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 (PNAS), 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 (www.massgeneral.org), 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.