria is lactobacilli. This doesn’t include the bacteria that scientists still haven’t figured out how to grow.(15) While there may be 10,000 different possible species of bacteria in the gut, it is generally accepted that any one individual will have about 160 distinct species.(16)  It is difficult to imagine how so few lactobacilli will make any difference in a person’s health.  It is not just this mania study that begs explanation.  We could pose this same question after any positive probiotics study; how can so few bacteria make such a significant difference?

Not having a decent answer for this question led me to reach out to Mark Davis ND to see if he could offer an explanation.  Dr. Davis practices in Maryland these days at the IBD Specialty Center (http://ibdspecialty.com/) in Bethesda, Maryland.  He pointed out that there are a growing number of published clinical trials that report positive effects from taking dead probiotics, that is studies that used heat processed lactobacilli that could not grow in the gut.(17-22) In most, though not all studies, these dead bacteria retained their therapeutic effects. Lactobacilli do not need to grow, to have an effect.  This is not how we have been describing how this works.

That bears repeating: Lactobacilli need not be alive to work.  They need not colonize the patient’s gut.  If they don’t have to be alive to work, there must be some factor within their ‘bodies’ or within their fragments, some factor X that triggers a response.  Think of all the effort you and your patients have put into keeping those products refrigerated over the years; it may not have mattered.

Dr. Davis provided me a useful analogy in an email:

…so if its abundance is so tiny, how does Lactobacillus help? First of all, it doesn’t seem implausible at all.  Ultra-wealthy people are an inordinately small part of our population but they have a lot of influence on how society works.  Politicians too, and doctors. There are all sorts of categories of humans that make up a tiny part of the population but influence the whole population for the better.  So what’s the mechanism of action?... I’ve thought that the way that other microbes in the gut and our own immune system are reacting to (probably proteins in) probiotic bacteria may be more important than the actual work the probiotic bacteria themselves are doing.

Maybe Dr. Davis is correct; maybe he’s not.  The thing is that we take it for granted that these probiotics help a wide range of conditions and yet if we stop and look carefully, we really do not understand how or why lactobacilli do what they do.

For many years I used a simple analogy with patients to explain why lactic acid-producing bacteria were so beneficial: it’s like preserving vegetables by canning—the whole Mason jar, pressure cooker production:

All foods can be divided into one of two categories when canning.  They are either ‘acid-safe’ or ‘non acid-safe’.  Foods that are acidic, say tomato products, whole tomatoes, puree or sauce, have a low pH and are acid-safe.  You cook them up, pour the stuff in clean jars and put a lid on it.  Period, done. Dangerous bacteria cannot grow in an acid environment. Foods with a higher pH are not so safe.  With non-acid foods you pack the food into sterile jars, then heat process it in a pressure cooker in the hope of sterilizing it and once done, throw the contents in the compost out of fear of botulism.  The difference is pH.  Pathogens don’t survive long in acid.  Same thing happens in your gut.  Probiotics lower the gut pH and keep out unwanted bacteria.

It sounds good but is obviously not accurate.  If dead bacteria still have effect, this whole image we have of the tiny amounts of lactobacilli that we take as probiotics supplements repopulating the gut with their offspring is not what happens.  Instead some surviving constituent of these bacteria drastically shift populations of other bacteria as they pass through the gut. What is this ‘factor’? 

When Columbus reached the New World, he thought he had reached India.  He was totally wrong of course.  I suspect that our understanding of gut microbiology may be as accurate as any map Columbus might have drawn of the world.  He was missing a few key facts, there was that whole North America business.  Lactobacilli may be our equivalent of Columbus and the East Indies.  We may be more certain of where we are than we should be….

Jacob Schor, ND, FABNO

Jacob Schor, ND, FABNO

Dr. Schor can be reached at drjacobschor1@msn.com

References

1. Dickerson F, et al. Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: A randomized controlled trial. Bipolar Disord. 2018 Nov;20(7):614-621.

2. Metchnikoff E. The prolongation of life. Optimistic studies. William Heinemann, London, United Kingdom; 1907.

 3. Buettner D. The Secrets of Longevity. National Geographic. November 2005.

 4. Buettner D. The Blue Zone: Lessons for Living Longer From the People Who've Lived the Longest.  National Geographic Books; April 2008. ISBN 1426202741.

 5. National Public Radio. Can ‘Blue Zone’ Help Turn Back the Biological Clock? June 8, 2008.

 6. Carlyle E. Dan Buettner’s Blue Zones teach nine secrets of a longer life. City Pages. February 3, 2010.

 7. Poulain M, et al. Identification of a geographic area characterized by extreme longevity in the Sardinia island: the AKEA study. Exp Gerontol. 2004 Sep;39(9):1423-9.

 8. Luckey T. Introduction to intestinal microecology. Am J Clin Nutr. 1972;25:1292–4.

 9. Sender R, Fuchs, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016 Aug; 14(8): e1002533.

 10. Vélez M1, De Keersmaecker SC, Vanderleyden J. Adherence factors of Lactobacillus in the human gastrointestinal tract. FEMS Microbiol Lett. 2007 Nov;276(2):140-8.

 11. Walter J. Ecological role of lactobacilli in the gastrointestinal tract: implications for fundamental and biomedical research.  Appl Environ Microbiol. 2008 Aug;74(16):4985-96.

 12. Frank DN, Pace NR. Gastrointestinal microbiology enters the metagenomics era. Curr Opin Gastroenterol. 2008;24:4-10.

 13. Ley RE Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124:837-848.

 14. Walter J. Ecological role of lactobacilli in the gastrointestinal tract: implications for fundamental and biomedical research. Appl Environ Microbiol. 2008 Aug;74(16):4985-96.

 15. Tannoc GWK, et al. Analysis of the fecal microflora of human subjects consuming a probiotic product containing Lactobacillus rhamnosus DR20. Appl. Environ. Microbiol. 2000;66:2578-2588.

 16. Xiao L, et al. A catalog of the mouse gut metagenome. Nat Biotechnol. 2015 Oct;33(10):1103-8.

 17. Shinkai S, et al. Immunoprotective effects of oral intake of heat-killed Lactobacillus pentosus strain b240 in elderly adults: a randomised, double-blind, placebo-controlled trial. Br J Nutr. 2013 May 28;109(10):1856-65

 18. Moroi M, et al. Beneficial effect of a diet containing heat-killed Lactobacillus paracasei K71 on adult type atopic dermatitis.  J Dermatol. 2011 Feb;38(2):131-9.

 19. Morisset M, et al. A non-hydrolyzed, fermented milk formula reduces digestive and respiratory events in infants at high risk of allergy.  Eur J Clin Nutr. 2011 Feb;65(2):175-83.

 20. Liévin-Le Moal V, et al. An experimental study and a randomized, double-blind, placebo-controlled clinical trial to evaluate the antisecretory activity of Lactobacillus acidophilus strain LB against nonrotavirus diarrhea. Pediatrics. 2007 Oct;120(4):e795-803.

 21. Peng GC, Hsu CH. The efficacy and safety of heat-killed Lactobacillus paracasei for treatment of perennial allergic rhinitis induced by house-dust mite. Pediatr Allergy Immunol. 2005 Aug;16(5):433-8.

 22. Xiao SD, et al. Multicenter, randomized, controlled trial of heat-killed Lactobacillus acidophilus LB in patients with chronic diarrhea. Adv Ther. 2003 Sep-Oct;20(5):253-60.