Necrotizing enterocolitis in premature infants, Crohn's disease in
children and adults and trauma can necessitate the removal of
significant quantities of small intestine resulting in short bowel syndrome (SBS) and
subsequently, in the body being unable to absorb nutrition from food
because of an inadequate length of small intestine.
In children, the
incidence of SBS is almost double that of childhood cancer and the
mortality rate at five years following surgery is approximately 30%.
Until now, the morbidity and mortality associated with SBS has been
related to malnutrition and liver fibrosis from intravenous nutritional
‘The genetic changes resulting from short bowel syndrome (SBS) using a novel zebrafish model and by performing intensive gene sequencing have been mapped by researchers.’
In a new study the researchers sought to determine systemic
effects attributable to the disease process alone.
Investigators at Children's Hospital Los Angeles, led by Tracy C.
Grikscheit, have mapped the genetic changes resulting from short
bowel syndrome using a novel zebrafish model and by performing
intensive gene sequencing.
This approach to determining which genes are
markedly over or under expressed in SBS may assist scientists in
developing future therapies for children and adults with this condition.
Results of the study have been published in BioMed Central Genomics
The research team conducted the study in zebrafish, using a
validated SBS model created in the Grikscheit laboratory. This model
allowed the investigators to study matched samples of small intestine
from zebrafish who had bowel surgery and those who underwent "sham" or
According to first author, Kathy A. Schall, "Most
studies of SBS focus on the epithelial cells that line the intestine but
this model allowed us to focus on systemic effects and the associated
genetic alterations responsible for those effects."
The paper reports that 29 fish had intestinal surgery compared to 28
fish that received sham surgery. After two weeks, a time previously
determined to be associated with maximal stem and progenitor cell
activity, RNA-sequencing analysis was performed. Zebrafish with SBS had
1346 significantly upregulated genes and 678 significantly downregulated
genes compared to sham-operated controls.
The upregulated genes were
related to processes that include cell proliferation, acute phase
response signaling, innate and adaptive immunity, bile acid regulation,
production of nitric oxide and reactive oxygen species, cellular barrier
maintenance and coagulation. Downregulated genes were associated with
folate synthesis, gluconeogenesis, glycogenolysis, fatty-acid oxidation
and activation and drug and steroid metabolism.
"We've identified marked changes in several metabolic pathways -
including some that had previously been considered an effect of
intravenous nutrition," said Grikscheit, who is also a tenured associate
professor of surgery at the Keck School of Medicine of the University
of Southern California.
"Knowing that these alterations are caused by
SBS in the absence of intravenous nutrition provides us multiple targets
for developing new therapies to modify these effects. Instead of
digging in random places we now have a map to follow in our search for
therapeutic approaches for SBS." Grikscheit adds that a reduction of
just 10% of U.S. patients requiring home intravenous nutrition
for SBS would result in an estimated saving of nearly $800 million in
health care costs.