Digestive Diseases News Summer 2011
Intestinal Alkaline Phosphatase Helps Balance Intestinal Bacteria
Intestinal alkaline phosphatase (IAP), an enzyme found among cells that line the gastrointestinal (GI) tract, helps balance intestinal bacteria, according to research funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The research helps explain how the body allows beneficial bacteria to flourish in the intestines while limiting the proliferation of harmful bacteria. The finding also provides clues to understanding and treating conditions linked to disturbances in intestinal ecology, such as Clostridium difficile (C. difficile)-associated disease.
The researchers studied the quantity and diversity of bacteria in the stools of normal mice, called wild-type (WT), and mice genetically altered so they are unable to produce IAP, called IAP-knockout (IAP-KO) mice.
“IAP-KO mice had dramatically fewer and also different types of aerobic and anaerobic microbes in their stool compared with WT mice,” wrote Richard A. Hodin, M.D., surgical director of the Massachusetts General Hospital’s Crohn’s and Colitis Center, and co-authors in their report, which appeared in the November 2010 issue of Gut.
Scientists increasingly recognize the important role the millions of microorganisms living in and on the human body play in maintaining health. Collectively known as the microbiota, these “bugs” liberate nutrients from food, fend off pathogenic microorganisms, and help regulate metabolism.
IAP was discovered more than 50 years ago. Its role in fat metabolism is well documented; however, during the past decade, IAP has also been recognized for its role in maintaining the gut mucosa—the epithelial cell barrier that lines the GI tract—according to Hodin and co-authors. Hodin is currently funded by the NIDDK to delineate the mechanisms that govern IAP gene regulation to better characterize the dynamic physiological role this enzyme plays in metabolism and immune defense.
The researchers also found that feeding mice IAP helps restore healthy intestinal bacteria and fends off bacterial pathogens. The scientists gave two groups of WT mice the antibiotic streptomycin for 3 days to disrupt the normal intestinal microbiota. One group was also given supplemental IAP purified from calves (cIAP). Escherichia coli bacteria returned to cIAP-fed mice about 2 days earlier than mice that were not fed cIAP. Four days after discontinuation of antibiotic treatment, the mice were infected with pathogenic Salmonella bacteria. Whereas 70 percent of cIAP-fed mice survived infection, only 20 percent of mice that were not fed cIAP survived.
“It is well known that enteric pathogenic bacteria compete with the endogenous microbiota and that enteric infections are more common in settings where the normal intestinal microbiota is lost or disrupted,” wrote Hodin and co-authors. IAP, through a yet unknown mechanism, somehow preserves the normal gut microbiota.
Age, immune status, pH of the GI tract, the presence of antimicrobial peptides, and other external factors are known to influence the intestinal microbiota; however, “no specific endogenous factor has been identified that functions either directly or indirectly to preserve the normal homeostatic number and composition of the intestinal microbiota,” wrote Hodin and co-authors. The researchers speculated that IAP favors the growth of good bacteria through an indirect mechanism that affects pH of the GI tract, inflammation, immunity, or other factors. The resulting increase in good bacteria thereby limits the availability of nutrients and anchorage sites for pathogenic bacteria.
Work by Hodin’s group and others suggests IAP has the potential to treat a number of conditions associated with the disruption of GI bacteria. For example, C. difficile-associated disease, which causes severe colitis, results when antibiotics wipe out good bacteria and allow pathogenic Clostridia bacteria to flourish.
“Orally administered IAP might be an effective treatment for bacterial pathogenesis as well as a variety of disease conditions associated with dysregulated intestinal microbiota,” wrote the researchers. Other conditions associated with dysregulated intestinal microbiota include inflammatory bowel disease (IBD), AIDS, and obesity.
The report proposed several ideas for future exploration of IAP’s role in balancing the gut microbiota, including studies to determine how the pH of the intestinal epithelial cell microenvironment—the space immediately adjacent to cells—affects IAP expression. Also helpful would be an investigation of the effect IAP supplementation has on gut bacterial populations in IBD mouse models.
The National Digestive Diseases Information Clearinghouse, an information service of the NIDDK, has free fact sheets and easy-to-read booklets about digestive diseases. For more information or to obtain copies, visit www.digestive.niddk.nih.gov.
NIH Publication No. 11–4552