Researchers define chain of events leading to dangerous intestinal
disorder in preemies

Date:
September 23, 2021
Source:
Johns Hopkins Medicine
Summary:
A research team has provided what may be the most definitive
view to date of the biological process leading to necrotizing
enterocolitis (NEC), a dangerous inflammatory disease that can
destroy a premature infant's intestinal lining and causes death
in up to a third of the cases.



FULL STORY ==========================================================================
In a study with mice reported today in the journal Science Translational Medicine, a Johns Hopkins Medicine research team has provided what may
be the most definitive view to date of the biological process leading to necrotizing enterocolitis (NEC), a dangerous inflammatory disease that
can destroy a premature infant's intestinal lining and causes death in up
to a third of the cases. The researchers showed that the loss of enteric
glia -- cells that support specialized nerves in the intestine -- leads
to intestinal dysmotility -- a condition in which the gastrointestinal
tract loses its ability to move food and other materials along (known as peristalsis) -- and that this malfunction is a key factor in the genesis
of NEC.


========================================================================== "Symptoms seen in premature infants, such as a distended abdomen
and intolerances to foods -- the things that result from intestinal
dysmotility - - have traditionally been considered consequences of NEC,"
says study senior author David Hackam, M.D., Ph.D., surgeon-in-chief at
Johns Hopkins Children's Center and professor of surgery at the Johns
Hopkins University School of Medicine. "Our findings suggest, perhaps for
the first time, that these conditions may actually be a cause, rather
than just a result, of NEC." Hackam and his colleagues say it seems
logical that the enteric nervous system and the glial cells supporting
its function play such a pivotal role in NEC's genesis. "This system
has been called 'the body's second brain' because of its importance to
overall health," he says.

In their study, the researchers also found that overproduction of a
protein called toll-like receptor 4 (TLR4) -- shown in previous Johns
Hopkins Medicine studies to be involved in NEC's onset -- triggers
the enteric glia loss. In separate experiments, they demonstrated that inhibiting TLR4 and ensuring enteric glia survival enables the cells
to produce a growth factor called brain-dependent neurotrophic factor
(BDNF), which in turn curtails the wayward immune response leading to NEC.

"This finding enabled us to test in mice the use of a compound that could 'kick-start' the intestine by preserving enteric glia and their ability
to produce BDNF, resulting in restored intestinal movement -- and most importantly, the prevention of NEC," says study lead author Mark Kovler,
M.D., a general surgery resident at the Johns Hopkins University School
of Medicine.

Seen in as many as 12% of newborn babies born before 37 weeks gestation,
NEC is a rapidly progressing gastrointestinal emergency in which normally harmless gut bacteria invade the underdeveloped wall of the premature
infant's colon, causing inflammation that can ultimately destroy healthy
tissue at the site. If enough cells become necrotic (die) so that a
hole is created in the intestinal wall, harmful bacteria can enter the bloodstream and cause life-threatening sepsis.

In earlier mouse studies, the Johns Hopkins Medicine researchers showed
that NEC results when the underdeveloped intestinal lining in premature
infants produces higher-than-normal amounts of TLR4. TLR4 in full-term
babies binds with bacteria in the gut and helps keep threatening microbes
in check. However, in premature infants, TLR4 can act like an immune
system switch, with excess amounts of the protein mistakenly directing
the body's disease defense mechanism against the intestinal wall instead.

"Knowing this, we designed our current study to see if TLR4 was involved
in the loss of enteric glia, and if so, how that might pave the way for
NEC to develop," says Kovler.

As a result of their experiments, the researchers were able to provide
five lines of evidence that intestinal dysmotility -- as a consequence
of TLR4- influenced loss of enteric glia -- is a critical factor in the development of NEC:
* Three different strains of mice bred without enteric glia showed
impaired
intestinal movement, and in turn, more severe NEC, than wild-type
(genetically normal) mice.

* Mice bred with enteric glia that cannot produce TLR4 did not
lose glial
cells, show dysmotility or develop NEC, indicating that TLR4 is
necessary for glial cell loss and its link to the disease.

* Giving BDNF to glial-deficient mice reduced the severity of NEC
in the
animals, suggesting that BDNF release from enteric glia helps the
cells protect the intestine from NEC.

* When too much TLR4 is present in the intestinal wall, the release
of BDNF
prevents the overabundant protein from signaling the immune system
to mistakenly attack healthy tissues.

* Oxolinic acid (designated compound J11 by the Johns Hopkins Medicine
team), a synthetic antibiotic developed in Japan and used in
veterinary medicine, was found to enhance BDNF release from enteric
glia, restore intestinal movement and reduce the severity of NEC
in wild-type mice. By comparison -- and as expected -- it didn't
work in mice lacking enteric glia and unable to produce BDNF.

The researchers also studied NEC-damaged intestinal tissues taken from
wild- type mice, piglets and human infants (whose tissues had been
removed during surgery to treat NEC), finding in all cases that enteric
glia were depleted.

"Because we have shown that enteric glia protect animal intestines
from the devastating effects of NEC, it is reasonable to assume a
similar scenario exists in humans," says Hackam. "And if we can one
day repair the system when it's broken and prevent NEC in premature
infants -- through the use of enteric glia therapies such as J11 --
then that will be one less obstacle for these tiny patients to overcome." ========================================================================== Story Source: Materials provided by Johns_Hopkins_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Mark L. Kovler, Andres J. Gonzalez Salazar, William B. Fulton,
Peng Lu,
Yukihiro Yamaguchi, Qinjie Zhou, Maame Sampah, Asuka Ishiyama,
Thomas Prindle, Sanxia Wang, Hongpeng Jia, Peter Wipf, Chhinder
P. Sodhi, David J. Hackam. Toll-like receptor 4-mediated
enteric glia loss is critical for the development of necrotizing
enterocolitis. Science Translational Medicine, 2021; 13 (612)
DOI: 10.1126/scitranslmed.abg3459 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210923115640.htm

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