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Probiotics

Remember this picture when I start talking about your wife.

Remember this picture when I start talking about your spouse.

The Wall Street Journal has an assessment of probiotics in the Jan 13, 2009 issue entitled “Bug Crazy: Assessing the Benefits of Probiotics.” For some reason when I wander around the hospital on rounds people show me articles such as this and ask, so whatcha think about this? Probiotics are interesting. They are live bacteria given to treat and prevent diseases. It is one of those overlap areas for scientific medicine and so called alternative medicine. There are good clinical trials to suggest areas where these agents are of benefit, but other aspects of their use are blown out of proportion for the real or imagined benefit probiotics may provide. Much of alternative medicine where it overlaps with real medicine is the art of making therapeutic mountains out of clinical molehills. The Wall Street Journal article is the kind of reporting that drives. Me. Nuts. It drives me nuts because the reporting acts as if the underlying assumptions of the therapies are true. Start with the second sentence.

Many medical experts believe that consuming healthy bacteria, called probiotics, improves the body’s overall balance of good versus bad micro-organisms, boosting general health.

Many? What is many? A few loudmouths like me? A consensus? Experts in what? What is a “healthy bacteria”? Are the bacteria healthy? Or does it make you healthy? Then the last part of sentence, “improves the body’s overall balance of good versus bad micro-organisms, boosting general health.” What the does that mean? Already there is the assumption, unchallenged, that there is an issue in people between good and bad bacteria that is affecting health. And which people? Which bacteria? Under what circumstances? The importance of understanding which patient populations may benefit from an intervention is key. My mind was boggled when they mentioned that there were 241 products released last year containing probiotics. Someone is getting a good balance of good income versus bad income, boosting some bank accounts’ health. Before we move on to the rest of the article, let’s talk about the colon and the bacteria that live there.

Your colon and the bacteria that live there

Your colon is a rich, complicated ecosystem. Each and every one of you has a metaphorical rainforest in your colon. Your colon is a complex environment containing hundreds of species of bacteria, 99.9% of which are anaerobes (bacteria that are killed by oxygen). Each gram* of stool, and a gram is not all that heavy, has 1011 anaerobes. That is one hundred billion organisms per gram of poo. This may surprise you, but your colon is not a particularly hospitable place, and there is not a lot of oxygen there. As a result, organisms that thrive in an oxygen low or deficient place, anaerobes and microaerophilic organisms, predominate in your colon. The predominant anaerobes are bacteroides species. Aerobes, i.e. oxygen requiring organisms like E. coli, make up only 0.1% of your stool, or 10^5 to 10^7 per gram of stool. That’s one to ten million aerobes per gram. And that’s the bacteria we can culture. It is estimated that we cannot grow about 80% of the bacterial species in the feces. Bowel mucosa is inhabited by Bifidobacteriumand Lactobacillus, the two most common bacteria in probiotics. These bacteria are minor constituents of the bowel flora, but since they live on the mucosa, along with Eubacterium, and Propionibacterium, they may have more beneficial effects. The female genital tract does have a Lactobacillus-predominant flora. The Lactobacillus community varies from person to person. Lactobacillus crispatus and Lactobacillus jensenii are the lactobacilli that predominate in the vagina. The Lactobacillus you eat is not the Lactobacillus that is part of your normal bacterial flora.

What the bacteria does down there

The normal gut bacterial flora is important in many ways. Micro-organisms block out potential pathogens. There are a limited number of niches in which bacteria can live. If the niches are filled with nonpathogenic bacteria, then there is no place for pathogens to get a toehold to grow. Overgrowth syndromes are a common complication of antibiotics and are frequently mistaken for a weakening of the host immune system. Wipe out some or all of the normal bacteria, free up some ecological niches, and bacteria or yeast not killed by the antibiotics will grow like blackberry bushes after a logging. Wipe out normal bacteria with antibiotics and get an overgrowth with yeast or Clostridium difficile, a particularly nasty form of infectious diarrhea. The immune system has not been compromised by the antibiotics, it is a result of the opening up of new living space for micro-organisms that were previously outcompeted for space. Normal microbiologic flora is important if for no other reason that it fills up a space that could be used by more pathogenic organisms. But micro-organisms do more than fill up a space. Bacteria, good, bad, and indifferent, are more than animate placeholders. They have been co-evolving with us for somewhere between six thousand and six million years. Genetic analysis shows that H. pylori came out of Africa with us 60,000 years ago and head lice have been with us and our ancestors for 1.6 million years. None of us are truly alone, and, after death, we will be consumed by the microbiology we have carried with us since the beginning of human existence. Introducing new strains of probiotics is akin to planting corn in a rain forest. You may get some benefit, but do not think you are reconstituting the normal ecosystem. During our co-evolution, bacteria have picked up some of the biochemical slack: micro-organisms make vitamin K, and help with the digestion and absorption of food. Most importantly, at least from the perspective of my 11 year old, bacteria are responsible for most of the gas of flatulence. Disturbing the normal flora with antibiotics, illness, surgery, or probiotics can lead to a variety of biochemical dysfunctions. I mention all this so there is context as we explore the biologic plausibility and clinical utility of probiotics .

Why bother?

The reason d’être for probiotics is inherently questionable: Normal bacteria gone, depleted, tuckered out? Take some extra bacteria and replete your ecosystem. Compared to the complexity of the GI microenvironment, probiotics contain just a few bacteria, and not even the most common bowel organisms. It is safe to say that the “good” bacteria so highly touted in probiotics are but a minor constituent of a complex flora. Some further fine points about the probiotics:

  • Lactobacillus in yogurt in not necessarily lactobacillus usually found in probiotic pills. Yogurt is usually L. acidophylis or L. bulgaricus. The yogurt bacteria turn sugar to lactic acid, making the milk curdle and turning it into yogurt. The Lactobacilli in probiotics contain one of more Lactobacillus casei, Lactobacillus plantarum, Lactobacillus reuteri , Lactobacillus rhamnosus, or Lactobacillus GG. As mentioned, these are not the Lactobacilli found in humans.
  • The Bifidobacterium found in probiotics are not necessarily the Bifidobacterium found in and on you. There are many strains of Bifidobacterium, only a fraction of which are included in probiotics.
  • Saccharomyces boulardii, found in some probiotics, is not a normal part of your flora.
  • Typical of the unregulated supplement industry, what is on the label may not be in the bottle of probiotic pills. In several studies that have compared what is on the label with what is actually grown, not only were the organisms misidentified, sometimes the bacteria were dead. Organisms not mentioned on the label, like Enterococcus, were sometimes isolated. But then Enterococcus is a real constituent of the GI tract.
  • Probiotics, not being part of the normal flora, are cleared and cannot be isolated soon after stopping eating the probiotic. They are not normal flora and will not persist unless you keep consuming them.

If you are worried about your normal gut bacteria, be reassured. We are always consuming fecal flora in the food you eat and the water you drink. The food, your spouse, and the world, is covered in a thin patina of gastrointestinal bacteria, so you are always repleting your bacterial flora orally. Bon appetite! Families tend have similar bacterial strains. My gut flora more closely resemble my parents than my wife’s, suggesting there may be a genetic predisposition for which strains of bacteria make up your gut. When you give probiotics to normal humans you are introducing, relative to the number and quantity of bacteria that are already there, a small amount of foreign bacteria. Continuing our metaphor, it is like trying to put a putting green in an Amazonian rain forest. For normal people, it makes no microbiologic sense to take probiotics.

On the virtues of coprophagia

For maximum benefit, scientists say, try to consume a variety of different bacteria, as each may contribute something slightly different.

Your best bet, with this reasoning, would be to eat a variety of human stool. That way you will get many different bacteria, all contributing something slightly different. Probiotics are defined as “live micro-organisms which when administered in adequate amounts confer a health benefit,” according to 2002 guidelines developed by the World Health Organization and the United Nations. Exactly how this works isn’t fully understood, but scientists believe that good types of bacteria have long lived in symbiosis with humans and that the positive health effects may have evolved over time. That’s right. So why take large amounts of foreign bacteria and yeast that are not a normal part of your gastrointestinal flora?

In choosing a probiotic, consumers should look for products that list a specific strain of bacteria on their label or on a Web site. Look for three names — in Lactobacillus rhamnosus GG, for example, the final two letters identify the strain. The GG strain has been well tested scientifically and has shown health benefits. A product that simply uses the first two names may include a similar, but not identical, bacterium that doesn’t have the same science behind it.

“Health benefits” is so nonspecific. There is science behind probiotics, but is it good science? My bias: at baseline in normal people, the colon has enough bacteria and, like supplements, does not need extra. The alleged health benefits of probiotics are often an example of spin. Per the WSJ, probiotics are helpful for the following. I will give the WSJ credit where credit is due, they make a point of mentioning that most of the studies that show benefit are funded by the makers of the probiotic, although they do not mention explicitly that studies show the source of funding biases clinical studies in favor of the funder.

  1. Gut health. What is gut health? It sound good, doesn’t it? How can you argue against health? Many supplements promote some kind of health. Gut health, vaginal health, immune health, etc. I have zero idea what this means. Water promotes health. Steak can promote health. Wine promotes health. Everything that is not poison can, under the right circumstances, be said to promote health. It is a content-free statement.
  2. Increased digestion. This manifests by reduced transit time. “…the company says a recent study, presented at a conference of the American College of Gastroenterology, found that a dairy drink with the same active ingredients as a four-ounce container of Yo-Plus reduced transit time to 21 hours from 31 hours.” This is good because? There is a myth that the colon is filled with toxins that need to be eliminated. Not true to my knowledge. Why might ingesting a large bolus of foreign bacteria lead to reduced transit time? Though most of human history, food poisoning was common. Eating tainted food was an unfortunate byproduct of a lack of refrigeration and food preservation combined with a starvation-level existence. There are three major ways people acquire infections: sex, inhalation and eating. Through most of human history the food supply was not clean, so it is not surprising that a large part of the immune system lines the gut. According to Dannon, 70% of your immune system is in the gut. True enough. It prevents the normal flora from getting into the bloodstream (a huge problem in people whose immune system is depressed from chemotherapy) and provides the first line of defense against ingested bacteria and toxins. If you inadvertently eat a large amount of bacteria, be it contaminated food or probiotic yogurt, the body gets rid of it with reduced transit time. If you really want to reduce transit time, take a probiotic laced with Salmonella. That is probably why you get reduced transient time with probiotics: the normal inflammatory response is attempting to rid the body of a bolus of foreign bacteria. Spin. Take an unimportant and perhaps normal physiologic response to infection and make it a benefit.
  3. Irritable bowel syndrome (IBS). The clinical trials do suggest benefit from various probiotic formulations for the symptoms of IBS. Curiously, there are numerous studies to suggest that IBS is a nonspecific sequela of infectious diarrheas of all etiologies. It is interesting that adding back bacteria would help symptoms, although the best probiotic formulation to treat IBS is not known. Since IBS is a post-infectious disease, one would wonder whether normal people taking large quantities of probiotics for a long period of time would develop IBS. My first prediction for probiotics: long term use in normal people will lead to increased risk of IBS.
  4. Colic. There is reasonable data to suggest that colic is improved with probiotics. If colic is due to alterations in bowel flora, then babies may be benefit from probiotics. The big benefit from probiotics, as mentioned, is probably by blocking pathogenic bacteria. Bacteria do not just float free in the colon. The have ecologic niches and often have to bind to specific sites on cells. Probiotics probably benefit their host by blocking the sites where the more-pathogenic organisms bind, if that is the cause of colic. Most parents with a colicky infant would do ANYTHING legal to quiet their baby and get just one good night of sleep, so I hope this one study is confirmed.
  5. Immune health. More spin. The woomeisters usually phrase it as “boosting the immune system.” First, the immune system in normal people does not need boosting. It is fine at baseline, and millions of years of evolution have given us what is presumably an optimal immunologic set point. When we are infected we respond with inflammation, and inflammation is not always good.

What about boosting or strengthening the immune system?

The data is contradictory. Some probiotic effects, such as on inflammatory bowel disease, are supposed to be due to decreasing immune function by depressing cytokines, while other effects are supposed to be due to increasing immune function in increasing local antibody production and T-cells. There are in vitro (test tube), animal, and human studies that show wide-ranging effects of probiotics on the immune system. Guess what? That is what is supposed to happen. Any time you take in large quantities of a living organism that is not part of your normal flora, the immune system is going to take notice and react. What they call boosting or increasing immune health, I call inflammation. I am going to limit discussion to the DanActive product by Dannon with the bacteria Lactobacillus casei. They have trademarked the name of their strain, Lactobacillus casei Immunitas. TM. Each bottle of DanActive has 10 billion live bacteria, so from a bacterial colony count, it is like eating a gram of stool. So what does that do for your immune system? Not much. They make a big deal about immune strengthening, but the supporting data they provide in their slick but almost substance-free scientific summary for providers is as follows (from the Dannon web site):

Consumption of yogurt containing L. casei Immunitas (TM) during 30 days resulted in a significant increase in the percentage of children with a concentration of Lactobacillus greater than 6 log10cfu/g of feces.

That must have been fun to collect. Children taking DanActive for thirty days increasingly have lactobacillus in their stool. Why is this good? Because they say so. They say it is regulating normal bowel flora. No they are not. They are taking a complex ecosystem and trying to replace it with a monoculture of “good” bacteria.

L. casei Immunitas (TM) stimulated DNA synthesis and cAMP (cyclic AMP) production in cultured IEC-6 (intestinal epithelial cell line) cells, indicating increased proliferation and cell activity.

Again. Why is this good? Any bacteria not part of the normal flora will cause an inflammatory response. Causing an immunologic response is how the immune system is supposed to respond to everything that is not you. Extrapolating from a typical test tube response to improving immune function in people is quite s stretch.

DanActive (TM) may modulate the innate immune cellular response, by reducing the depression of natural killer (NK) cell concentration, induced during intense physical exercise.

So what? That’s enhancing the immune system? And the study to demonstrate this earth shattering immune enhancement? They looked at 13 parameters in 25 athletes whose NK cells decreased with exercise. First they took milk for a month, then Lactobacillus for a month and found one parameter that decreased less after taking Lactobacillus for a month: NK cells. Milk had a 5% decrease in NK cells after exercise and Lactobacillus had a 3% decrease. Whoa. No controls (each patient served as their own control), I’m convinced. This is the basis of the immune enhancement of Danactive. The result in one of 13 parameters is probably random noise. If you do a Pubmed search on L. casei and other Lactobacilli you can find a variety of effects immunomodulatory effects reported. Now here is the secret: flood any animal with any organisms and you will get the same response. For example, the literature on Candida, which is more of a pathogen. If you expose animals or cells in culture to Candida you get immunomodulation. You can activate or turn off the immune system, depending on which part of the immune system you are measuring and what pathogen you are testing. If the organism, be it Candida or Lactobacillus, induces an inflammatory response, you can protect animals from subsequent infection and from cancer. If you prime the immune system before hand, you get a better host response to subsequent infection. This is a nonspecific response to all foreign bacteria, including probiotics. More spin. Calling the normal response to pathogens (or to relative nonpathogens in the case of Lactobacillus) an immune enhancement rather than inflammation is clever advertising, as is making the result seem like something special rather than the same old inflammatory response the immune system has to all foreign organisms. There is an interesting literature on the consequences on chronic inflammation and vascular disease: the NEJM had a recent article on how chronic periodontitis leads to endothelial cell activation (the cells that line your arteries) and may account for the long-known association between periodontitis and heart attacks. The cardiology literature is filled with epidemiologic studies correlating chronic inflammation and heart attacks. Acute infection is a prothrombotic state: if you have an acute infection the inflammatory state increases your risk of clot formation and increases your risk for heart attack, stroke, and pulmonary embolism. That risk is increased for up to a year after an infection. Inflammation, which is what taking 10 billion extra bacteria should cause, may not be such a good idea. The other interesting feature of infections is that after inflammation comes anti-inflammation. For every action there is an opposite and sometimes excessive reaction as the body tries to get back to baseline equilibrium. Patients with severe infections, if they survive the acute disease, are at increased risk of acquiring a new infection in the month after the infection is cured due to the anti-inflammation phase increasing the risk for another infection.

More predictions

I will make two more predictions about taking chronic probiotics.

  1. Population studies will show an increased risk of heart attacks, strokes, and pulmonary emboli as a consequence of the mild increase in the inflammatory state induced by chronic probiotics.
  2. Infections will increase in the month or two after stopping chronic probiotics.

Any budding epidemiologist out there, feel free to run with these ideas.

Super pooper

Antibiotic-associated diarrhea – here is where probiotics have the best data to support their use. I think the data is clear that they are effective in preventing antibiotic-associated diarrhea. So much so that at several of my hospitals we give live yogurt to normal patients who get antibiotics. Probiotics for the treatment of diarrhea? I am not so sure. The data is not as compelling and the treatment is potentially more risky. Complications from probiotics are rare and may be more common when being used to treat an acute inflammatory diarrhea. If you have a bacillary diarrhea like C. difficile, Shigella, or E. coli, you can get an impressively-inflamed colon. Intact bowel is an important barrier to infection, just like intact skin. Most people would be disinclined to rub large numbers of living bacteria or yeast on a raw, oozing, macerated wound. One would think this is a bad idea and could give the micro-organisms access to the blood stream. That is what has happens with probiotics. You immune system recognizes most of your bacterial flora, so it is rare to get bloodstream infections from normal flora during infectious colitis. You do not have that innate immunity against the bacteria in probiotics. Almost all the fungemias due to S. boulardii occur when it is given to treat an inflammatory diarrhea. While it is very rare, if you give people a large oral bolus of live bacteria to which they have no existing immunity and their gut looks like the colonic equivalent of bad road rash, expect the occasional organism in the blood stream. This should come as no surprise to anyone in ID. If you give normal animals a large oral inoculation of some relatively nonpathogenic organism it can overwhelm local defenses and lead to a bloodstream infection in the absence of colitis. My career is based on treating weird bugs, so I have a bias against possibly giving a patient an infection they don’t already have. I have seen two cases of S. boulardii fungemia in patients receiving this yeast to treat C. difficile. The medical literature does not indicate an increased bacteremia from Lactobacillus due to the use of probiotics. Population studies do not find an increase of Lactobacillus in the blood, but there are a few case reports of people with either severe mechanical or immunologic problems taking probiotics and getting Lactobacillus in the blood stream, for example an AIDS patient with lymphoma. Giving large amounts of a live strain of bacteria to the immuno-incompetent may not be the best idea.

Conclusion

Probiotics are useful for the prevention of antibiotic-associated diarrhea. Probiotics may be helpful in preventing other overgrowth syndromes or diseases associated, and perhaps with perturbations of the gut microbial flora such as IBS and colic. Probiotics are foreign bacteria that are not a normal part of your GI tract; they do not enhance your immune system and, in normal people do not promote the nebulous bowel health. If you are a normal human, with a normal diet, save your money. Probiotics have nothing to offer but an increased cost.


*For you metrically challenged, one teaspoon is about five grams and I found out that the US dollar bill weighs about a gram. So imagine a dollars sized smear of poo. There are 100 billion bacteria in it.

Posted in: Basic Science, Science and Medicine, Science and the Media

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