QUESTION AND ANSWER SESSION

 Audience Question: In the United States we have a biased view of probiotics in that we use them to treat diseases as opposed to prevention. In Europe and in Asia , probiotics are used more in a preventive measure. Do you recommend the prophylactic use of probiotics in children, or do you think that we should be using them in a reactive fashion?

 Dr. Sherman: Most of the studies that I showed you were prevention studies. So the acute diarrhea, the h. pylori study, was a treatment study. The one setting where it has been looked at was not children it was adults with antibiotic-associated diarrhea and clostridium difficile. For prevention probiotics seemed to be much better than for intervention or as treatment, so there probably is a big difference in how you approach it, and in general most people think the better approach is probably a prevention strategy rather than an intervention strategy.

Q : Considering how transient the colonization is with most of these probiotics, how then do you ascribe the beneficial effects to that particular probiotic?

Dr. Sherman: Probiotics, they only transiently colonize, and prebiotics only transiently change the gut flora beyond a year of age. As soon as you stop the prebiotic or the probiotic, the flora goes back to how it was before, and that is the same with antibiotics - the flora goes back to its normal state. So it depends on how you look at it. The drug company or the industry thinks it is a good idea because you have to keep taking the agent. It turns out that the regulatory agencies also think it’s a good thing, because they are worried about safety. If something untoward was to happen, or an organism wants to take up DNA that turns it into a pathogen instead of a commensal, you could stop its colonization by getting rid of it. So genetically modified probiotics are here and are being tested.

Genetically modified probiotics are called “designer probiotics” because the public does not like the term “genetically modified.” But designer probiotics are actually done where the gene has been mutated so they can’t survive outside of a mammalian host and that is what the future of probiotics will be. The one thing that might be different though, is in the child under a year of age. Changing the flora early might have lifetime effects, and that is where we really don’t know what happens. So if you want to have lifelong effects you probably want to intervene early. If you don’t want to have lifelong affects you probably want to wait until the flora is settled and established and then introduced.

Q: Would you be able to or want to comment on long-term implications of young children who are on a lot of antibiotic therapy?

Dr. Sherman: I can only make general comments, because I just don’t know. Joe told you that a lot of those long-term studies have not been done. The one thing we do know, and these are pre-genomic studies, that after a year of age, you have the flora for life and the way those studies were done, is if you were born in Bangladesh and you moved to New York you had a Bangladeshi flora for your whole life. If you were a New Yorker and you moved to Bangladesh , you have New York flora for your whole life. These studies were published in the New England Journal, and the way they did it is they were looking for a readout of the microbial flora. The study was actually looking at metabolism of digoxin. So it turns out that there is an organism in the microflora that degrades digoxin. It makes you a rapid degrader or not. So your flora, unless you get antibiotics or you get intestinal infection, is with you for life, unless something happens. That is why the c. diff is a big problem in many - not so much in children, but certainly in the elderly and in hospitalized patients. If you get a c. diff infection you change that flora and it stays long term. It is not like a rotavirus where it lasts for two or three days. It can be weeks or months, and then it is very hard to get the flora to come back to its original state. And you know that c. diff is often caused by an introduction or excessive use of antibiotics.

Q: But what I was asking is are there any thoughts about children under one year of age who have been on very long-term or a lot of antibiotic therapy, where down the road there might be some problem in terms of their immunity or more potential risks for cancer or things like that?

 Dr. Neu: Not that I know of.

 Dr. Sherman: Those studies need to be done.

 Dr. Neu: Yes, they do need to be done. There are some places that are able to follow their patients for a fairly long period of time, but especially in the United States , we have a very mobile society, so sometimes you lose a lot of your patients for these long-term follow-up studies. So they are very difficult.

Q: Has anybody looked at the flora difference in breast-fed, exclusively breast-fed babies, and bottle-fed babies?

 Dr. Sherman: Yes. The flora of an exclusively breast-fed baby is entirely different than a bottle-fed and weaning baby and it has a predominance of these so-called good organisms, bifido bacteria, lactic acid producing bacteria, and very few anaerobes, and usually not E. coli.

Q: Does it stay like that for a long time?

Dr. Sherman: Until you wean. So if you’re still breastfeeding but you start introducing solids, the flora changes or so it says in one published paper, and the study was on fourteen babies, two twins. Their feces were followed every two weeks for a year. It is only one study out of Stanford, and what it showed was that flora of these babies was different each one from the other, and even the two twins, they were dizygotic twins, and they changed over that year in time, and the big change came about when weaning started.

The other thing that is interesting is the flora themselves. In the adult flora, in the post genomic area, there is one paper published in Science. The study was on three people, and those three people are Canadians. I verified this because I wasn’t sure. They were from Winnipeg . That’s really all we know. The study on the number of flora in the gut is on three healthy volunteers from Winnipeg . So what the microbiome project that you heard about is going to compare that microbiome to people in Europe and urban and rural and South America , and the hint is that there is going to be huge differences. And the hint has come from one paper out of China - One family of seven and the microbiome in that family was entirely different than the three Canadians. So there are going to be regional differences and there are going to be over-time differences. So we’ve got lots to learn now that we have the molecular tools to understand it.

Q: Given the association we’ve seen between the prenatal steroids and lower rates or incidence of NEC, and knowing that the inflammatory response in the preemie is somewhat exaggerated, might there be a role, and this is purely hypothetical and theoretical, might there be a role for chronic anti-inflammatory therapy for this high-risk group of infants?

 Dr. Sherman: Yes there might, but remember that we have had lots and lots of misadventures in neonatal care, and one of them had been steroids, early use of steroids, and one of the things that we have seen with long-term use of steroids is increased incidence of Cerebral Palsy. We have seen intestinal perforations with a combination of steroids and other drugs in premature babies. So I think that there might be a role but we need to proceed very cautiously.

Q : In the future, should we expect single-bacteria type probiotic, or a cocktail variety given the information we have until now?

Dr. Sherman: I don’t really know what the answer is. There are commercial ventures on both sides. I think the future is going to be designer probiotics - probiotics that do more than what I just described to you. It is known that you can put in a gene for an anti-inflammatory cytokine that will be expressed in the gut and delivered into the gut. It has already been done in a mouse, and a study is now underway in the Netherlands . It is a randomized controlled trial of probiotics, genetically engineered to express human recombinant interleukin 10, an anti-inflammatory cytokine. It dampens the immune response. This study is in adults with Crohn’s Disease and the results will be presented at the Digestive Disease week in May, 09. It is not just a one-off on interleukin 10. You can put in toxin binding receptors. You can put in food antigens to modulate the immune system, if you want to deal with the TH2 response. You can put in antigens that will upregulate regulatory T-Cells. Companies like that, because it is something special that separates out their material from the others. In a competitive environment, that might help. So I think the future will be these designer probiotics.

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