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Dr. Josephine Briggs>> Pat, thank you for
a really wonderful lecture,
and we're delighted to have Claire and Gloria here as well.
I'm sure there are a lot of questions from the audience.
We're really proud to be supporting this work.
It's really terrific.
One thing my first to start the questions,
I was actually struck, was aware of the very careful data
you have done on the lactobacillus trial
in healthy elderly subjects,
and what you're seeing is,
pretty consistent with the presence of the organism
at 28 days documentable, slightly differently
by different methods, and then its rapid disappearance.
And this is quite at slight odds with the notion that one can
permanently manipulate the microbiome by,
say, fecal transplantation or other thoughts.
So I'd be very interested in your thoughts.
Dr. Hibberd>> Well, I can certainly comment that it has
indeed seemed like a paradox, and in fact one of the things I
was hugely concerned about was that it seems that it is
necessary to continue taking a probiotic,
at least to have any effect that we are measuring
at this period of time.
I know in the pediatric population,
certainly administering the probiotics very close to birth,
it may be easier
to more permanently establish colonization.
But I think this could...
[inaudible comment] - yes, yes, yeah -
but I think it could also be a two-edged idea
because we may not actually want these probiotics
to be around for life, so it may actually be
advantageous that it disappears as well.
Dr. Claire Fraser>> I think you raise an interesting question
and just one other thought.
Clearly this is speculation without a whole lot of data
behind it, but if you look at some of the protocols for fecal
transplants, not unlike what you see with bone marrow
transplants, there is often an initial step with high doses of
antibiotics with the effect being to really knock down the
numbers of bacteria that are present in the GI tract.
So whether that has some role to play in setting the stage for
recolonization during a transplant,
it certainly seems plausible, but and that may be one way
—that may be one difference between
what the kinds of studies that Pat was talking about today
but clearly that's speculative.
Dr. Gloria Solano-Aguilar>> One of the things I want to add to
previous comments too, it's also a matter of time.
The more time that you give these probiotics to the
patients, the more time that it's going to take
for the bacteria to disappear.
So somehow it looks like there's an adaptation of that bacteria
to the system in order to be maintained in there,
and we have seen that in these studies.
Dr. Killen>> Along these same lines,
what, if anything, do we know about changes in omic data
following treatment of like antibiotic resistant
antibiotic-associated diarrhea, where at least the lore is that
probiotics seem to be useful?
Do we know anything about that at this point?
In other words, you know, you start with normals and you don't
see a change over the long haul.
But you start with a disrupted ecology,
is there any evidence of long-term change or short-term
change, what happens or do we know anything?
Dr. Hibberd>> As best I understand,
I believe there is at least one trial—is that right, Linda?
that is analyzing those data right as we speak,
but I don't think they've been investigated at least at this
level of using the omics technology.
So I think it's going to be really fascinating
to see how that works.
Of course the really unfortunate thing is that if people have
already got antibiotic-associated diarrhea,
they've already got a disrupted microbial ecology,
and so you don't quite know where you might end up going
back to because you don't know where they were before.
But I think it's going to be very interesting probably within
the next year would you imagine -
six months, that should be coming out.
FS>> Any omics data on colon cancer or probiotic use
in GI cancers?
Dr. Hibberd>> I must admit that truly
isn't my area of expertise.
I do believe there is some information.
Are you aware... ?
FS>> No, not anything systematic.
It's very ad hoc.
Dr. Hibberd>> Yeah, yeah.
No, there are some interesting questions being raised
in that circumstance.
And you know I think this is where we've got
to be awfully careful.
You know if we're going to move into these other areas,
which I think it makes sense to do so,
we've got to understand how to get to use the tools well
such that we can get the answers as quickly as possible,
but I but I think it's probably a little bit early
to comment on that.
MS>> Yes, question is about the cohousing effect.
You mentioned in this paper last Thursday.
I think it is because the mice eat each other's poop.
So that is why they mix.
You mentioned what's happening, in our house.
In our house, probably not.
Dr. Hibberd>> I'm just a tad worried that
people don't always wash their hands
quite as well as they should.
But I do agree with you. [laughter]
Dr. Briggs>> There was a very nice piece in
The New York Times Magazine by Michael Pollan,
and he cited a paper claiming that people households with dogs
shared their microbiome greater than households without dogs.
And perhaps Claire knows the work,
but it is clear that we tend to probably share our microbiomes
in our families at least to some degree.
MS>> Hi, Dr. Hibberd, it was a nice talk. [indiscernible]
You mentioned about the down regulation of IG by FCR2.
FCR2 plays into which organism,
and how we down regulate and what level it down regulates,
can you please elaborate a little bit?
Dr. Hibberd>> I think, Gloria, this is for you.
Dr. Solano-Aguilar>> Okay.
When we look at the analysis of the transcript on these
patients, we were trying to see the full changes that were
present on the genes.
And one of the genes that came significantly different that was
down regulated was the FCR2, which is the lower infinity
receptor that is involved in the induction of IGE production,
and as you know, it's also associated with
initiation of allergic responses in patients.
The level that we found of difference is a very low level,
it was 1.8 fold, so when you interpret these data under the
biological application, typically a two-fold,
1.5 two-fold is not that big of a change.
But one of the things that was consistently,
as we analyzed the data, we did all the filtering,
that this gene came popping out.
So this is interesting and this is something that is going to be
validated further because, as Dr. Hibberd mentioned,
there are also some other studies coming behind this one
where we have larger populations,
and we are going to be able to validate
and see if this is consistent, because, you know,
it's a small group of patients too.
MS>> Very interesting.
Dr. Solano-Aguilar>> Yes.
Dr. Briggs>> Dr. Sorkin
Dr. Barbara Sorkin>> One question about
the micro ecology.
What about the role of bacteriaphage,
and to what extent might that account for some of the
individual differences in variability in microbiome and in
the effects of probiotics?
And I think people are starting to look but I was wondering.
Dr. Fraser>> Yeah, I think that's another excellent point
that you raise and I think we clearly have to take this into
consideration as we're looking at this as a complete ecosystem.
We generated some data from our meta transcriptomic studies that
Dr. Hibberd didn't have time to show,
and we were able to find a lot of transcripts that mapped back
to known viruses in phage in the databases.
They tended, though, to look most like viruses
that may have been associated with diet,
but of course there's always a population of unknown unknowns
in each of these groups of data that we can only speculate
at this point what they might be doing.
But you're absolutely right, there's no way to fully
understand what's going on without taking all of this
into account as well.
FS>> Hi, Barbara Gerratana, NIGMS.
I really like your commentary but I would like that the
methods that you introduce are limited.
Transcriptomics is not a good way to look at function.
Oftentimes there's not a good correlation between function
because proteins are co-regulated by
post-translational modification and [indiscernible],
and variety of other mechanism so I wish in the next time,
next talk, you would add more functional
like chemical aspect to it.
But I completely agree with all aspects of biology and medical
issues should be considered in looking it at the microbiome.
And so my own...
Dr. Briggs>> So it's even more complicated
than Pat's excellent...
Dr. Hibberd>> Yes.
I totally agree with you.
I think honestly, we're really early in the analytics at this
stage, and you're right, we haven't exploited these data to
the level that we need.
We have to go across the entire spectrum.
So I strongly agree.
FS>> It's past RNAs, it's proteins and chemicals.
Dr. Hibberd>> Yes.
MS>> Thank you for this excellent talk.
With my limited knowledge, I was confused before this talk and
now I am confused more.
Dr. Hibberd>> Uh-oh!
MS>> So could you please give your advice to those who regularly
use probiotics in their diet, any advice?
You know. Thank you.
Dr. Hibberd>> Ay yi yi.
[laughter] This really is a tough one,
and I must admit as a practicing physician,
I get a lot of questions about, well,
should I take a probiotic, should I not take a probiotic,
and unfortunately I really—I'm just not sure that we know
enough to reliably suggest that people are going to benefit
for sure from probiotics.
And when I say that, people get very angry.
"But you're studying it!
What's wrong with you?"
But the real issue is,
I just don't think we have enough information.
One thing I'm pretty sure about, though,
is that most of the probiotics that are in widespread use that
are high quality products are safe,
people are not having bacteremias or invasive infections
or any other unexplained event in huge numbers.
If it seems like they are beneficial in one's diet,
and one is comfortable with that,
I certainly would not recommend against it,
but it is hard if somebody is saying could should I take a
probiotic to do "x"?
Truthfully, I don't think we have the answer yet.
So I apologize,
I wish I could give an answer to your great question.
I think it's going to take a little bit more time before we
know how to use probiotics effectively.
Dr. Briggs>> Pat has worked very hard with the FDA to develop
approaches to the regulation of these products with a lot of
assistance from Linda Duffy.
You can see as a food safety regulator,
this would be posing all sorts of complicated issues because
after all, you can't cook it to make it sterile.
And similarly, the regulatory structure for administering
living organisms has grown up around vaccines and isn't
totally an ideal fit for the problems faced here.
So we're actually pleased that the FDA has been working closely
with our investigators to get at least some of the safety steps.
But it is complex.
But when NCCAM is asked about this issue,
we try to avoid giving a lot of health advice and turn to people
like Pat to ask what they would say to this question.
I think the evidence-based reviews do suggest that
probiotics are helpful for antibiotic-produced diarrhea or
at least not harmful, and the pediatricians considered them to
be appropriate mechanism to prevent necrotizing enterocolitis
in certain groups of premature children.
That's what my simple summary
of the state of the evidence would be.
Well, it's a great audience, but wonderful talk,
and thank you so much, Pat.