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MGH study identifies enzyme that protects
against intestinal bacterial toxin
Discovery may answer how feeding
can prevent infection in critically ill patients
BOSTON - February 18, 2008 - A persistent mystery in human
medicine is how the lining of the small intestine, through which
nutrients are absorbed, also prevents intestinal bacteria and their
toxins from entering the bloodstream and causing serious infections.
A team of researchers from Massachusetts General Hospital (MGH)
has found that a specific intestinal enzyme may be able to block
the action of the bacterial toxin involved in the overwhelming infection
known as sepsis. The findings, which will appear in the Proceedings
of the National Academy of Sciences, may also explain why patients
recovering from serious injury are less likely to develop infections
if they receive gastrointestinal nutrition.
"It's been known for many years that people who don't eat,
particularly those who are ill or recovering from injury, are more
susceptible to infections derived from the gut," says Richard
Hodin, MD, of the MGH Department of Surgery, the study's senior
author. "We know that eating - even small amounts of nutrients
delivered through a feeding tube - can help prevent infections,
and it may be that the production of this enzyme is the key to that
protection. Everyone that takes care of critically ill patients
knows the importance of 'feeding the gut,' but how that feeding
works to prevent infection has been a mystery."
Intestinal alkaline phosphatase (IAP) is produced by cells lining
the small intestine, and several previous studies suggested that
IAP might block the action of lipopolysaccharide (LPS), a molecule
on the surface of many pathogenic bacteria that is responsible for
their toxic effects. In order to investigate the normal function
of IAP in the intestine - something that has not been understood
- the MGH research team conducted a number of experiments with intestinal
cell lines and confirmed that those cells' expression of IAP could
block the toxic effects of LPS.
A comparison of normal mice with mice in whom the IAP gene had
been knocked out showed that the animals lacking IAP lost their
protection against intestinal bacteria. The investigators also showed
that IAP expression and the ability to detoxify LPS were decreased
markedly when the animals did not eat for two days, a defect that
was reversed when feeding resumed.
"Our results show that IAP produced in the intestinal lining
and secreted into the gut can detoxify LPS and prevent bacteria
from becoming harmful," Hodin says. "In addition to explaining
how feeding can protect ICU patients from infection, these findings
may have significant implications for a variety of conditions, including
inflammatory bowel disease. Studies are ongoing to determine the
role that IAP may play in those disorders." Hodin is a professor
of Surgery at Harvard Medical School.
The work was performed in Hodin's lab, which is supported by grants
from the National Institutes of Health. First author Ross Goldberg,
MD, is now at St. Vincent's Hospital, New York. Additional co-authors
are William Austen, Jr, MD, Xiaobo Zhang, Gitonga Munene, Golam
Mostafa, Shaluk Biswas, Michael McCormack, Kyle Eberlin, John Nguyen,
MD, and Hamit Tatlidede of MGH Surgery; H. Shaw Warren, MD, MGH
Pediatrics; and Sonoko Narisawa, PhD, and Jose Millan, PhD, Burnham
Institute for Medical Research, La Jolla, Calif.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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