Friday, March 10, 2006

Revisting probiotics

Although the last time I wrote on the subject of probiotics was somewhat pessimistic in tone, it should be emphasized that I think the entire concept is a really good idea. For one thing, bacteria as a general rule have a bad reputation among the general public that is worse than any other group of organisms. After all, microbes are linked to terrorism, disease, cooties and generally thought of as being associated with unhygienic practices. The number of people who cringe at the idea that milk is consistent mostly of bacteria is quite substantial. Very clearly, microbes have a major public relations problem and probiotics are a way of conveying to the public that there are ‘good guys’.

In fact, before I continue with the remaining substance of this post, I should point out the majority of normal bacteria aren’t out to get you. Microbes do numerous important things for every person on the planet and all completely without thanks or even a simple acknowledgement. For example, one of the most important functions bacteria that live on your body is to inhibit the growth of pathogenic microorganisms that try to establish themselves. As a further bonus, the gut microflora may communicate with the immune system, helping to appropriately target hostile microorganisms (see references of the previous post and below for some more information).

Obviously, these facts are essentially the basis for probiotics and what makes them such attractive options for treating certain illnesses. How exactly probiotics are supposed to do so and if they are even effective is somewhat under contention. To discuss this, some questions that arose from a comment left by impatientpatient are worth addressing below.

To begin:

1.VSL-3 is a fairly new product on the market and has specifically been tested on colitis, I believe, at the University of Alberta. It was a tiny study with what looks to be promising results. Pain and dysfunction was relieved a a fair majority of patients using this. Is this a place to start in seeing if probiotics or blends work?
Almost certainly, although small study sizes can only give indications that something is working or not. A much larger study that follows people for a longer period of time is required to definitively establish a protective effect, but many initial results do look good. The science is there to suggest probiotics can be an effective treatment for certain inflammatory bowel disorders, which are predominantly thought to be caused by abberant immune reactions between the native microbiota and the host immune system.

2.I was fortunate to have a doctor that recognized C Diff when she saw it. But I continue to have flare-ups of excuciatingly painful magnitude (drop to the floor clutching my stomach) on occasion a year after this infection.

I did use Lactobacillus Acidophilus, as Flagyl and Vancomycin pretty much have a fair bit of a failure rate. It was an education, trying to find something that would benefit me in any way. Yeast- used like pool shock once, and lactobacillus and time seemed to resolve the acute infection. I do not know why I continue on occasion to be in pain and all, but a dose of lactobacillus seems to help.

Herein lies the problem. As a patient, I decry pseudoscience. I would like to know if somthing has efficacy and why- I am not about to take anyone's word for something these days without researching it extensively. I think that is not a terrible attitude to have. I did research probiotics and I did find what seemed to me a plausible cause and effect- over the short term only. But until someone does a giant study-- and a proper double blind placebo trial- I rely on a fairly sketchy body of evidence. Was it LB, time or placebo effect that caused my condition to lessen? I don't know. I hope it wasn't the placebo effect. I hope it was a combination of time and LB.

Without any direct familiarity with the particular disorder and what may be going on, I would possibly guess that the Lactobacillus acidophilus may be helping. At the same time, it’s possible that the probiotic isn’t doing anything other than aiding the reestablishment of the microflora. The original infection of the Clostridium difficile may have thrown things out of whack and the antibiotics compounded the problem. All that may have been required was some time to reestablish the microflora and put things back to semi-normal. I could imagine that flare ups may reoccur after a subsequent encounter with another pathogen (not always another bacterium at that), with the resulting immune response re-activating ‘confused’ immune cells that attack the normal microflora again.

3. The other problem is that many doctors have really no idea of how horrid C Diff can be. And many do not recognize it. That can cause C DIff to morph into colitis, Crohns and even death. How can this be addressed?
There really isn’t a lot that can be done here except to educate and retrain doctors. In many respects the worst aspects of disease is that the early symptoms are all very similar. For example, most cases of meningitis start as something that just looks identical to the flu and can be very easily misdiagnosed. As New Zealand is currently experiencing an epidemic of bacterial meningitis, caused by Neisseria meningitidis, this issue is a considerable problem. With many diseases the line between a painful long lasting disorder or even death, can often be the time between onset of symptoms and recognition and treatment of the disease at early stages. The response from health authorities here was to provide more information to the general public to spot symptoms, promote greater awareness of the disease among health authorities and analyse potential cases more closely.
4.How can you measure gut flora in people? And could you do an experiment that did this before, during and after treatment with probiotics? NEOPHYTE but curious. Can stool cultures be helpful in this regard? Could you measure levels of C Diff and probiotics in a stool culture?

There are several ways of analyzing the gut flora of people and the majority of methods all involve pooh in some way. The first method is to simply take a nice slice of waste material, set it up on a microscope slide and eyeball what is there. Generally, you can find a lot more microorganisms by such cursory examinations than you can manage to actually culture. Obviously, looking at a bunch of rods, cocci and various squiggly things isn’t actually going to tell you overly much.

As a result, molecular methods are a much better way of finding out what the microbiota actually consists of. The way this is done is by exploiting wide amounts of natural variation among different bacterial strains in their 16S ribosomal RNA (rRNA) sequences. This little gene is useful because it has some regions that are constant (not changing) and other parts that are hyper-variable and change a whole lot. This allows scientists to easily amplify a range of 16S rRNA fragments by a technique called PCR (Polymerase chain reaction). These sequences can be separated out by gel electrophoresis and sequenced to identify what organisms are present. During an experiment, an investigator can determine if known bacteria are present before, during and after an experiment, so the answer to the second part of your question is also yes.

Of course this “poo print” has its problems, which a paper in Science by Eckburg P. et al illuminated quite clearly. The first problem is fairly simple, what bacterial species we have identified conclusively through sequencing is a tiny part of what is really there. We may be able to identify general groups of bacteria, but for families we don’t really have a lot of information on it makes identification hard. The other problem comes from the fact stool cultures are used as a model for the entire gut microbiota. This may not actually reflect reality very well, as some species may not be present in high numbers or may be hard to detect for other reasons.

Lastly of course, because this is a molecular technique that can work off even a single strand of 16S rRNA (theoretically at least), it’s difficult to verify the exact numbers that an organism is actually present in. This is one of the other problems with probiotics as a whole, you may be able to show they are present and possibly even persist, but the probiotic organism may end up an oppressed minority and not be able to affect anything.

On the whole however, I see a considerable amount of benefit to the use of probiotics, especially to recover from using antibiotics and serious infections of the gastrointestinal tract like Clostridium difficile. Obviously, more basic work needs to be done on the gastrointestinal tract microflora, particularly on how they interact with the immune system and which members are prominent in this interaction. This research would have obvious benefits to the understanding of probiotics as well.


Eckburg P.B., E.M. Bik, C.N. Bernstein, E. Purdom, L. Dethlefsen, M. Sargent, S.R. Gill, K.E. Nelson and D.A. Relman (2005). Diversity of the Human Intestinal Microbial Flora. Science, 308:1635-1638.

Patel J.B. (2001). 16S rRNA Gene Sequencing for Bacterial Pathogen Identification in the Clinical Laboratory. Molecular Diagnosis, 6:313-323.