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Breastmilk and Microbiota in Protection from NEC in Prematures
Allan Walker
Tuesday, Sept. 24, 2019 · 3:01 p.m. · 28m 51s
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the view to persist
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that's all it's difficult to get the last lecture so i'll try to go through it very quickly
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i want to talk to about breast milk and michael bowden the
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premature got as a potential mechanism for preventing neck revising enter collide
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first before we uh we can sort of those we have to consider the clinical problem
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and then way is that have been used previously um
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to prevent next such as the expression of mother's breast milk
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and probe attics and then add a different approach which is
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prob attics in breast milk fed infants before we summarise and conclude
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let's begin with the clinical problem we all
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know how devastating neck purchasing enter clyde is yes
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even if the infant exist um survives
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that has lifelong problems so it's a very
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important that we prevent rather than treat the condition
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ten percent of babies under fifteen hundred grams develop adequate testing and rick letters
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that represents one to five percent of nick you admissions
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in greater than ninety percent of cases that
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occurs in premature infants and it occurs um
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very commonly seven to fourteen days after delivery at
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a time when the and fun has been fat
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and susceptibility is inversely related to just station
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age uh this looks very familiar because was taken
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from the same article drawn i wrote review article on that this is
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a patient with nectar tracing and trick lettuce and tomatoes is in test analysis
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thirty percent of patients with mac require surgery
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surgery invariably leads to short pile syndrome
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and about up to fifty percent of babies
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whether they're operated on or not diet this condition
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sit quietly are enormous and our lifelong short stature is very common
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years too late neurologic development project when cognitive function all of these have a lifelong
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persistent problem and the medical costs are prohibitive cost about two billion dollars per year
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several years ago we hypothesise that network has seen
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and throw collide as was caused by an inmate sure
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and appropriate innate immune response to collin eyes in bacteria in the gastrointestinal tract
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support this hypothesis we used organ
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culture of intestinal biopsies from newborns
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and and tissue obtained from therapeutic lee board
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feel just as in we challenge these tissues
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i would like to apply saccharine and i'll one beta which
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are common causes of the neck advising and to collide is
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as you can see the dial eight protein level and that gene level
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was much higher in feel just as that was in the knee an egg
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suggesting that the excess of uh immaturity the intestine
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was a factor in the hyper ron i'm information
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no the it and maybe immune it were response uh inflammatory response
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uh occurs when bacteria interacts with the whole receptors
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which trigger signal trance structure molecules searches n.
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y. d. eighty eight craft and and a track
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and it leads to a transcription factor which enters the new
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players in causes transcription of inflammatory sided kinds searches file eight
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t. n. f. alpha and yemen or for uh
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not under normal conditions this is so
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self limited process because there are other components
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that uh interfere with the signal trance traction and information
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uh that uh address different aspects of the signalling process
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we decided we would look at the components of the innate immune response
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in a major intestine in mid intestine from uh
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aborted feel just as an intestine from the
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respected portion of nectar tries you and rick lightest
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and as expected we saw a a a strikingly elevated i'll eat response
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in amateur intestine and yeah and um the nectar tasting under collide is patient
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we looked at the signalling molecules and the receptors we
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found that in each instance till our two two or four
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in my da da craft and n. f. kappa b. were elevated
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what was most makes it interesting was when
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we look at the negative regulators of the uh
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innate immune response was in a controlled as response
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we found that the church heston had higher levels
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and amateur intestine and never try xena collide is considerably lower levels which
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we felt contributed to the hyper
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information that occurs in advertising enter collide
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right with that brief introduction let's consider approaches to
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the prevention of this disease we know and joe's already
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talked a little bit about that that both breast
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milk and problematic so been used to treat the condition
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uh this is that not analysis that joe
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referred to a showing that yeah and small cases
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small numbers of cases using different robotics a
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different doses that there appears to be an improvement
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but you heard the other aspects of that that have um
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that he discussed so i want per is that right now
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there's also met analysis of a bra studies breast
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milk studies us as mothers express pressed will add
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to the amp and and as you can see in each instance uh this was very a successful
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no we we know and appreciate that
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breast milk influences the development because some unity
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it does so through the micro by own which we heard about earlier today
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it does so through protected nutrients such is pretty by attics
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and anti inflammatory factors such as like to fair and and make it three
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fatty acids which will hear about tomorrow immune enhancing substances such as nuclear time
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what you might not appreciate is that breast milk acts as substrate
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for communism bacteria to produce but terrible lights that are anti inflammatory
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we did a study i'm looking at the influence of breast milk
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infant formula and then the combination of um banked pressed now
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plus infant formula as you can see this is a different
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in each of these circumstances we also the the whole
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genome sequencing route and we recognise that genes from breast null
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in the microbe over there were different from those of formula
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yeah
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so we decided to look at what happens when probe
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attics or how honest in bacteria interact with breast now
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recently we did this was we knew that trip to fame rich
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foods that are bad animals or adults can produce but tab lights
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which are anti inflammatory in the intestine of experimental collide as patients
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as well as a um the the actual i. b. d. patient
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we also know that when high fibre and complex carbohydrates are fed to
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uh i individuals or into animals that they
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use uh under the conditions of bacterial conversation
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uh and certain bacteria searches but back to
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reduce be jealous can produce short chain fatty acids
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which by a variety of mechanisms are not important in got home you spaces for example
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fibre fed to animals produced
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sure sure chain fatty acid
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the use short chain fatty acids interacted with g. couple protein receptor
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in this case forty three that are present or anti regulatory cells
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has seen an increase in the uh expression of these cells
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is this is the microbe oh the itself and user specific
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yeah and mixture of i'm sure chain fatty acids all
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of which cause an increase the regulatory cells as opposed
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to germ free that has no increase or also caused
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a increase and i'll hand which is an inflammatory static right
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yeah we were most uh enthused about those
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approach to prevention when we noted in a
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paper that appeared in pediatrics research that
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one problematic for use with breastfed infants
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they were much more effective than use with formula fed and depending on the degree of
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breast feeding is uh it it increased the a dependency and
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um um be preventing breast uh the next generation and collide us
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we had previously shown
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that the father bacteria impetus
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secretions free from the bacteria were anti inflammatory what we
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did is we separated bacteria from the uh media itself
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we then use feel intestinal cells which we
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pretty incubate it with various fractions of the media
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and we showed an anti inflammatory fact that occurred
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uh when we used the less than three k. m. three k. fractions
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in collaboration with the group in um salerno at the
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uh a research institute in somewhere no we found that
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the three k. and and three to ten k. had a peak that didn't exist in the media
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now using data a database we found that this was a
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in dull lactic acid which is a metabolism trip to fine
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we know that breast milk has a large quantities of trip the fine and so we
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felt that this was a potential source of answer
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information in the patience with neckties in general clitoris
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what we did is we repeated the studies using fuel cell line
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incubator with various concentrations of in the
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lactic acid before we challenged with i one
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data and as you can see there's a striking drew reduction in the um information
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to confirm are in vitro observation and human
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fuel cells we used uh it intact mice
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both feel in the tour and found that
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we could repeat those uh approach using feel mice
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but it was not the same as me termites suggesting
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that it was a specific um i feel a a fact
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and we know that handles from trip to train interact with
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arrow hydrogen receptors which can function as a transcription factor
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to produce i only a but when we use the inhibitor
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of the use 'em hydrocarbon receptor we found that we lost the anti
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inflammatory effect strongly suggesting that this was the mechanism by which this occur
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the let me try to summarise what we have shown here we have
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shown that one breast milk which contains a large amount of trip to feign
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enter x. with the for all bacteria impetus
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this produces candle lactic acid
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which is then transported across to feel countryside interacting with
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the arrow hydrogen receptor in causing the down regulation in information
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we also know that complex carbohydrates in breast no
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interacting with certain bacteria such as back to readies
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for jealous can hat can produce short chain fatty acids
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but we didn't know was you sure change their yeses have an anti inflammatory effect
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and a few underside so what we did is
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we incubate did a a different concentrations of acetate
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appropriate nate imbued array and found that each cause
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a reduction in information suggesting again and anti inflammatory effect
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we looked at the mouse model we found that
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the anti inflammatory effect persisted and the small intestine
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as well as in the colon
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and looking at the mechanism we know that i'm
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sure chain fatty acids affect the a seven laces
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causing a reduction in there for reducing their apple genetic effect
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and um uh the inflammatory side kinds so
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here we show that when we used the three
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sure chain fatty acids
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what to do
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feel
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the us the laces that in most instances they reduce the effect
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we also know that i'm sure chain fatty acids work through g. protein coupled receptor worse
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in in the case of the me in a this is a a one o. nine eighty a
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t. g. protein receptor in what we showed is that when um the use short chain fatty acids
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we're we're we're really into baited with fuel
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cells that they cause an increase in this receptor
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no only used and then had ever of the receptor
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it suggested that we we lost in the inflammatory effect
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suggesting that one o. nine am was the receptor for this process
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again let me try to read review with you what we've shown you shown that
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i'll one data which is a common
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students and uh and exercising and rick letters
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can pass through its receptor and cause an increase
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in the us ever laces which plan at the genetic
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defect has a increase in file eight and increased information
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short chain fatty acids through the one o. nine a receptor can cause a reduction
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in the the us several uses less of an apple genetic effect and therefore fact information
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so these are two examples of how bacteria acting with
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breast milk in a different capacity can produce anti inflammatory um
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anti inflammatory facts
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so let me try to summarising conclude what i've sat said the neck
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purchasing enter collide is is a devastating
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disease that must be prevented not treated
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that the best way to prevent those is to use pressed nope in conjunction with the probe attic
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and that although breast null prevent snack wild
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ride in mechanisms including all of the sack rides
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and has of substrates that also works by producing that anti inflammatory probable addict
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the tabloids and then i've suggested the breast milk trip the thing the tab alliances p. and for those
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i would have less by d. m. for those produces in all three lactic acid
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which is anti inflammatory but only in the fuel intestine
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and also that breast no interacting with other uh substances can produce
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metabolism lecture chain fatty acids which are anti inflammatory thank you very much
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questions
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yes sure of different compounds in the milk with and time from other yeah
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activities and somehow i actually i do remember modify but i think we are now
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that's why i oh
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robotics
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the tabloids personnel i ga maybe every important component just looking at that time that's right
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any other questions right
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yeah
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yeah okay
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yeah okay
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do you see a neck attracting antiquated seen breastfed babies at all
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yes and at what level do you see them yes now
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let me let me preface by saying i'm not indian intelligence
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me neither joan new yeah that's what i'm trying to work out ways that we can
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do some preclinical studies right that can then be done in march um
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clinical studies that hopefully will help prevent mac and the second question i had was
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are there any animal models in primates uh
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where i don't know actual circumstances you scenic
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joe
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i don't know of any you know i i i i think
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the closest one is if you take uh for example okay good
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yeah if you uh do not give that a good
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i g. g. how uh and uh you artificially p. technically
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uh where you do not to allow any mothers not acting
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like within one week backed up it will develop uploaded test in
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uh i can't uh it looks like recognising uh quite a you know they're showing call that's
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are really different from humans they don't have any and leave it on jeans and may require
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a a breast feeding to get function so i don't think that's well that's why i think
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that's the question right yeah yeah i did tell question i had again is related to the
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underlying better physiology of what we call neck you know yeah what is
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the role of high pox yeah in in this regard we're looking at two
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which which creates love holes and you put a lot of a lot of it
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uh i thought it was some early observations we suggest to hype box and they have a
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very important role in induction of yeah i agree with show that this is a very complex disease
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and that there are lots of factors that are involved i passe has been uh no
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i'm just looking up one aspect of other context a lot of these things which you see
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purely because of somewhat banish uh all the i.
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l. eight yeah and other uh younger kind secretions
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maybe purely related to the cell damage rather then well as usual bacteria
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s. s. o. i. g. a. i. g. a. uh i l. a.
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and never tries you know collide as an amateur justin so i think those are factors that are involved
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but i don't mean to imply that the only situation as an amateur
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uh and made immune response but it is true that inhuman
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parameters and and nectar tracing and clyde us tissue that the says
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that the case uh in terms of an image or anywhere immune response
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okay
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i am i correct anything curve feature
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off mike while ah compensation and function in ah oh i
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this guy and add en francais sang like archiving it
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areas um the number of people including joan move have shown
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that there is a change in the microphone up before
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neckties you know places hers can he explain that in his
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talk that there are changes in the back my corpora prior to
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the yeah the institution of advertising or whatever it is not true
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i'm not a comic i found a area ha i think
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in some species eight ah now i have to say here
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yeah
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that uh you have a uh this bios is with a a
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a chip in the uh uh two different file a one is
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a a increase in probably a bacteria which is largely gram negatives
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and uh the other one is a decrease in from acute switches gram positives
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oh those bacteria that are featured guests it producing some of the same uh
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uh uh the cadillacs that ellen was talking about we had previously reported that um
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commence affects very or or bacteria that are good bacteria
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can cause inflammation in the field test so i
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think that's part of the problem that response is abnormal
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mm one thing uh thinking software preterm low back plate
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whether you are including can be raised to the incorporating into collect is
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any feeling problem that related to that included interconnected and and that the condition
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so what i'm doing our preclinical studies before we can recommend
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what we do with previous we have to call trial that's something
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i'm just pointing out hold on the larry observations that's just that pressed neil
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combination for i may be a factor in creating a uh anti inflammatory for
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okay
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yes
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do we think uh if the difference between them
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you breath thinking along the path you could composition
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i think the cocking even be pressed it into or so
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if they would yep passing out because i think they are family
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yeah i think come see me anything like that to make sure redundancies in
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um go ahead joe you wanna talk
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so uh yeah i did bring that up a little bit in a in a
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talk i gave where the skin to skin contact in the interim every system that was
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i described so nicely in the late nineteen seventies by l. in uh colleagues
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uh i think that that's clear role and it's a bit with the as far as the evidence
00:27:10
is concerned behind back i i think that uh we still don't have hard evidence we have uh
00:27:16
good associations uh uh we had the uh the studies that were done is real also in western australia
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but has to a colleague so where a it appears that they
00:27:26
actually get there that this uh interim every system actually does occur which
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necessitates a close contact between the mother and the baby
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and this is one of the reasons why india they'll intensive care units in
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many parts of the world would try to encourage the mothers to come in
00:27:45
yeah to start with the babies having babies on their breasts uh and uh uh not
00:27:51
just a a feed them to know itself but to have acted direct skin to skin contact
00:27:57
i should point out that mothers expressed
00:28:01
bra smell is far superior to thank now
00:28:05
because it has so many different factors that are
00:28:09
that road of one you patched rise and actually mothers
00:28:14
a pressman right press well from for us banks are later or a small and it doesn't contain a lot of the
00:28:21
very important protective factors just with the
00:28:25
class strum and mothers who deliver prematurely
00:28:33
any other questions
00:28:36
okay um what we have ended early because we are short one
00:28:41
of our speakers and um no lead you have some comments to make
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