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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.
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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.
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 lactobacillibacteria 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?
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