May 3, 2024 • 57 mins
In this episode of the Defiant Health podcast, I have a special guest: microbiologist Kiran Krishnan, PhD. In addition to conducting research on microbiome and health issues, Dr. Krishnan also built a successful company called Microbiome Labs, a major provider of unique probiotic products.
Dr. Krishnan has gained an international reputation for innovative thinking on microbiome issues pioneering, for instance, the science and application of spore-forming microbes. His studies have shown that such spore formers can reduce endotoxemia, minimize the damage done by antibiotics, and increase microbial diversity.
In this interview, Dr. Krishnan tells us about a novel approach to skin health he and his team have developed.
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Books:
Super Gut: The 4-Week Plan to Reprogram Your Microbiome, Restore Health, and Lose Weight
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
William Davis, MD (00:05):
In this episode of the Defiant Health
Podcast, I have a special guest,someone you might already be
familiar with, as he has beenprolific in providing education,
built a successful companycalled Microbiome Labs and is an
active researcher in studyingmicrobiome issues.
Our guest is Dr Kiran Krishnan,who has gained an international
reputation for innovativethinking on microbiome issues,
(00:29):
pioneering, for instance, thescience and application of
spore-forming microbes studiesthat have shown that such spore
formers can reduce endotoxemia,minimize the damage done by
antibiotics and increasesmicrobial diversity.
In this interview, dr Prishnantells us about a novel approach
to skin health he and his teamhave developed, and later in the
(00:51):
podcast I'd like to tell youabout Defiant Health's sponsors
Paleo Valley, our preferredprovider of many excellent
organic and grass-fed foodproducts, and BioDequest, my
number one choice for probioticsthat are scientifically
formulated, unlike most othercommercial probiotic products
available today.
(01:11):
Dr Krishnan, thank you verymuch for joining me in this
Define Health podcast.
I know you're doing a lot ofwork and off-camera.
You mentioned to me that you'regetting involved in the skin
microbiome.
Could you tell us more aboutwhat you're doing?
Kiran Krishnan, PhD (01:26):
Yeah, absolutely Well.
First of all, thank you so muchfor having me.
Your early books were some ofthe things that really got me
inspired to put more focus inthe microbiome.
So you know the wheat belly andso on, and Supergut is a
fantastic book.
So thank you so much for havingme.
It's exciting to be here.
(01:47):
So the skin microbiome is suchan interesting area, right?
So I've been working on the gutmicrobiome for more than a
decade, probably published maybe18 or 19 research papers
associated with the gutmicrobiome.
And then you know, as you startthinking about the gut
microbiome and what thatecosystem looks like, how
(02:08):
complex it is, but more so, howmuch the function of the organs
are determined by the types ofmicrobes that exist in the organ
, right, we know, for example,the small bowel completely
changes in how it functions.
If you have dysbiosis in thesmall bowel, you have microbes
in the small bowel thatshouldn't be there in the case
(02:29):
of SIBO, whether they come fromthe mouth or different areas, it
completely changes how thesmall bowel functions, and then
the small bowel no longerfunctions the way it should, and
that's true for throughout thewhole gut, the stomach as well,
and we know that, you know.
So then we started thinkingabout the largest, what should
be the largest organ of the body, the skin.
And is the skin a risk factorin chronic disease?
(02:54):
And that has been a questionthat's been on my mind for some
time.
We know that the skin has avery complex ecosystem.
We know that there are upwardsof a thousand different species
that can exist on the skin.
We know that different parts ofthe skin have very different
ecosystems.
So the face, a sebaceous arealike the face, where you have a
(03:15):
lot of anaerobic environments,high oil and so on, compared to,
say, the forearms and the legsthat are much drier.
They're very differentorganisms, very different
ecosystems and thereby differentfunctionality on the skin.
And at the end of the day, oneof my questions has been how
much does the microbe populationon the skin impact the function
(03:37):
of skin?
And the function of skinprimarily is a barrier, right?
That's one of the largestbarriers in our body and it's a
different barrier than the gutbarrier in that it's less
dynamic.
The gut barrier has to let alot of things through that need
to get through, but then ofcourse, cinch up a little bit to
prevent things that shouldn'tbe going through.
But the skin largely acts as afirm barrier.
(04:00):
It doesn't let a lot of thingsthrough, if anything, a few
things maybe.
But that barrier functionbecomes really important.
And then I came across thisfascinating study called the
Baltimore Longitudinal Study onAging.
And this was a fascinatingstudy because, you know, it was
the first time where they tookindividuals when they were young
(04:23):
, in their early late 20s toearly 30s, and these researchers
decided, you know what, insteadof aging studies where we take
an older cohort and compare themto a younger cohort and look at
differences, let's just takeeach individual and follow them
for the next 50 years.
Right, and that's fascinatingbecause it really gives you now
(04:43):
a whole different picture.
Because if you take80-year-olds today and compare
them to 30-year-olds today,those 80-year-olds went through
a very different life and systemand ecosystem than the
30-year-olds have been goingthrough.
Right, when they were 30, theworld was a very different place
and their environment was avery different place.
A very different place andtheir environment was a very
(05:06):
different place.
And so using each individual astheir own control seems to be a
really, really interesting wayof studying aging, because you
can follow that individual andother individuals that are
similar to them and look at alltheir choices and the things
that change within their systemand how that impacts risk, and
one of the things that they'veconcluded is that aged skin was
(05:28):
an independent risk factor forchronic disease, and these are
diseases distilled to the skin.
So these are things likeosteoporosis, alzheimer's,
dementia, cardiovascular disease.
Aged skin is a risk factor, andthese researchers were able to
use skin health and thecondition of the skin as a very
(05:49):
accurate predictor of morbidityand mortality in individuals,
and so that became reallyfascinating to me, because then
the dots started to connect,going okay, so as skin ages and
loses its barrier function, it'snow acting as a risk factor for
chronic disease.
(06:10):
This sounds very similar to thegut, right?
As your gut becomes moredysfunctional and loses its
barrier capabilities, you getleaky gut, which then becomes a
risk factor for disease.
In the case of the gut, it'sthe microbial dysbiosis that
leads to the dysfunction.
In the case of the skin, it'sthe microbial dysbiosis that
leads to the dysfunction.
In the case of the skin, it'sgot to be the microbial
dysbiosis as well.
So that's when we starteddigging in, going oh wow, it is
(06:33):
because there's a lot of reallystrong correlative data, some
causative data that shows thatcertain changes on skin microbes
affect the function and thestructure of the skin, and that
to me becomes really interesting, beyond the cosmetic aspect of
it, because it's an independentrisk factor.
William Davis, MD (06:53):
Any notions?
What exactly is being mediatedin the crosstalk between gut and
skin?
Kiran Krishnan, PhD (06:59):
Yeah, so from the gut skin component to
it, and so there's the skin,skin, what's happening between
the microbes on the skin andthen the resulting immune
responses in that local region.
But then there's also what ishappening between the microbes
in the skin and the gut, and thegut, of course, then dictates
in large part how your immunesystem responds to things right.
(07:21):
So one of the dots that we'vebeen able to connect is when you
look at inflammatory conditionson the skin, things like
dermatitis, different forms ofdermatitis, whether it's atopic,
or a different version or evenpsoriasis, or even acne skin,
where the immune system isplaying a role in driving the
(07:44):
inflammation and then, as aresult, driving the damage to
the layers of the skin, right,that we then can see the
comedones that are developing inthe case of acne are
inflammation and filling in ofthe pores with immune responders
, and all that, and then samething with dermatitis and
psoriasis, and all the rednessand dryness of the skin, is a
(08:07):
result of the immune systemfunctioning there.
Then the question becomes okay,why is the immune system going
there and why is it doing that?
Well, to me, it seems likethere are two things that need
to happen for an eczema-likeresponse on the skin or a
psoriasis-like response, or evenan acne-like response on the
skin.
Number one there has to be atrigger on the skin that causes
(08:30):
the immune system to need torespond to that area.
Right, and often that triggeris microbial dysbiosis.
Now, if you have, for exampleand this is why they've shown
lots of very strong correlativedata that staph aureus
overgrowth in certain regions isassociated with dermatitis,
psoriasis and so on, in the caseof the face, cutibacteria and
(08:51):
magnesis is associated withincreased risk for acne
development, right, so there arethese opportunistic or
pathogenic-like organisms thatare present in the regions where
these lesions develop, whichmeans that they are likely
triggering the need for theimmune system to respond.
And then, sure enough, when youdig into the literature, it's
(09:11):
true, they're immunogenic, theyproduce toxins, they produce
things that cause the immunesystem to respond.
But why is it that the immunesystem is responding in such a
way that it causes all thisdamage to the skin?
Right, the redness, theinflammation, the dryness and
all that?
Well, that's because the gut isalso dysfunctional in many of
these individuals, which meansthey've got an immune system
(09:34):
that doesn't have propertolerance messaging.
Right, they're not expressingTregs very well, the T
regulatory cells.
They're not expressing IL-10very effectively, right, they're
not expressing the regulatorycomponents of the immune system
that don't allow the innateimmune responses to overreact,
and so they tend to have animmune system already that's
(09:57):
overreactive to things.
So they may be histamineintolerant, from histamine from
foods, for example.
They may have environmentalallergies, they may have chronic
sinusitis, they may have lotsof things where the immune
system seems to be overreactingin response to stimuli.
So these individuals have thatdouble whammy They've got a
microbe that's causing an immunetrigger on that part of the
(10:18):
skin and they have an immunesystem that tends to go full
inflammatory, isonophilic,basophilic, inflammatory-type,
damaging response, right.
So they have the best of thosetwo.
And I compare it to individualsthat don't have the second part
.
They don't have an immunesystem that is very
pro-inflammatory, very IgE, veryisonophilic, basophilic type
(10:42):
responder.
The difference between thosetwo individuals is one could get
staph aureus or get a physicalstimuli.
I give people an example of somepeople who wear a backpack all
day and wherever the straps havebeen rubbing they get super red
and itchy and inflammatory.
What's the difference betweenthat individual versus someone
that can wear a backpack and befine all day?
(11:03):
Well, that's the immune systemresponding to that rubbing.
Right, we call it contactdermatitis, right?
Contact dermatitis is just well, your skin rubbed against
something and was irritated.
Your immune system responded ina very inflammatory manner.
Now you have dermatitis and thedifference there is that the
individual that doesn't get thatdermatitis has a well-tolerant,
(11:26):
well-balanced immune responsebecause their gut is healthier.
The other individual doesn't,right?
So that double whammy, I think,seems to be driving a lot of
this.
William Davis, MD (11:36):
So if the skin microbiome can be the
initiating factor, are you anycloser to a microbial solution?
Kiran Krishnan, PhD (11:44):
Are you any closer to a microbial solution?
Yeah, that's a great question.
So we developed this quorumsensing product to effectuate
(12:07):
the population of microbes bydirectly competing with or
producing compounds that inhibitthe growth of dysfunctional
microbes and or enhancing orproducing compounds that enhance
the growth of beneficialmicrobes.
On top of that, some of thesequorum-sensing microbes also do
a great job of recruiting theimmune system in the right way
to flag and deal withproblematic microbes, right?
So the class of microbes thatwe worked on in the gut for a
(12:30):
number of years in that are thespores, the Bacillus endospores.
Now, bacillus endospores arefascinating because we have a
long history with them, right,we've co-evolved with these
organisms because they're prettyubiquitous in the environment.
Some of the early recordings ofthe use of Bacillus endospores
(12:50):
for quorum sensing comes fromthe 1950s, for example, when the
German army was in North Africain World War II, a lot of the
soldiers were dying and gettingsick from dysentery, more so
than the war, and one of thethings that they observed was
that the locals, when they wouldget an upset stomach, would
(13:11):
actually seek out and eat driedcamel dung as a therapeutic to
help the gut, right?
So then, research studiesstarted in the late 1940s, early
1950s to look at what's in thiscamel dung that actually seemed
to be helping with gutinfections.
And what they found out wasthis Bacillus subtilis, a
(13:33):
quorum-sensing, competitiveexclusion microbe that was
coming out through the stool inthese camels that were
ubiquitous in the environment.
If you consumed enough of it,it would actually seek out and
identify the dysfunctionalmicrobes and bring their numbers
down specifically.
So Sanofi Aventis, apharmaceutical company, launched
(13:56):
that product as a treatment fordysentery in 1952.
And that product is still inthe market today as a treatment
for traveler's diarrhea,dysentery, chronic upper
respiratory symptoms and so on,and it's called entro germina
and that product has been in themarket now for well over 60
years as a prescription drug inEurope, latin America and so on.
(14:19):
So Bacillus has this longhistory of being able to read
other microbial signatures,identify dysfunctional microbes
and then bring their numbersdown.
We published a couple of studieslike that on the gut.
So it got me to thinking OK,bacillus is pretty ubiquitous.
We find it on our skin, we findit everywhere.
Maybe they can do the samething on the skin.
And so we developed a productwith a specific carrier that was
(14:43):
skin memetic, so it didn'tinterfere with anything with the
skin.
And then we put two bacillusendospores in it, a coagulant
and a subtilis, and we starteddoing some studies on it.
We started with some initialskin swabs on people with acne.
So we would see really highcutibacterium magnesis in these
individuals right.
So they have inflammatorylesions all over the forehead.
(15:05):
You swab the forehead, they'vegot 80% cutibacterial magnesis
and of course that's why theforehead looks the way it does.
Then they start applying thisquorum sensing serum on their
forehead once a day.
In 14 days, 21 days, you know,60 days, and so on, we took
samples and what we saw was adramatic reduction in the
cutibacteria magnesis and, as aresult, the lesions go down as
(15:28):
well.
So the first individual that wedid this with, in a 30-day
period we saw more than 50%reduction in inflammatory
lesions and the cutibacteriamagnesis went from almost 80% to
about 30% prevalence on theforehead right to about 30%
prevalence on the forehead right, and so we started.
Then a whole other thing We'vejust completed 317 subjects on
(15:50):
acne and inflammation.
We saw the same thing.
So the product is actuallycalled this.
It's called Sib.
Oh, where is that camera?
It's a we call it a biomebalancing serum, because what
we've been able to show is thatwhen you add the spores onto
your skin just once a day, theyseem to effectuate change.
Now we don't know exactly whatmechanism they're doing the
(16:14):
change through.
That's going to require morestudy but we know the change is
happening and we know that theskin is improving dramatically
as well.
William Davis, MD (16:24):
Is it you're thinking that you apply this as
a spore and it germinates on theskin?
You know.
Kiran Krishnan, PhD (16:30):
I would hesitate to think that it
actually germinates on the skin,because we know that spores
themselves are immunogenic andeven as a spore, even though
they're not metabolically active, they do have receptors that
are expressed on the outer sporecoat that on its own can
modulate immune responses in agiven area.
(16:51):
We actually, a long time ago,while we were working on the gut
, did a simple study and lookingat quorum sensing and
competitive exclusion.
For those that are listening,competitive exclusion if you're
not familiar with it, that meansone microbe competing with and
thereby eliminating anothermicrobe, right?
Spores do this really wellagainst pathogens.
(17:12):
And so we did a competitiveexclusion study on the surface
of a cell phone, right, becausewe know that cell phones are
probably one of the filthiestthings we all have around us,
right?
There's so much fecal matterand other things on it from
everything that we touch andother people touch, and we set
it down everywhere.
And so we took a couple of thespores and we just mixed it in a
(17:34):
little bit of water and a tinybit of alcohol and we swabbed a
couple of phones with it, andthen we did kind of before and
after swabs of the phone.
After about a week we foundcompared to phones that were
handled in very similar waysthat did not have the spores on
it.
The ones that did had muchfewer environmental and
(17:55):
pathogenic organisms on it.
So the spores somehow preventthe establishment of pathogenic
organisms, even on an inanimatesurface like the phone.
And so then it starts thinkinglike okay, maybe there are some
ways in which the spores, evenin the spore form, can
(18:16):
effectuate biofilm formation andso on.
Right, we know they themselvesare good biofilm producers.
They produce enzymes that canbreak down other pathogenic
biofilms.
So that part of the mechanismto me is very fascinating.
I would guess that the sporesare not necessarily germinating
(18:36):
on the skin and living on theskin, because what's interesting
about the skin swabs is we add,you know, a billion or so CFU
to the skin once a day in agiven area like the forehead.
You would think in seven days,once we swab to look at the
changes in the microbiome, we'dpick up a lot of bacillus.
But we don't.
(18:57):
So we hardly pick up anybacillus at all, which means
that they're not actuallyhanging out on the skin.
They're there for a period oftime and I think they transit,
they leave the skin, but theyeffectuate an immunological
difference or they may affectsomething like staph epidermidis
, which is a good beneficialbacteria, because we do see the
beneficial bacteria on the skinincreasing in growth, right.
(19:20):
So some really interestingthings there.
Now you go back to theevolutionary biology
significance of that and itcomes back to like, well, the
benefits we all know being inthe outside environment playing
in the dirt, you know gettingdirt on us, desert dust blowing
across different parts of Europeand the ability of the desert
dust to sit on the skin andprovide some transient microbes
(19:42):
to the skin that can effectuatechange.
So I think a lot of thosethings kind of help explain some
of the empirical value of doingsomething like this.
But we're super excited to keepdigging into the research.
The next phase of research withthis because we've gotten a lot
of empirical reports on this isage-related changes.
So one of the things that a lotof people have reported we
(20:05):
probably have 30 cases on it atleast on dramatic reduction in
fine lines and wrinkles in ashort period of time and
improvements in the tone of theskin.
So hyperpigmentation of theskin and what people are
expressing is texture of theskin.
So one of the things we knowthat occurs over time, if you
(20:26):
look at the topography of theskin, the pores start to
increase in size, right, so theybecome more visible, and then
the skin looks like it's notsmooth anymore.
It doesn't have that nicesmooth, baby-like texture,
because our pores become biggerand you see more creeks and
valleys and things like that.
So we're starting to see peoplereporting uniformity on the
skin as well, and the microbesmust be making that change.
William Davis, MD (20:52):
I recognize this is not a drug, but do you
plan to explore other conditionslike psoriasis or rosacea?
Kiran Krishnan, PhD (20:59):
We are.
Yeah, we actually have a coupleof conditions that, in speaking
with dermatologists, friends ofmine, are difficult to treat.
So one of them and this is acondition that seems to have
popped up in higher prevalencesince the pandemic and it may be
related to people wearing masksall the time.
But perioral dermatitis, thatseems to be something that a lot
(21:21):
of people are struggling with.
You know, and my dermatologyfriends tell me that it's really
hard to treat.
They use a lot of steroids,they go through Nystatin and
different antibiotics and manyof these patients they seem to
be pretty resilient.
We've done a few cases withperioral dermatitis and it seems
to dramatically help.
(21:42):
And then we also have done anumber of cases with just your
standard eczema, you know, andwe also have done a number of
cases with just your standardeczema.
You know your run of the milleczema dry, flaky, red,
irritated, itchy skin.
We're seeing a much higherprevalence of that now in kids,
(22:09):
you know, and you know that ifyou're, if you've got a five,
six year old with eczema andyou're treating their skin with
steroids, long term it's goingto impact the structure of that
skin right.
That area of the skin willbecome thinner, like most people
say, there'll be a lot of moreinflammatory response in that
area.
There's some rebound responseswith steroids and all that.
So one of the things we want todo is provide parents with
something else they can look atand do to try to help that.
So I think we would stick withthe kind of cosmeceutical route.
(22:31):
We wouldn't look at doing adrug route with it, but it'd be
similar to, like you know,cerave, which is a lotion that
seems to be used quite a bitwith people with dermatitis
because of the additionalceramides that they've added in
there.
That can help.
So we'd look at doing somethinglike that ceramides that
they've added in there.
William Davis, MD (22:50):
That can help .
So we look at doing somethinglike that.
What's your suspicion?
If those two microbes thecoagulants and the subtilis
applied topically are beneficial, do you think there might be an
additional effect if takenorally concurrently?
Kiran Krishnan, PhD (23:01):
I 100% feel that that's true Now, because
in part because we've done anumber of case studies that way
as well.
You know, when I was atmicrobiome labs, one of the last
technologies I developed beforewe sold to Novozymes and then I
exited was a product calledSerene Skin, which is a specific
(23:21):
for spore formula.
That was for acne and forinflammatory conditions on the
skin.
In fact, we got issued a USpatent on it.
We've published two papers onit, one of the papers I think
you know don't quote me on this,but I think it's published in
the British Journal ofDermatology.
So a pretty high-impact paperand what we showed was that just
(23:45):
from oral consumption of thespores and these were a specific
formula to increase theproduction of acetate in the gut
, one of the things that wefigured out was that acetate
production, which is one of theshort-chain fatty acids, acetate
production in the gut is reallyimportant for skin health and
(24:06):
in part for people who are veryprone to acne.
And the reason for that isacetate seems to, of course,
leave the gut.
It's butyrate as opposed tobutyrate that stays
predominantly in the gut andfunctions in the gut with all
kinds of important things.
Propionate comes in and out.
Propionate also goes outside ofthe gut and functions in other
areas, but acetate seems to beable to build up in a good
(24:28):
amount and then leave the gutand function outside of the gut
and functions in other areas.
But acetate seems to be able tobuild up in a good amount and
then leave the gut and functionoutside of the gut.
We saw that acetate productioncan actually reduce the amount
of sebum that's being producedby the sebaceous glands and can
actually reduce inflammation inthe skin, and so we looked at
okay, what does the gut of acneindividuals look like?
(24:50):
And there's a lot of really gooddata showing that people with
acne tend to have lowruminococcus and low microbes
that produce acetate and otherforms of short-chain fatty acids
.
So we formulated this product,we created a version that can
create higher amounts of acetate, and what we saw in the 12-week
(25:10):
study that published was thatwe saw a 75% reduction in
lesions all lesions,inflammatory and
non-inflammatory in that 12-weekperiod, without the use of
antibiotics, and that's right onpar with any antibiotic that's
used for acne.
It's about 70% reduction inthat period of time.
(25:32):
So that was very exciting to us, and so then, when we first
launched SIV, what we did is wetook some of our estheticians
and skincare professionals andsaid do both Do the serene skin
orally and then do the SIVtopically, and then in some
cases just do one or the other.
And we always saw betterresults with doing them both.
Because I think it comes downto that modulating the trigger
(25:54):
on the skin right, thepathogenic organism, and then
also modulating the immuneresponse, and doing that through
the gut is the most effectiveway of doing it.
William Davis, MD (26:06):
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Listeners, now let's get backto our discussion.
Do you think that thesemicrobes, these spore formers,
(29:02):
take up residence in the GItract?
Kiran Krishnan, PhD (29:05):
You know we see that they do, but for a
short amount of time.
They're really interesting inthat in the gut modeling studies
that we've done we've used asystem called a SHIME system,
right, the simulated gastricsystem and it's really
interesting because it has allthe components of a digestive
tract, starting from the stomach, small and large bowel.
(29:26):
It has all the specificcomponents of those structures
and then it's inoculated withthe full human microbiome and
then you stabilize themicrobiome in there over a two,
three week period.
You continuously feed it foodlike you would an individual and
then it has a mucosa and animmune system and all that.
So you really get really greatinsights in what's happening
(29:47):
with the microbiome as you addsubstrates into the system.
So when we've done studies withthat, we've hit the system with
lots of spores and then we lookat the microbiome changes
throughout the small and thelarge bowel.
What we always see, no matterhow many spores we're given
whether we're dosing it at 5billion a day, 50 billion a day
(30:09):
didn't matter what we always seeis a certain threshold of the
spores that are reached in thatgut that doesn't get exceeded.
So the spores have their ownlimiting factor within the gut
right.
So in the gut, what we normallysee is around 10 to the 6 CFUs
(30:30):
per gram of stool right or pergram of you know, whatever we
pull out the titrate or whateverwe pull out of the gut.
So 10 to the 6, for people thataren't familiar is one with six
zeros right.
So it's not a lot of bacteria,but they don't exceed that level
in any given area, which isreally fascinating.
Even if we hit it with a lot,we actually just get more coming
(30:51):
out.
So the spores have a veryinteresting transient quality
where they do take up residencefor a period of time.
But then if you follow anyindividual spore, what it does
is it tends to take up residencein certain parts of the gut and
then re-sporulate and move onand then take up residence re of
the gut and then resporulateand move on and then take up
residence, resporulate and moveon.
(31:12):
We know, for example, that whenyou consume the spores in the
duodenum itself, the spores comeout of the spore state right,
so they're a vegetative cell inmuch of the duodenum and the
jejunum.
Then when they move to theileum, as they're kind of
tumbling through and they'rerolling through, they
resporulate in the ileum, whichis really fascinating, because
(31:34):
the ileum has that huge areacalled the Peyer's patches,
right, massive immune samplingarea, and in fact one of the
characteristics of the Peyer'spatches is that they're
dendritic cells, these immunecells that reach across the
lining and they grab ontocertain microbes and pull it
across and they can take thosemicrobes to the mesenteric lymph
(31:55):
nodes and then do things withthem that may be beneficial.
One of the microbes that we'vedone a lot of studies showing
that that happens is apsychobiotic, the Biflongum 1714
.
We can talk about that if wehave time.
But what we see is that thespores, if they resporulate, if
they leave the vegetative stateand become a spore in the ileum,
(32:18):
they're actually moreimmunogenic to the immune tissue
in the ileum.
They trigger more immuneresponses in a positive way.
They upregulate tolikereceptors, they upregulate Treg
and so on Pardon me a littledryness in the throat and so
they upregulate these immunefactors and then in some cases
(32:41):
they can actually getphagocytized or consumed by
dendritic cells and pulledacross and then transported to
mesenteric lymph nodes wherethey can upregulate the
proliferation of T cells and Bcells, which is fascinating,
right.
So they have a very interestinglife cycle throughout the GI
(33:03):
tract.
They enter then the large bowelstill in spore state, but then
by the time they move past thesigmoid they become a vegetative
cell again and then they spendmuch of their life in the large
bowel as a vegetative cell.
Within two to three weeks theytend to leave, and part of that,
I think, is their evolutionaryadaptation of being a ubiquitous
(33:27):
yet transient organism in lotsof different guts.
Right, they are what we wouldcall universal colonizers.
They're found in the digestivetract of virtually every animal
that they've been looked for,including insects, including
honeybees and so on.
They're in every mammal in thedigestive tract.
They come in through eating andinteracting with the
(33:49):
environment.
They do some things in the gutand then they leave through
defecation.
That's how they spread acrossthe globe.
There was a really fascinatingstudy on glacial ice cores and
these scientists took ice coresfrom the Tibetan Plateaus, from
the North Pole, from the SouthPole, and they take these, you
know, mile-long ice cores andthey can take slivers out of the
(34:10):
ice core to look at what was inthe environment during that
time.
That's now captured in the iceand they find that even three to
five million years ago thesebacillus endospores were
ubiquitous in the environment,even in the South Pole, north
Pole, tibetan plateaus and so on.
And the most fascinating partabout it is most of the strains
(34:31):
that they identified in theglacial ice cores that were
three, five million years old.
Not only were they still alive,they could still be plated, but
they had more than 95% genetichomology to the strains that we
have around the environmenttoday.
So they haven't changed much inthe last 95, in the last three
million years, they have barelychanged, and that's fascinating
(34:54):
for bacteria, because, as youknow, bacteria mutate and adapt
all the time, right, which thenleads us to believe that, okay,
they're pretty supremely adaptedfor this environment, and part
of that environment includes ourdigestive tract.
William Davis, MD (35:08):
Have you had a chance to explore the change
in microbial composition in theGI tract with implanting
Bacillus coagulans and Subtilis?
Kiran Krishnan, PhD (35:18):
Yeah, so actually that was one of the
papers we published that Ithought was the most fascinating
.
We had a hypothesis becausethere was a lot of studies
before that done by other peoplesince the 1950s showing the
competitive exclusion capabilityof the spores.
Right, you could put the sporesnext to a pathogen.
They're going to reduce theamount of the pathogen through
(35:40):
one mechanism or the other.
Actually, there's a fascinatingstudy that we did ourselves
with Cleveland Clinic on C diffthat I'll mention after this.
It just speaks to the utilityof the spores, their arsenal of
capabilities that they have.
But we saw that and we said,okay, they're quorum-sensing
microbes, they can identify andbring down dysfunctional
(36:01):
bacteria.
Maybe they can do the oppositeand bring up beneficial bacteria
.
And so we did a SHIME study on asomewhat dysfunctional
microbiome that had very lowkeystone species.
So this uh, many of the uh, theindividuals had, um, almost no
detectable acromantia, lowbifidol longum, low bifidol
adolescentes, low uh, fecal andbacterioposnitza and so on, um,
(36:26):
you know, low and no root array.
Of course nobody has root arrayanymore.
Uh, we, we basically uh,somehow eliminated that that
very, very important strain outof our normal guts.
And so then what we did is wetook, okay, normal diet three
weeks.
Look at changes on the gutmicrobiome no real changes,
nothing dynamic.
(36:47):
And then we startedsupplementing with spores, and
what we saw at the end of thethree-week period and this is
using a Simpson diversity index,which is one of the very
accepted diversity scoringmechanisms for the gut we saw
almost a 30% increase indiversity, right, which is
fascinating.
Now the first question mostpeople ask is okay, we know,
(37:09):
diversity is the number ofviable organisms, but the index
also looks at uniformity of theorganisms.
Right, you might have 700species in there, but if 100 of
them make up 90% of thepopulation, your diversity score
is still going to be low.
So the index looks at both thenumber and the uniformity.
So we can increase diversitynot only by having more viable
(37:33):
species, but also improving theuniformity of the ecosystem,
which then stabilizes theecosystem more, makes it more
resilient, because it createsmore competition, right, which
is a good thing for anyecosystem.
And so what we saw, though thatwas fascinating, was that the
uniformity was increasing.
So, to a certain degree, thespores were kind of going hey,
(37:54):
these guys are too low, theseguys are too high, we're going
to modulate their levels to acertain degree and I think, as
the spores start to do that, itcreates a rolling effect where
the other microbes then start torebalance themselves out.
We know that many of thekeystone species play a role in
balancing and creating stabilitywithin the microbiome.
So, let's say, the spores evenincrease one or two keystone
(38:17):
species, then they start to takeover the job of creating
uniformity and stability in themicrobiome.
But we also saw microbes thatwere not detectable in the
baselines that were now presentat really high levels.
Right, acromantia is one ofthem.
Now some people say, well, okay,well, where did that come from?
Because you didn't put it in.
Now some people say, well, okay, well, where did that come from
(38:38):
?
Because you didn't put it in.
Well, then it becomes importantto understand how some of these
genetic analysis work.
Is that anytime you're doing astool genetic analysis, you're
really looking at a probabilityof finding an organism, right?
Because organisms aren't uniformin any sample, and so if an
organism is very prevalent,there's a high chance that if
you take three or four samples,you're going to find the
(38:59):
presence of that organism in atleast two or three of those
samples right.
But if an organism is so low inits prevalence, then you take
three or four samples, there's alower chance that you will even
pick it up in that samplingright, because you're not
sampling the entire stool mass.
And so what we hypothesize isthat likely in these cases where
(39:20):
there was no detectableacromantia and then all of a
sudden we see 10 to the 8, 10 tothe 9 CFUs per gram.
Is that acromantia was alwaysthere?
It was just at such low levelswe couldn't even pick it up.
The probability was too low,presuming that if we sampled
enough we would find it.
But the level was so low thatnow the spores and the changes
in the microbiome increased itsprevalence so much that now we
(39:43):
have a much higher chance ofpicking it up right.
So we do see this amazingdramatic increase in keystone
and other beneficial species anda general increase in diversity
and, if I can make a point onthat, competitive exclusion with
C diff.
This is fascinating and this isa study done by Gail Cressy at
(40:05):
Cleveland Clinic, and shepublished two studies on this.
So what we took?
She has a very well establishedC diff model in mice.
She was one of the few peoplethat can stabilize C diff for
long-term infection in mice and,as it turns out, one of the
ways she does it is by actuallytreating the mice with
vancomycin, funny enough.
(40:26):
So you use the treatment for Cdiff and it makes the mice more
susceptible for long-terminfection of C diff.
So she treats the mice withvanco, she then inoculates them
with C diff and then shestabilizes the infection over a
short period of time.
Then she can add in any othersubstrate.
So then she added in the sporesand what she found was a
(40:51):
dramatic reduction in the amountof C diff in these animals,
especially when using antibiotictreatment as another arm.
We could reduce the level of Cdiff as much as an antibiotic
can, but what she was able todiscover was a mechanism by
which the spores went after Cdiff.
Right.
(41:11):
So spores can produceantibiotics.
We know that they can produceantimicrobial antibiotics in
their little microbialenvironment which can bring down
certain bacteria.
They produce things likesubtilisin and so on.
Now, clostridium is also aspore former, so they likely can
be resistant to antibiotics.
(41:31):
So the spores don't useantimicrobials to go after
Clostridia.
What they did is theyeffectively surround the
Clostridia, like kind ofcircling the wagons around them,
and they produce a chelatingagent to starve the Clostridia
of iron.
And we know that Clostridia,like many pathogens, require
(41:52):
iron as part of its metabolicprocess, right?
This is part of why Clostridiaeats through your tissue to get
to the blood, right, and peopleget bloody diarrhea, and so
Clostridia is looking for iron.
The spores are starving it todeath by keeping iron away from
it, by chelating the iron.
Right?
That's just the mind-bogglingbrilliance of nature.
(42:15):
Right, we can't engineerbacteria to do this, no matter
what our budgets are and howmany brilliant researchers you
give us.
That's where a lot of myphilosophy around research and
therapeutics and all comes fromis.
A lot of these things havealready been figured out by
nature.
We just have to be smart enoughto know where to look and
verify that it's working andthen utilize it Right.
(42:36):
And so, yeah, it's fascinatingthat these microbes can adjust
our microbiome better than wecan try to do it ourselves.
That's fascinating.
William Davis, MD (42:48):
I know you're a lover of spore formers.
Have you had a chance to workwith any of the beneficial
clustering like Bitericum?
Kiran Krishnan, PhD (42:56):
I have.
Yeah, so we actually worked witha couple the beneficial
Clostridia like Butyricum I have.
Yeah, so we actually workedwith a couple of other species.
One of them is a it's aButyricicoccus polycecum.
And then the ClostridiaButyricum is another one that I
think is a fascinating organism.
You know, I would say that themajority of Clostridia you find
(43:16):
in your gut are probablybeneficial, and we know many of
them are very important forproper immune function.
But we did work with thebutyricum and the butyricicum,
which is another genus, all ofthem because we're working on
metabolic health and we'retrying to see okay, how do we
(43:37):
naturally increase butyrateproduction in individuals?
Right, Because of course, thatgoes a long way for diabetes and
weight management and all that,but then also it plays a
significant role in dealing withreally inflammatory conditions
in the gut like IBD.
So I've had a chance to workwith Clostridia as well, and I
think it's a fascinating,amazing organism.
(43:57):
We didn't end up coming outwith the commercial product.
We had it in the pipeline,though, but I left before we
could come out with it as acommercial product.
William Davis, MD (44:10):
Any thoughts or opinions on what's going on
in the Akkermansia world?
Kiran Krishnan, PhD (44:15):
Yeah, you know it's fascinating, right?
So a lot of people ask me aboutthat because of course, there's
a brand that's done a reallygood job from the marketing
standpoint of really talkingabout Akkermansia.
Now, I've been talking aboutAkkermansia for a long time
because there's clearly somereally good population
(44:35):
longitudinal data showing acorrelation between good levels
of acromancia and protectionagainst metabolic syndrome and
lots of things under thatmetabolic syndrome umbrella.
I do believe it's an importantkeystone species that is likely
low and missing in many missingand when I say missing I
(44:56):
typically mean not detectable,so at such low levels that it's
not functional in manyindividuals.
When I was at Microbiome Labs,I think we had done somewhere
around 15,000 to 20,000 stooltests in the US, and so I had a
good sense of the collated dataand we would always, I'd say I
would say 60, 70% undetectableAkkermansia in individuals,
(45:20):
right?
So I think it's such animportant microbe and I think a
number of our behaviors makesense in why Akkermansia itself
would be low.
I think number one is we'reoverfed, right, Akkermansia is
one of those microbes that tendto do well in a fasted state.
Number two Akkermansia doesreally well with polyphenols,
(45:43):
right.
It's really good atmetabolizing polyphenols, and
these are colored fruits andvegetables and certain types of
nuts that have a lot of agalicacid and so on.
So things like almonds andmacadamia nuts and so on, we
don't consume those things right.
We consume processed foodmostly.
So Akkermansia doesn't have thefood that it needs and we're
(46:03):
overfed, so it doesn't haveenough period of time to do what
it's supposed to do as amucinophilia microbe and live in
the mucus and eat off the mucusto some degree.
So I think it makes sense whyour numbers would be low.
Then the question I get is canyou supplement with Akkermansia
right?
To me, that's where it becomesreally, really, you know,
(46:27):
questionable.
Because Akkermansia is anobligant anaerobe right.
Oxygen is basically toxic to it, same with the polycecum
microbe that we worked with.
There's lots of microbes thatare obligate anaerobes 15
seconds of oxygen exposure andthey could be dead.
And so can you actually grow ananaerobic bacteria in a
(46:52):
facility?
Because you can build ananaerobic facility we did that
at a pilot scale to growanaerobes but then you have to
encapsulate it in an anaerobicfacility.
You have to store it, ship it.
Everything has to be anaerobicright or it's going to be dying
in the bottle and then themoment you consume it.
Akkermansia was never designednaturally to go through the
(47:14):
digestive tract over and overagain, especially not a mature
digestive tract like an adultdigestive tract that has lots of
acid in the stomach and bilesalts and all the gauntlet that
microbes have to go through.
So I don't think you areengrafting or inoculating
yourself with Akkermansia whenyou take the supplement form.
(47:34):
With Akkermansia, when you takethe supplement form, I think
there could be some metabolicresponse based on what may be
receptors or stimuli on theouter membrane of the
Akkermansiaa cell when it diesand goes in, and I think the
company has shown somebeneficial effects.
They're pretty minor but theremay be some beneficial effects.
(47:56):
But to me, when it's a keystonespecies and it should be there
in your gut, we should alwaysfocus on how do you grow it
endogenously right?
How do you increase your ownacromantia?
And that to me, is a reallyimportant thing and I've put out
a few videos on this sayingthat hey, there's data showing
(48:18):
polyphenol intake increasesAkkermansia.
Fasting increases acromantia.
Exercise increases Akkermansia.
Increasing diversity in generalincreases Akkermansia.
So instead of taking what wouldbe, you know, the perceived
shortcut of going, I'm justgoing to try to take this as a
supplement and hope that this isengrafting in my gut.
(48:39):
I would rather see people youknow try to grow their
endogenous levels, especiallywith the large bowel anaerobic
microbes they're just so hard totake as supplements?
William Davis, MD (48:52):
Mind if I ask you a personal question.
Yeah, I mean, everyone knowsyou're a microbiologist and how
do you manage your intake foryou and your family of fermented
foods?
Kiran Krishnan, PhD (49:04):
Ah, okay, so we don't eat it as regularly
as I would probably like to.
So I grew up in India andMalaysia and in both cultures
fermented foods are a staplepart of your diet.
Right In India, most of thebreads and all that are made
from fermented flour.
There's lots and lots ofdifferent fermented dishes that
are commonplace, so fermentedfoods were a normal part of my
(49:28):
diet.
Now, moving here, it becomeshard, because one to really get
the benefit to me out offermented foods is you should be
doing the fermentation yourself, right, I've I found very
little benefit in grabbing whatis a fermented food out of
grocery store shelves because inmost cases you know they're not
(49:49):
taking the fermentation to its,to its ultimate end, where it
should be taken to, because ofcourse economically that's not
viable.
You look at the kombuchas on themarket.
They cut the fermentation shortby 50% at least, right, and
then, and also the flavorprofile of a fully fermented
product is probably not broadlyappealing, so they cut it short,
(50:09):
they add sugars and flavors andthings like that, and so it's
less desirable.
And so I've always looked at OK, can I do some of my own
fermentation and make it easy,make it not something that's
been overwhelmingly difficult todo.
So I started with fermentationwith the spores.
(50:31):
What we did is we bought theseregular old jars right that can
do anaerobic fermentation and westarted this about eight, nine
years ago.
So I fill the bottom third ofthe jar with fruits you know
things that have good amount ofsugar, so so berries and
(50:51):
pineapple and things like thatMash it up just a little bit and
then I add about a tablespoonof sugar and things like that,
mash it up just a little bit andthen I add about a tablespoon
of sugar and then the other twothirds.
I add water and then I add somebacillus spores, normally
subtilis and or subtilis andcoagulants.
You mix it up and you let itsit on the counter and normally
in about three or four days youstart to see a little bit of
(51:13):
bubbliness and things like thatto it.
It becomes a nice littlefermented beverage that we've
enjoyed.
So I've been able to do thatfrom time to time.
But actually in our lastconversation with your
recommendation for using root toferment the yogurt, that's
something I've been able to doand that's been super easy but
(51:33):
also really beneficial.
So that to me was one of theeasy things to do and you know
that gives you the closest thingyou're doing as home
fermentation and you'recontrolling what all is going in
it, and you know you do it, andyou do it at your own pace and
leisure.
So that's the extent of thefermentation that we do.
(51:54):
I would love to be able to dosome natto or sauerkraut or
kimchi on my own, but we justdon't have the time to do it.
You know I wish we did but wejust don't.
Yeah.
But the yogurt fermentation,though, with the root rice, is
phenomenal because it's easy andit doesn't take much and it
(52:15):
tastes good.
William Davis, MD (52:17):
Can you share what kind of experience you and
your family have had with it?
Kiran Krishnan, PhD (52:21):
Yeah.
So my my reason for wanting todo it was twofold, actually
threefold.
One was you know ourconversation about the emotional
impact that rooterai has, right, that bonding.
I actually think the work thatI was able to learn from the
(52:42):
researcher out of the APC inIreland his name is skipping me
now but he's done a lot of workwith the tribes near New Zealand
and Australia, the Papua NewGuinea tribes, right and he's
looked at ruderi Ruderi is oneof his favorite things and one
of the things he's noticed aboutthose tribes is that they tend
(53:05):
to have very high levels ofruderi and they have very high
bonding.
They have very high expressionof oxytocin and Westerners we
tend to have very low expressionof oxytocin and so to me that
hormone is so important in termsof the stability, emotional
(53:25):
stability, in a household withthe family, right.
That was one of my goals andone of my targets.
The second thing was weightmanagement.
We all always have to look atweight management.
I think root or rye plays animportant role in helping with
digesting resistant starches andthings like that right to get
(53:46):
more benefit out of them.
So feelings of satiety andmaybe even increasing fat burn.
And then the third thing wasreduction in bloat after you eat
.
Right, I think through ourconversation I had recommended
to a number of people who haveSIBO that, hey, they take a
really high root-oride dose.
They do some of it fermentation, some of it through
(54:09):
supplementation, and normallywhat people report is they see a
lot of reduction in the bloat.
Normally what people report isthey see a lot of reduction in
the bloat.
So those are the threemotivations and I could say and
this is just you know our ownNF4 study that certainly the
emotional aspect is improved.
(54:29):
Right, you notice that younotice a different type of
bonding.
You notice a differenttolerance, I would say, for the
things that you would normallybe irritated of with your family
members.
You know the things thattrigger you.
Your tolerance level for thosethings tends to improve.
And then the other side of itfor me, the bloat.
(54:52):
Especially when I eat certainfoods, like if I have a big
Indian meal right and I'm eatinglots of bread and naan and rice
and all that, I tend to feelreally full and bloated after
that.
That reduces quite dramaticallyif I take a high dose of either
the root-or-iron capsules orthe fermented product afterwards
and, funny enough, one of thestaples in India is, after a big
(55:17):
meal, you eat curds, right, youeat fermented dairy, and that
is a way of settling the stomachand reducing the bloat and the
discomfort.
And you walk right, that's whatthey do.
They go for a walk and they eattheir curds and it's kind of
the same thing the fermenteddairy here in this case and it
really helps through the gut.
So that's been our experience.
(55:39):
The emotional part is reallyfascinating to me, you know.
I think that that's afundamental issue in society
today is you mix a reduction inthe bonding and love hormones
that people can produce and thenyou add anonymity through
social media and all that.
You're going to get the worstout of people, right, because
(56:01):
now they don't have the judgmentof society the same, because
they can be anonymous with theirtrolling comments and all the
crazy things that people do andsay, right.
So I think that's a fascinatingarea and I think that's one
area that I would love to seemore research on.
William Davis, MD (56:19):
Dr Krishnan, I will take it away your time.
Always a pleasure.
I learn a hundred new thingsevery time I hear you speak and,
as you know, this is a reallyexciting time.
It's like AI and changingtechnology.
Microbiome is changingeverything and I hope I can
interest you in coming backagain everything and I hope I
can interest you in coming backagain.
Kiran Krishnan, PhD (56:39):
I would love to.
I've always been a fan of youand your work and your teaching
and all that, and I think whenwe met recently, over the last
year, I'd mentioned to you.
We met briefly when you did alecture at a conference, I think
maybe 10 years ago, and maybeyour first book was just out at
the time and I'd always admiredthe work you've done in
(57:00):
educating people and all that.
William Davis, MD (57:01):
So it would be my pleasure to come back.
Kiran Krishnan, PhD (57:03):
So yeah, absolutely.
Thanks, Kiran.
In this episode of the Defiant Health
Podcast, I have a special guest,someone you might already be
familiar with, as he has beenprolific in providing education,
built a successful companycalled Microbiome Labs and is an
active researcher in studyingmicrobiome issues.
Our guest is Dr Kiran Krishnan,who has gained an international
reputation for innovativethinking on microbiome issues,
(00:29):
pioneering, for instance, thescience and application of
spore-forming microbes studiesthat have shown that such spore
formers can reduce endotoxemia,minimize the damage done by
antibiotics and increasesmicrobial diversity.
In this interview, dr Prishnantells us about a novel approach
to skin health he and his teamhave developed, and later in the
(00:51):
podcast I'd like to tell youabout Defiant Health's sponsors
Paleo Valley, our preferredprovider of many excellent
organic and grass-fed foodproducts, and BioDequest, my
number one choice for probioticsthat are scientifically
formulated, unlike most othercommercial probiotic products
available today.
(01:11):
Dr Krishnan, thank you verymuch for joining me in this
Define Health podcast.
I know you're doing a lot ofwork and off-camera.
You mentioned to me that you'regetting involved in the skin
microbiome.
Could you tell us more aboutwhat you're doing?
Kiran Krishnan, PhD (01:26):
Yeah, absolutely Well.
First of all, thank you so muchfor having me.
Your early books were some ofthe things that really got me
inspired to put more focus inthe microbiome.
So you know the wheat belly andso on, and Supergut is a
fantastic book.
So thank you so much for havingme.
It's exciting to be here.
(01:47):
So the skin microbiome is suchan interesting area, right?
So I've been working on the gutmicrobiome for more than a
decade, probably published maybe18 or 19 research papers
associated with the gutmicrobiome.
And then you know, as you startthinking about the gut
microbiome and what thatecosystem looks like, how
(02:08):
complex it is, but more so, howmuch the function of the organs
are determined by the types ofmicrobes that exist in the organ
, right, we know, for example,the small bowel completely
changes in how it functions.
If you have dysbiosis in thesmall bowel, you have microbes
in the small bowel thatshouldn't be there in the case
(02:29):
of SIBO, whether they come fromthe mouth or different areas, it
completely changes how thesmall bowel functions, and then
the small bowel no longerfunctions the way it should, and
that's true for throughout thewhole gut, the stomach as well,
and we know that, you know.
So then we started thinkingabout the largest, what should
be the largest organ of the body, the skin.
And is the skin a risk factorin chronic disease?
(02:54):
And that has been a questionthat's been on my mind for some
time.
We know that the skin has avery complex ecosystem.
We know that there are upwardsof a thousand different species
that can exist on the skin.
We know that different parts ofthe skin have very different
ecosystems.
So the face, a sebaceous arealike the face, where you have a
(03:15):
lot of anaerobic environments,high oil and so on, compared to,
say, the forearms and the legsthat are much drier.
They're very differentorganisms, very different
ecosystems and thereby differentfunctionality on the skin.
And at the end of the day, oneof my questions has been how
much does the microbe populationon the skin impact the function
(03:37):
of skin?
And the function of skinprimarily is a barrier, right?
That's one of the largestbarriers in our body and it's a
different barrier than the gutbarrier in that it's less
dynamic.
The gut barrier has to let alot of things through that need
to get through, but then ofcourse, cinch up a little bit to
prevent things that shouldn'tbe going through.
But the skin largely acts as afirm barrier.
(04:00):
It doesn't let a lot of thingsthrough, if anything, a few
things maybe.
But that barrier functionbecomes really important.
And then I came across thisfascinating study called the
Baltimore Longitudinal Study onAging.
And this was a fascinatingstudy because, you know, it was
the first time where they tookindividuals when they were young
(04:23):
, in their early late 20s toearly 30s, and these researchers
decided, you know what, insteadof aging studies where we take
an older cohort and compare themto a younger cohort and look at
differences, let's just takeeach individual and follow them
for the next 50 years.
Right, and that's fascinatingbecause it really gives you now
(04:43):
a whole different picture.
Because if you take80-year-olds today and compare
them to 30-year-olds today,those 80-year-olds went through
a very different life and systemand ecosystem than the
30-year-olds have been goingthrough.
Right, when they were 30, theworld was a very different place
and their environment was avery different place.
A very different place andtheir environment was a very
(05:06):
different place.
And so using each individual astheir own control seems to be a
really, really interesting wayof studying aging, because you
can follow that individual andother individuals that are
similar to them and look at alltheir choices and the things
that change within their systemand how that impacts risk, and
one of the things that they'veconcluded is that aged skin was
(05:28):
an independent risk factor forchronic disease, and these are
diseases distilled to the skin.
So these are things likeosteoporosis, alzheimer's,
dementia, cardiovascular disease.
Aged skin is a risk factor, andthese researchers were able to
use skin health and thecondition of the skin as a very
(05:49):
accurate predictor of morbidityand mortality in individuals,
and so that became reallyfascinating to me, because then
the dots started to connect,going okay, so as skin ages and
loses its barrier function, it'snow acting as a risk factor for
chronic disease.
(06:10):
This sounds very similar to thegut, right?
As your gut becomes moredysfunctional and loses its
barrier capabilities, you getleaky gut, which then becomes a
risk factor for disease.
In the case of the gut, it'sthe microbial dysbiosis that
leads to the dysfunction.
In the case of the skin, it'sthe microbial dysbiosis that
leads to the dysfunction.
In the case of the skin, it'sgot to be the microbial
dysbiosis as well.
So that's when we starteddigging in, going oh wow, it is
(06:33):
because there's a lot of reallystrong correlative data, some
causative data that shows thatcertain changes on skin microbes
affect the function and thestructure of the skin, and that
to me becomes really interesting, beyond the cosmetic aspect of
it, because it's an independentrisk factor.
William Davis, MD (06:53):
Any notions?
What exactly is being mediatedin the crosstalk between gut and
skin?
Kiran Krishnan, PhD (06:59):
Yeah, so from the gut skin component to
it, and so there's the skin,skin, what's happening between
the microbes on the skin andthen the resulting immune
responses in that local region.
But then there's also what ishappening between the microbes
in the skin and the gut, and thegut, of course, then dictates
in large part how your immunesystem responds to things right.
(07:21):
So one of the dots that we'vebeen able to connect is when you
look at inflammatory conditionson the skin, things like
dermatitis, different forms ofdermatitis, whether it's atopic,
or a different version or evenpsoriasis, or even acne skin,
where the immune system isplaying a role in driving the
(07:44):
inflammation and then, as aresult, driving the damage to
the layers of the skin, right,that we then can see the
comedones that are developing inthe case of acne are
inflammation and filling in ofthe pores with immune responders
, and all that, and then samething with dermatitis and
psoriasis, and all the rednessand dryness of the skin, is a
(08:07):
result of the immune systemfunctioning there.
Then the question becomes okay,why is the immune system going
there and why is it doing that?
Well, to me, it seems likethere are two things that need
to happen for an eczema-likeresponse on the skin or a
psoriasis-like response, or evenan acne-like response on the
skin.
Number one there has to be atrigger on the skin that causes
(08:30):
the immune system to need torespond to that area.
Right, and often that triggeris microbial dysbiosis.
Now, if you have, for exampleand this is why they've shown
lots of very strong correlativedata that staph aureus
overgrowth in certain regions isassociated with dermatitis,
psoriasis and so on, in the caseof the face, cutibacteria and
(08:51):
magnesis is associated withincreased risk for acne
development, right, so there arethese opportunistic or
pathogenic-like organisms thatare present in the regions where
these lesions develop, whichmeans that they are likely
triggering the need for theimmune system to respond.
And then, sure enough, when youdig into the literature, it's
(09:11):
true, they're immunogenic, theyproduce toxins, they produce
things that cause the immunesystem to respond.
But why is it that the immunesystem is responding in such a
way that it causes all thisdamage to the skin?
Right, the redness, theinflammation, the dryness and
all that?
Well, that's because the gut isalso dysfunctional in many of
these individuals, which meansthey've got an immune system
(09:34):
that doesn't have propertolerance messaging.
Right, they're not expressingTregs very well, the T
regulatory cells.
They're not expressing IL-10very effectively, right, they're
not expressing the regulatorycomponents of the immune system
that don't allow the innateimmune responses to overreact,
and so they tend to have animmune system already that's
(09:57):
overreactive to things.
So they may be histamineintolerant, from histamine from
foods, for example.
They may have environmentalallergies, they may have chronic
sinusitis, they may have lotsof things where the immune
system seems to be overreactingin response to stimuli.
So these individuals have thatdouble whammy They've got a
microbe that's causing an immunetrigger on that part of the
(10:18):
skin and they have an immunesystem that tends to go full
inflammatory, isonophilic,basophilic, inflammatory-type,
damaging response, right.
So they have the best of thosetwo.
And I compare it to individualsthat don't have the second part
.
They don't have an immunesystem that is very
pro-inflammatory, very IgE, veryisonophilic, basophilic type
(10:42):
responder.
The difference between thosetwo individuals is one could get
staph aureus or get a physicalstimuli.
I give people an example of somepeople who wear a backpack all
day and wherever the straps havebeen rubbing they get super red
and itchy and inflammatory.
What's the difference betweenthat individual versus someone
that can wear a backpack and befine all day?
(11:03):
Well, that's the immune systemresponding to that rubbing.
Right, we call it contactdermatitis, right?
Contact dermatitis is just well, your skin rubbed against
something and was irritated.
Your immune system responded ina very inflammatory manner.
Now you have dermatitis and thedifference there is that the
individual that doesn't get thatdermatitis has a well-tolerant,
(11:26):
well-balanced immune responsebecause their gut is healthier.
The other individual doesn't,right?
So that double whammy, I think,seems to be driving a lot of
this.
William Davis, MD (11:36):
So if the skin microbiome can be the
initiating factor, are you anycloser to a microbial solution?
Kiran Krishnan, PhD (11:44):
Are you any closer to a microbial solution?
Yeah, that's a great question.
So we developed this quorumsensing product to effectuate
(12:07):
the population of microbes bydirectly competing with or
producing compounds that inhibitthe growth of dysfunctional
microbes and or enhancing orproducing compounds that enhance
the growth of beneficialmicrobes.
On top of that, some of thesequorum-sensing microbes also do
a great job of recruiting theimmune system in the right way
to flag and deal withproblematic microbes, right?
So the class of microbes thatwe worked on in the gut for a
(12:30):
number of years in that are thespores, the Bacillus endospores.
Now, bacillus endospores arefascinating because we have a
long history with them, right,we've co-evolved with these
organisms because they're prettyubiquitous in the environment.
Some of the early recordings ofthe use of Bacillus endospores
(12:50):
for quorum sensing comes fromthe 1950s, for example, when the
German army was in North Africain World War II, a lot of the
soldiers were dying and gettingsick from dysentery, more so
than the war, and one of thethings that they observed was
that the locals, when they wouldget an upset stomach, would
(13:11):
actually seek out and eat driedcamel dung as a therapeutic to
help the gut, right?
So then, research studiesstarted in the late 1940s, early
1950s to look at what's in thiscamel dung that actually seemed
to be helping with gutinfections.
And what they found out wasthis Bacillus subtilis, a
(13:33):
quorum-sensing, competitiveexclusion microbe that was
coming out through the stool inthese camels that were
ubiquitous in the environment.
If you consumed enough of it,it would actually seek out and
identify the dysfunctionalmicrobes and bring their numbers
down specifically.
So Sanofi Aventis, apharmaceutical company, launched
(13:56):
that product as a treatment fordysentery in 1952.
And that product is still inthe market today as a treatment
for traveler's diarrhea,dysentery, chronic upper
respiratory symptoms and so on,and it's called entro germina
and that product has been in themarket now for well over 60
years as a prescription drug inEurope, latin America and so on.
(14:19):
So Bacillus has this longhistory of being able to read
other microbial signatures,identify dysfunctional microbes
and then bring their numbersdown.
We published a couple of studieslike that on the gut.
So it got me to thinking OK,bacillus is pretty ubiquitous.
We find it on our skin, we findit everywhere.
Maybe they can do the samething on the skin.
And so we developed a productwith a specific carrier that was
(14:43):
skin memetic, so it didn'tinterfere with anything with the
skin.
And then we put two bacillusendospores in it, a coagulant
and a subtilis, and we starteddoing some studies on it.
We started with some initialskin swabs on people with acne.
So we would see really highcutibacterium magnesis in these
individuals right.
So they have inflammatorylesions all over the forehead.
(15:05):
You swab the forehead, they'vegot 80% cutibacterial magnesis
and of course that's why theforehead looks the way it does.
Then they start applying thisquorum sensing serum on their
forehead once a day.
In 14 days, 21 days, you know,60 days, and so on, we took
samples and what we saw was adramatic reduction in the
cutibacteria magnesis and, as aresult, the lesions go down as
(15:28):
well.
So the first individual that wedid this with, in a 30-day
period we saw more than 50%reduction in inflammatory
lesions and the cutibacteriamagnesis went from almost 80% to
about 30% prevalence on theforehead right to about 30%
prevalence on the forehead right, and so we started.
Then a whole other thing We'vejust completed 317 subjects on
(15:50):
acne and inflammation.
We saw the same thing.
So the product is actuallycalled this.
It's called Sib.
Oh, where is that camera?
It's a we call it a biomebalancing serum, because what
we've been able to show is thatwhen you add the spores onto
your skin just once a day, theyseem to effectuate change.
Now we don't know exactly whatmechanism they're doing the
(16:14):
change through.
That's going to require morestudy but we know the change is
happening and we know that theskin is improving dramatically
as well.
William Davis, MD (16:24):
Is it you're thinking that you apply this as
a spore and it germinates on theskin?
You know.
Kiran Krishnan, PhD (16:30):
I would hesitate to think that it
actually germinates on the skin,because we know that spores
themselves are immunogenic andeven as a spore, even though
they're not metabolically active, they do have receptors that
are expressed on the outer sporecoat that on its own can
modulate immune responses in agiven area.
(16:51):
We actually, a long time ago,while we were working on the gut
, did a simple study and lookingat quorum sensing and
competitive exclusion.
For those that are listening,competitive exclusion if you're
not familiar with it, that meansone microbe competing with and
thereby eliminating anothermicrobe, right?
Spores do this really wellagainst pathogens.
(17:12):
And so we did a competitiveexclusion study on the surface
of a cell phone, right, becausewe know that cell phones are
probably one of the filthiestthings we all have around us,
right?
There's so much fecal matterand other things on it from
everything that we touch andother people touch, and we set
it down everywhere.
And so we took a couple of thespores and we just mixed it in a
(17:34):
little bit of water and a tinybit of alcohol and we swabbed a
couple of phones with it, andthen we did kind of before and
after swabs of the phone.
After about a week we foundcompared to phones that were
handled in very similar waysthat did not have the spores on
it.
The ones that did had muchfewer environmental and
(17:55):
pathogenic organisms on it.
So the spores somehow preventthe establishment of pathogenic
organisms, even on an inanimatesurface like the phone.
And so then it starts thinkinglike okay, maybe there are some
ways in which the spores, evenin the spore form, can
(18:16):
effectuate biofilm formation andso on.
Right, we know they themselvesare good biofilm producers.
They produce enzymes that canbreak down other pathogenic
biofilms.
So that part of the mechanismto me is very fascinating.
I would guess that the sporesare not necessarily germinating
(18:36):
on the skin and living on theskin, because what's interesting
about the skin swabs is we add,you know, a billion or so CFU
to the skin once a day in agiven area like the forehead.
You would think in seven days,once we swab to look at the
changes in the microbiome, we'dpick up a lot of bacillus.
But we don't.
(18:57):
So we hardly pick up anybacillus at all, which means
that they're not actuallyhanging out on the skin.
They're there for a period oftime and I think they transit,
they leave the skin, but theyeffectuate an immunological
difference or they may affectsomething like staph epidermidis
, which is a good beneficialbacteria, because we do see the
beneficial bacteria on the skinincreasing in growth, right.
(19:20):
So some really interestingthings there.
Now you go back to theevolutionary biology
significance of that and itcomes back to like, well, the
benefits we all know being inthe outside environment playing
in the dirt, you know gettingdirt on us, desert dust blowing
across different parts of Europeand the ability of the desert
dust to sit on the skin andprovide some transient microbes
(19:42):
to the skin that can effectuatechange.
So I think a lot of thosethings kind of help explain some
of the empirical value of doingsomething like this.
But we're super excited to keepdigging into the research.
The next phase of research withthis because we've gotten a lot
of empirical reports on this isage-related changes.
So one of the things that a lotof people have reported we
(20:05):
probably have 30 cases on it atleast on dramatic reduction in
fine lines and wrinkles in ashort period of time and
improvements in the tone of theskin.
So hyperpigmentation of theskin and what people are
expressing is texture of theskin.
So one of the things we knowthat occurs over time, if you
(20:26):
look at the topography of theskin, the pores start to
increase in size, right, so theybecome more visible, and then
the skin looks like it's notsmooth anymore.
It doesn't have that nicesmooth, baby-like texture,
because our pores become biggerand you see more creeks and
valleys and things like that.
So we're starting to see peoplereporting uniformity on the
skin as well, and the microbesmust be making that change.
William Davis, MD (20:52):
I recognize this is not a drug, but do you
plan to explore other conditionslike psoriasis or rosacea?
Kiran Krishnan, PhD (20:59):
We are.
Yeah, we actually have a coupleof conditions that, in speaking
with dermatologists, friends ofmine, are difficult to treat.
So one of them and this is acondition that seems to have
popped up in higher prevalencesince the pandemic and it may be
related to people wearing masksall the time.
But perioral dermatitis, thatseems to be something that a lot
(21:21):
of people are struggling with.
You know, and my dermatologyfriends tell me that it's really
hard to treat.
They use a lot of steroids,they go through Nystatin and
different antibiotics and manyof these patients they seem to
be pretty resilient.
We've done a few cases withperioral dermatitis and it seems
to dramatically help.
(21:42):
And then we also have done anumber of cases with just your
standard eczema, you know, andwe also have done a number of
cases with just your standardeczema.
You know your run of the milleczema dry, flaky, red,
irritated, itchy skin.
We're seeing a much higherprevalence of that now in kids,
(22:09):
you know, and you know that ifyou're, if you've got a five,
six year old with eczema andyou're treating their skin with
steroids, long term it's goingto impact the structure of that
skin right.
That area of the skin willbecome thinner, like most people
say, there'll be a lot of moreinflammatory response in that
area.
There's some rebound responseswith steroids and all that.
So one of the things we want todo is provide parents with
something else they can look atand do to try to help that.
So I think we would stick withthe kind of cosmeceutical route.
(22:31):
We wouldn't look at doing adrug route with it, but it'd be
similar to, like you know,cerave, which is a lotion that
seems to be used quite a bitwith people with dermatitis
because of the additionalceramides that they've added in
there.
That can help.
So we'd look at doing somethinglike that ceramides that
they've added in there.
William Davis, MD (22:50):
That can help .
So we look at doing somethinglike that.
What's your suspicion?
If those two microbes thecoagulants and the subtilis
applied topically are beneficial, do you think there might be an
additional effect if takenorally concurrently?
Kiran Krishnan, PhD (23:01):
I 100% feel that that's true Now, because
in part because we've done anumber of case studies that way
as well.
You know, when I was atmicrobiome labs, one of the last
technologies I developed beforewe sold to Novozymes and then I
exited was a product calledSerene Skin, which is a specific
(23:21):
for spore formula.
That was for acne and forinflammatory conditions on the
skin.
In fact, we got issued a USpatent on it.
We've published two papers onit, one of the papers I think
you know don't quote me on this,but I think it's published in
the British Journal ofDermatology.
So a pretty high-impact paperand what we showed was that just
(23:45):
from oral consumption of thespores and these were a specific
formula to increase theproduction of acetate in the gut
, one of the things that wefigured out was that acetate
production, which is one of theshort-chain fatty acids, acetate
production in the gut is reallyimportant for skin health and
(24:06):
in part for people who are veryprone to acne.
And the reason for that isacetate seems to, of course,
leave the gut.
It's butyrate as opposed tobutyrate that stays
predominantly in the gut andfunctions in the gut with all
kinds of important things.
Propionate comes in and out.
Propionate also goes outside ofthe gut and functions in other
areas, but acetate seems to beable to build up in a good
(24:28):
amount and then leave the gutand function outside of the gut
and functions in other areas.
But acetate seems to be able tobuild up in a good amount and
then leave the gut and functionoutside of the gut.
We saw that acetate productioncan actually reduce the amount
of sebum that's being producedby the sebaceous glands and can
actually reduce inflammation inthe skin, and so we looked at
okay, what does the gut of acneindividuals look like?
(24:50):
And there's a lot of really gooddata showing that people with
acne tend to have lowruminococcus and low microbes
that produce acetate and otherforms of short-chain fatty acids
.
So we formulated this product,we created a version that can
create higher amounts of acetate, and what we saw in the 12-week
(25:10):
study that published was thatwe saw a 75% reduction in
lesions all lesions,inflammatory and
non-inflammatory in that 12-weekperiod, without the use of
antibiotics, and that's right onpar with any antibiotic that's
used for acne.
It's about 70% reduction inthat period of time.
(25:32):
So that was very exciting to us, and so then, when we first
launched SIV, what we did is wetook some of our estheticians
and skincare professionals andsaid do both Do the serene skin
orally and then do the SIVtopically, and then in some
cases just do one or the other.
And we always saw betterresults with doing them both.
Because I think it comes downto that modulating the trigger
(25:54):
on the skin right, thepathogenic organism, and then
also modulating the immuneresponse, and doing that through
the gut is the most effectiveway of doing it.
William Davis, MD (26:06):
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Listeners, now let's get backto our discussion.
Do you think that thesemicrobes, these spore formers,
(29:02):
take up residence in the GItract?
Kiran Krishnan, PhD (29:05):
You know we see that they do, but for a
short amount of time.
They're really interesting inthat in the gut modeling studies
that we've done we've used asystem called a SHIME system,
right, the simulated gastricsystem and it's really
interesting because it has allthe components of a digestive
tract, starting from the stomach, small and large bowel.
(29:26):
It has all the specificcomponents of those structures
and then it's inoculated withthe full human microbiome and
then you stabilize themicrobiome in there over a two,
three week period.
You continuously feed it foodlike you would an individual and
then it has a mucosa and animmune system and all that.
So you really get really greatinsights in what's happening
(29:47):
with the microbiome as you addsubstrates into the system.
So when we've done studies withthat, we've hit the system with
lots of spores and then we lookat the microbiome changes
throughout the small and thelarge bowel.
What we always see, no matterhow many spores we're given
whether we're dosing it at 5billion a day, 50 billion a day
(30:09):
didn't matter what we always seeis a certain threshold of the
spores that are reached in thatgut that doesn't get exceeded.
So the spores have their ownlimiting factor within the gut
right.
So in the gut, what we normallysee is around 10 to the 6 CFUs
(30:30):
per gram of stool right or pergram of you know, whatever we
pull out the titrate or whateverwe pull out of the gut.
So 10 to the 6, for people thataren't familiar is one with six
zeros right.
So it's not a lot of bacteria,but they don't exceed that level
in any given area, which isreally fascinating.
Even if we hit it with a lot,we actually just get more coming
(30:51):
out.
So the spores have a veryinteresting transient quality
where they do take up residencefor a period of time.
But then if you follow anyindividual spore, what it does
is it tends to take up residencein certain parts of the gut and
then re-sporulate and move onand then take up residence re of
the gut and then resporulateand move on and then take up
residence, resporulate and moveon.
(31:12):
We know, for example, that whenyou consume the spores in the
duodenum itself, the spores comeout of the spore state right,
so they're a vegetative cell inmuch of the duodenum and the
jejunum.
Then when they move to theileum, as they're kind of
tumbling through and they'rerolling through, they
resporulate in the ileum, whichis really fascinating, because
(31:34):
the ileum has that huge areacalled the Peyer's patches,
right, massive immune samplingarea, and in fact one of the
characteristics of the Peyer'spatches is that they're
dendritic cells, these immunecells that reach across the
lining and they grab ontocertain microbes and pull it
across and they can take thosemicrobes to the mesenteric lymph
(31:55):
nodes and then do things withthem that may be beneficial.
One of the microbes that we'vedone a lot of studies showing
that that happens is apsychobiotic, the Biflongum 1714
.
We can talk about that if wehave time.
But what we see is that thespores, if they resporulate, if
they leave the vegetative stateand become a spore in the ileum,
(32:18):
they're actually moreimmunogenic to the immune tissue
in the ileum.
They trigger more immuneresponses in a positive way.
They upregulate tolikereceptors, they upregulate Treg
and so on Pardon me a littledryness in the throat and so
they upregulate these immunefactors and then in some cases
(32:41):
they can actually getphagocytized or consumed by
dendritic cells and pulledacross and then transported to
mesenteric lymph nodes wherethey can upregulate the
proliferation of T cells and Bcells, which is fascinating,
right.
So they have a very interestinglife cycle throughout the GI
(33:03):
tract.
They enter then the large bowelstill in spore state, but then
by the time they move past thesigmoid they become a vegetative
cell again and then they spendmuch of their life in the large
bowel as a vegetative cell.
Within two to three weeks theytend to leave, and part of that,
I think, is their evolutionaryadaptation of being a ubiquitous
(33:27):
yet transient organism in lotsof different guts.
Right, they are what we wouldcall universal colonizers.
They're found in the digestivetract of virtually every animal
that they've been looked for,including insects, including
honeybees and so on.
They're in every mammal in thedigestive tract.
They come in through eating andinteracting with the
(33:49):
environment.
They do some things in the gutand then they leave through
defecation.
That's how they spread acrossthe globe.
There was a really fascinatingstudy on glacial ice cores and
these scientists took ice coresfrom the Tibetan Plateaus, from
the North Pole, from the SouthPole, and they take these, you
know, mile-long ice cores andthey can take slivers out of the
(34:10):
ice core to look at what was inthe environment during that
time.
That's now captured in the iceand they find that even three to
five million years ago thesebacillus endospores were
ubiquitous in the environment,even in the South Pole, north
Pole, tibetan plateaus and so on.
And the most fascinating partabout it is most of the strains
(34:31):
that they identified in theglacial ice cores that were
three, five million years old.
Not only were they still alive,they could still be plated, but
they had more than 95% genetichomology to the strains that we
have around the environmenttoday.
So they haven't changed much inthe last 95, in the last three
million years, they have barelychanged, and that's fascinating
(34:54):
for bacteria, because, as youknow, bacteria mutate and adapt
all the time, right, which thenleads us to believe that, okay,
they're pretty supremely adaptedfor this environment, and part
of that environment includes ourdigestive tract.
William Davis, MD (35:08):
Have you had a chance to explore the change
in microbial composition in theGI tract with implanting
Bacillus coagulans and Subtilis?
Kiran Krishnan, PhD (35:18):
Yeah, so actually that was one of the
papers we published that Ithought was the most fascinating
.
We had a hypothesis becausethere was a lot of studies
before that done by other peoplesince the 1950s showing the
competitive exclusion capabilityof the spores.
Right, you could put the sporesnext to a pathogen.
They're going to reduce theamount of the pathogen through
(35:40):
one mechanism or the other.
Actually, there's a fascinatingstudy that we did ourselves
with Cleveland Clinic on C diffthat I'll mention after this.
It just speaks to the utilityof the spores, their arsenal of
capabilities that they have.
But we saw that and we said,okay, they're quorum-sensing
microbes, they can identify andbring down dysfunctional
(36:01):
bacteria.
Maybe they can do the oppositeand bring up beneficial bacteria
.
And so we did a SHIME study on asomewhat dysfunctional
microbiome that had very lowkeystone species.
So this uh, many of the uh, theindividuals had, um, almost no
detectable acromantia, lowbifidol longum, low bifidol
adolescentes, low uh, fecal andbacterioposnitza and so on, um,
(36:26):
you know, low and no root array.
Of course nobody has root arrayanymore.
Uh, we, we basically uh,somehow eliminated that that
very, very important strain outof our normal guts.
And so then what we did is wetook, okay, normal diet three
weeks.
Look at changes on the gutmicrobiome no real changes,
nothing dynamic.
(36:47):
And then we startedsupplementing with spores, and
what we saw at the end of thethree-week period and this is
using a Simpson diversity index,which is one of the very
accepted diversity scoringmechanisms for the gut we saw
almost a 30% increase indiversity, right, which is
fascinating.
Now the first question mostpeople ask is okay, we know,
(37:09):
diversity is the number ofviable organisms, but the index
also looks at uniformity of theorganisms.
Right, you might have 700species in there, but if 100 of
them make up 90% of thepopulation, your diversity score
is still going to be low.
So the index looks at both thenumber and the uniformity.
So we can increase diversitynot only by having more viable
(37:33):
species, but also improving theuniformity of the ecosystem,
which then stabilizes theecosystem more, makes it more
resilient, because it createsmore competition, right, which
is a good thing for anyecosystem.
And so what we saw, though thatwas fascinating, was that the
uniformity was increasing.
So, to a certain degree, thespores were kind of going hey,
(37:54):
these guys are too low, theseguys are too high, we're going
to modulate their levels to acertain degree and I think, as
the spores start to do that, itcreates a rolling effect where
the other microbes then start torebalance themselves out.
We know that many of thekeystone species play a role in
balancing and creating stabilitywithin the microbiome.
So, let's say, the spores evenincrease one or two keystone
(38:17):
species, then they start to takeover the job of creating
uniformity and stability in themicrobiome.
But we also saw microbes thatwere not detectable in the
baselines that were now presentat really high levels.
Right, acromantia is one ofthem.
Now some people say, well, okay,well, where did that come from?
Because you didn't put it in.
Now some people say, well, okay, well, where did that come from
(38:38):
?
Because you didn't put it in.
Well, then it becomes importantto understand how some of these
genetic analysis work.
Is that anytime you're doing astool genetic analysis, you're
really looking at a probabilityof finding an organism, right?
Because organisms aren't uniformin any sample, and so if an
organism is very prevalent,there's a high chance that if
you take three or four samples,you're going to find the
(38:59):
presence of that organism in atleast two or three of those
samples right.
But if an organism is so low inits prevalence, then you take
three or four samples, there's alower chance that you will even
pick it up in that samplingright, because you're not
sampling the entire stool mass.
And so what we hypothesize isthat likely in these cases where
(39:20):
there was no detectableacromantia and then all of a
sudden we see 10 to the 8, 10 tothe 9 CFUs per gram.
Is that acromantia was alwaysthere?
It was just at such low levelswe couldn't even pick it up.
The probability was too low,presuming that if we sampled
enough we would find it.
But the level was so low thatnow the spores and the changes
in the microbiome increased itsprevalence so much that now we
(39:43):
have a much higher chance ofpicking it up right.
So we do see this amazingdramatic increase in keystone
and other beneficial species anda general increase in diversity
and, if I can make a point onthat, competitive exclusion with
C diff.
This is fascinating and this isa study done by Gail Cressy at
(40:05):
Cleveland Clinic, and shepublished two studies on this.
So what we took?
She has a very well establishedC diff model in mice.
She was one of the few peoplethat can stabilize C diff for
long-term infection in mice and,as it turns out, one of the
ways she does it is by actuallytreating the mice with
vancomycin, funny enough.
(40:26):
So you use the treatment for Cdiff and it makes the mice more
susceptible for long-terminfection of C diff.
So she treats the mice withvanco, she then inoculates them
with C diff and then shestabilizes the infection over a
short period of time.
Then she can add in any othersubstrate.
So then she added in the sporesand what she found was a
(40:51):
dramatic reduction in the amountof C diff in these animals,
especially when using antibiotictreatment as another arm.
We could reduce the level of Cdiff as much as an antibiotic
can, but what she was able todiscover was a mechanism by
which the spores went after Cdiff.
Right.
(41:11):
So spores can produceantibiotics.
We know that they can produceantimicrobial antibiotics in
their little microbialenvironment which can bring down
certain bacteria.
They produce things likesubtilisin and so on.
Now, clostridium is also aspore former, so they likely can
be resistant to antibiotics.
(41:31):
So the spores don't useantimicrobials to go after
Clostridia.
What they did is theyeffectively surround the
Clostridia, like kind ofcircling the wagons around them,
and they produce a chelatingagent to starve the Clostridia
of iron.
And we know that Clostridia,like many pathogens, require
(41:52):
iron as part of its metabolicprocess, right?
This is part of why Clostridiaeats through your tissue to get
to the blood, right, and peopleget bloody diarrhea, and so
Clostridia is looking for iron.
The spores are starving it todeath by keeping iron away from
it, by chelating the iron.
Right?
That's just the mind-bogglingbrilliance of nature.
(42:15):
Right, we can't engineerbacteria to do this, no matter
what our budgets are and howmany brilliant researchers you
give us.
That's where a lot of myphilosophy around research and
therapeutics and all comes fromis.
A lot of these things havealready been figured out by
nature.
We just have to be smart enoughto know where to look and
verify that it's working andthen utilize it Right.
(42:36):
And so, yeah, it's fascinatingthat these microbes can adjust
our microbiome better than wecan try to do it ourselves.
That's fascinating.
William Davis, MD (42:48):
I know you're a lover of spore formers.
Have you had a chance to workwith any of the beneficial
clustering like Bitericum?
Kiran Krishnan, PhD (42:56):
I have.
Yeah, so we actually worked witha couple the beneficial
Clostridia like Butyricum I have.
Yeah, so we actually workedwith a couple of other species.
One of them is a it's aButyricicoccus polycecum.
And then the ClostridiaButyricum is another one that I
think is a fascinating organism.
You know, I would say that themajority of Clostridia you find
(43:16):
in your gut are probablybeneficial, and we know many of
them are very important forproper immune function.
But we did work with thebutyricum and the butyricicum,
which is another genus, all ofthem because we're working on
metabolic health and we'retrying to see okay, how do we
(43:37):
naturally increase butyrateproduction in individuals?
Right, Because of course, thatgoes a long way for diabetes and
weight management and all that,but then also it plays a
significant role in dealing withreally inflammatory conditions
in the gut like IBD.
So I've had a chance to workwith Clostridia as well, and I
think it's a fascinating,amazing organism.
(43:57):
We didn't end up coming outwith the commercial product.
We had it in the pipeline,though, but I left before we
could come out with it as acommercial product.
William Davis, MD (44:10):
Any thoughts or opinions on what's going on
in the Akkermansia world?
Kiran Krishnan, PhD (44:15):
Yeah, you know it's fascinating, right?
So a lot of people ask me aboutthat because of course, there's
a brand that's done a reallygood job from the marketing
standpoint of really talkingabout Akkermansia.
Now, I've been talking aboutAkkermansia for a long time
because there's clearly somereally good population
(44:35):
longitudinal data showing acorrelation between good levels
of acromancia and protectionagainst metabolic syndrome and
lots of things under thatmetabolic syndrome umbrella.
I do believe it's an importantkeystone species that is likely
low and missing in many missingand when I say missing I
(44:56):
typically mean not detectable,so at such low levels that it's
not functional in manyindividuals.
When I was at Microbiome Labs,I think we had done somewhere
around 15,000 to 20,000 stooltests in the US, and so I had a
good sense of the collated dataand we would always, I'd say I
would say 60, 70% undetectableAkkermansia in individuals,
(45:20):
right?
So I think it's such animportant microbe and I think a
number of our behaviors makesense in why Akkermansia itself
would be low.
I think number one is we'reoverfed, right, Akkermansia is
one of those microbes that tendto do well in a fasted state.
Number two Akkermansia doesreally well with polyphenols,
(45:43):
right.
It's really good atmetabolizing polyphenols, and
these are colored fruits andvegetables and certain types of
nuts that have a lot of agalicacid and so on.
So things like almonds andmacadamia nuts and so on, we
don't consume those things right.
We consume processed foodmostly.
So Akkermansia doesn't have thefood that it needs and we're
(46:03):
overfed, so it doesn't haveenough period of time to do what
it's supposed to do as amucinophilia microbe and live in
the mucus and eat off the mucusto some degree.
So I think it makes sense whyour numbers would be low.
Then the question I get is canyou supplement with Akkermansia
right?
To me, that's where it becomesreally, really, you know,
(46:27):
questionable.
Because Akkermansia is anobligant anaerobe right.
Oxygen is basically toxic to it, same with the polycecum
microbe that we worked with.
There's lots of microbes thatare obligate anaerobes 15
seconds of oxygen exposure andthey could be dead.
And so can you actually grow ananaerobic bacteria in a
(46:52):
facility?
Because you can build ananaerobic facility we did that
at a pilot scale to growanaerobes but then you have to
encapsulate it in an anaerobicfacility.
You have to store it, ship it.
Everything has to be anaerobicright or it's going to be dying
in the bottle and then themoment you consume it.
Akkermansia was never designednaturally to go through the
(47:14):
digestive tract over and overagain, especially not a mature
digestive tract like an adultdigestive tract that has lots of
acid in the stomach and bilesalts and all the gauntlet that
microbes have to go through.
So I don't think you areengrafting or inoculating
yourself with Akkermansia whenyou take the supplement form.
(47:34):
With Akkermansia, when you takethe supplement form, I think
there could be some metabolicresponse based on what may be
receptors or stimuli on theouter membrane of the
Akkermansiaa cell when it diesand goes in, and I think the
company has shown somebeneficial effects.
They're pretty minor but theremay be some beneficial effects.
(47:56):
But to me, when it's a keystonespecies and it should be there
in your gut, we should alwaysfocus on how do you grow it
endogenously right?
How do you increase your ownacromantia?
And that to me, is a reallyimportant thing and I've put out
a few videos on this sayingthat hey, there's data showing
(48:18):
polyphenol intake increasesAkkermansia.
Fasting increases acromantia.
Exercise increases Akkermansia.
Increasing diversity in generalincreases Akkermansia.
So instead of taking what wouldbe, you know, the perceived
shortcut of going, I'm justgoing to try to take this as a
supplement and hope that this isengrafting in my gut.
(48:39):
I would rather see people youknow try to grow their
endogenous levels, especiallywith the large bowel anaerobic
microbes they're just so hard totake as supplements?
William Davis, MD (48:52):
Mind if I ask you a personal question.
Yeah, I mean, everyone knowsyou're a microbiologist and how
do you manage your intake foryou and your family of fermented
foods?
Kiran Krishnan, PhD (49:04):
Ah, okay, so we don't eat it as regularly
as I would probably like to.
So I grew up in India andMalaysia and in both cultures
fermented foods are a staplepart of your diet.
Right In India, most of thebreads and all that are made
from fermented flour.
There's lots and lots ofdifferent fermented dishes that
are commonplace, so fermentedfoods were a normal part of my
(49:28):
diet.
Now, moving here, it becomeshard, because one to really get
the benefit to me out offermented foods is you should be
doing the fermentation yourself, right, I've I found very
little benefit in grabbing whatis a fermented food out of
grocery store shelves because inmost cases you know they're not
(49:49):
taking the fermentation to its,to its ultimate end, where it
should be taken to, because ofcourse economically that's not
viable.
You look at the kombuchas on themarket.
They cut the fermentation shortby 50% at least, right, and
then, and also the flavorprofile of a fully fermented
product is probably not broadlyappealing, so they cut it short,
(50:09):
they add sugars and flavors andthings like that, and so it's
less desirable.
And so I've always looked at OK, can I do some of my own
fermentation and make it easy,make it not something that's
been overwhelmingly difficult todo.
So I started with fermentationwith the spores.
(50:31):
What we did is we bought theseregular old jars right that can
do anaerobic fermentation and westarted this about eight, nine
years ago.
So I fill the bottom third ofthe jar with fruits you know
things that have good amount ofsugar, so so berries and
(50:51):
pineapple and things like thatMash it up just a little bit and
then I add about a tablespoonof sugar and things like that,
mash it up just a little bit andthen I add about a tablespoon
of sugar and then the other twothirds.
I add water and then I add somebacillus spores, normally
subtilis and or subtilis andcoagulants.
You mix it up and you let itsit on the counter and normally
in about three or four days youstart to see a little bit of
(51:13):
bubbliness and things like thatto it.
It becomes a nice littlefermented beverage that we've
enjoyed.
So I've been able to do thatfrom time to time.
But actually in our lastconversation with your
recommendation for using root toferment the yogurt, that's
something I've been able to doand that's been super easy but
(51:33):
also really beneficial.
So that to me was one of theeasy things to do and you know
that gives you the closest thingyou're doing as home
fermentation and you'recontrolling what all is going in
it, and you know you do it, andyou do it at your own pace and
leisure.
So that's the extent of thefermentation that we do.
(51:54):
I would love to be able to dosome natto or sauerkraut or
kimchi on my own, but we justdon't have the time to do it.
You know I wish we did but wejust don't.
Yeah.
But the yogurt fermentation,though, with the root rice, is
phenomenal because it's easy andit doesn't take much and it
(52:15):
tastes good.
William Davis, MD (52:17):
Can you share what kind of experience you and
your family have had with it?
Kiran Krishnan, PhD (52:21):
Yeah.
So my my reason for wanting todo it was twofold, actually
threefold.
One was you know ourconversation about the emotional
impact that rooterai has, right, that bonding.
I actually think the work thatI was able to learn from the
(52:42):
researcher out of the APC inIreland his name is skipping me
now but he's done a lot of workwith the tribes near New Zealand
and Australia, the Papua NewGuinea tribes, right and he's
looked at ruderi Ruderi is oneof his favorite things and one
of the things he's noticed aboutthose tribes is that they tend
(53:05):
to have very high levels ofruderi and they have very high
bonding.
They have very high expressionof oxytocin and Westerners we
tend to have very low expressionof oxytocin and so to me that
hormone is so important in termsof the stability, emotional
(53:25):
stability, in a household withthe family, right.
That was one of my goals andone of my targets.
The second thing was weightmanagement.
We all always have to look atweight management.
I think root or rye plays animportant role in helping with
digesting resistant starches andthings like that right to get
(53:46):
more benefit out of them.
So feelings of satiety andmaybe even increasing fat burn.
And then the third thing wasreduction in bloat after you eat
.
Right, I think through ourconversation I had recommended
to a number of people who haveSIBO that, hey, they take a
really high root-oride dose.
They do some of it fermentation, some of it through
(54:09):
supplementation, and normallywhat people report is they see a
lot of reduction in the bloat.
Normally what people report isthey see a lot of reduction in
the bloat.
So those are the threemotivations and I could say and
this is just you know our ownNF4 study that certainly the
emotional aspect is improved.
(54:29):
Right, you notice that younotice a different type of
bonding.
You notice a differenttolerance, I would say, for the
things that you would normallybe irritated of with your family
members.
You know the things thattrigger you.
Your tolerance level for thosethings tends to improve.
And then the other side of itfor me, the bloat.
(54:52):
Especially when I eat certainfoods, like if I have a big
Indian meal right and I'm eatinglots of bread and naan and rice
and all that, I tend to feelreally full and bloated after
that.
That reduces quite dramaticallyif I take a high dose of either
the root-or-iron capsules orthe fermented product afterwards
and, funny enough, one of thestaples in India is, after a big
(55:17):
meal, you eat curds, right, youeat fermented dairy, and that
is a way of settling the stomachand reducing the bloat and the
discomfort.
And you walk right, that's whatthey do.
They go for a walk and they eattheir curds and it's kind of
the same thing the fermenteddairy here in this case and it
really helps through the gut.
So that's been our experience.
(55:39):
The emotional part is reallyfascinating to me, you know.
I think that that's afundamental issue in society
today is you mix a reduction inthe bonding and love hormones
that people can produce and thenyou add anonymity through
social media and all that.
You're going to get the worstout of people, right, because
(56:01):
now they don't have the judgmentof society the same, because
they can be anonymous with theirtrolling comments and all the
crazy things that people do andsay, right.
So I think that's a fascinatingarea and I think that's one
area that I would love to seemore research on.
William Davis, MD (56:19):
Dr Krishnan, I will take it away your time.
Always a pleasure.
I learn a hundred new thingsevery time I hear you speak and,
as you know, this is a reallyexciting time.
It's like AI and changingtechnology.
Microbiome is changingeverything and I hope I can
interest you in coming backagain everything and I hope I
can interest you in coming backagain.
Kiran Krishnan, PhD (56:39):
I would love to.
I've always been a fan of youand your work and your teaching
and all that, and I think whenwe met recently, over the last
year, I'd mentioned to you.
We met briefly when you did alecture at a conference, I think
maybe 10 years ago, and maybeyour first book was just out at
the time and I'd always admiredthe work you've done in
(57:00):
educating people and all that.
William Davis, MD (57:01):
So it would be my pleasure to come back.
Kiran Krishnan, PhD (57:03):
So yeah, absolutely.
Thanks, Kiran.
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