Ulcer-Causing Bacteria Use Stomach Inflammation To Their Advantage

The researchers found that infection of the stomach by the bacterium Helicobacter pylori (H. pylori) leads first to mild inflammation. As the inflammation occurs, cells lining the stomach produce a specific kind of sugar molecule and display it on their surface. Normally, that sugar, known as sialyl-di-Lewis x (sLex), serves as a flag to attract immune cells to the infection site. The worse the inflammation, the more sLex the cells display.

The investigators also discovered, however, that H. pylori latches on to the new sugar using a previously unknown bacterial adhesin protein, enabling the bacteria to draw closer to the stomach cells, presumably where more nutrients are available. This worsens the inflammation and further increases the amount of sLex on the stomach cells. Some of the bacteria, which are loosely attached, may then move a microbial arms-length away from the cells and thereby avoid destruction by immune cells that are attracted to the increasing display of sLex. The investigators believe that the degree of inflammation may then subside enough that those bacteria that move in close again will have a good chance of survival and, once more, profit from the better nutrient supply.

"These findings should improve our understanding of how H. pylori infection happens, how our immune system responds to it, and how the bacteria cope with that response," says Douglas E. Berg, Ph.D., Alumni Professor in Molecular Microbiology and professor of genetics at the School of Medicine and co-author of the study. "We also hope that understanding how these adhesins work will lead to a vaccine against H. pylori infections and to new drugs to treat or diminish their severity."

The findings also could help explain why the stomach inflammation that often accompanies the infection periodically flares up, then subsides, and why the infection persists for so long, says Berg, who also is a member of the tumor immunology program at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

"The ability of Helicobacter pylori to adjust its adherence properties to the level of inflammation it causes at the stomach surface could help explain how this bacterium maintains its persistent, decades-long infection in the stomach of millions worldwide," says lead investigator Thomas Borén, D.D.S., Ph.D., assistant professor of odontology and oral microbiology, at UmeÅ University, UmeÅ, Sweden.

H. pylori colonizes the stomach of more than half of all people worldwide. Scientists believe the infection starts in infancy and lasts for decades, perhaps for a lifetime. Adherence to the epithelial cells that line the stomach is thought essential for the infection to occur. There's been a long-standing effort to find the molecules that H. pylori recognizes on stomach cells and to find the corresponding adhesins that it makes to recognize those host molecules.

In 1993, Borén, working in collaboration with researchers at Washington University, learned that H. pylori used a molecule known as Lewis B antigen (Leb) to adhere to stomach cells, findings that also were published in Science. This study was followed up in 1998 when Borén's team, working in collaboration with Berg and other investigators at Washington University, identified the attachment protein used by the bacterim, calling it Lewis B antigen binding adhesin (BabA). That discovery also appeared in Science. The present study began with the intriguing observation that a mutant H. pylori strain engineered to lack BabA still adhered to highly inflamed stomach tissue from an H. pylori infected person, but could not adhere to healthy stomach tissue from an uninfected person. The bacterium, it seemed, had another adhesin, one that recognized a molecule associated with inflammation.

Further study revealed that the bacteria were binding to sLex antigen, which is rare on healthy cells but present on inflamed cells.

The investigators captured a fragment of the bacterial adhesin protein using a technique called receptor activity-directed affinity tagging, which they developed for the 1998 study. They then determined the amino-acid sequence of this fragment and used that to identify the gene encoding the protein. They called the new bacterial protein sialic-acid binding adhesin (SabA).

Last, the researchers developed a strain of H. pylori that lacked the SabA gene and found that those bacteria were unable to adhere to inflamed stomach lining, thereby confirming SabA was responsible for the observation that triggered the study.

Overall, the study suggests a dynamic and constantly evolving relationship between bacteria and host. Of the millions of H. pylori bacteria that live in an infected person's stomach, the researchers believe some reside for a time close to stomach cells, while others reside a short distance away in the film of mucus that protects stomach cells from the secreted acids in the stomach cavity. The bacterial population thereby achieves a beneficial trade-off: In any given patch of stomach tissue, bacteria sitting close to stomach cells are well nourished but are at higher risk of attack by the prowling immune cells, while bacteria lying farther away are less nourished and grow less rapidly, but also are less susceptible to immune-system attack.

"Our findings stress the importance of studying bacterial-host relationships as they exist during infection," says Borén. "We must always correlate findings from the research laboratory with findings in patients because cross-talk between bacteria and host may change the process of infection."

Reference:

Mahdavi J, Sondén B, Hurtig M, Olfat FO, Forsberg L, Roche N, Ångström J, Larsson T, Teneberg S, Karlsson K-A, Altraja S, Wadström T, Kersulyte D, Berg DE, Dubois A, Petersson C, Magnusson K-E, Norberg T, Lindh F, Lundskog BB, Arnqvist A, Hammarström L, Borén T. Helicobacter pylori SabA adhesin-binding sialyl-di-Lewis x antigens expressed during persistent infection. Science, 297, 573-578, July 26, 2002.

Other institutions contributing to this study are The Swedish Institute for Infectious Disease Control; Institute of Medical Biochemistry, Göteborg University; Institute of Molecular and Cell Biology, Tartu University; Department of Infectious Diseases and Medical Microbiology, Lund University; Laboratory of Gastrointestinal and Liver Studies, Uniformed Services University of the Health Sciences; Department of Health and Environment, Linköping University; Department of Chemistry, Swedish University of Agricultural Sciences; IsoSepAB; Center for Biotechnology, Karolinska Institute.

This research was supported by funding from the UmeÅ University Biotechnology Fund, Swedish Society of Medicine/Bengt Ihre's Fund, Swedish Society for Medical Research, Lion's Cancer Research Foundation at UmeÅ University, County Council of Västerbotten, Neose Glycoscience Research Award Grant, Swedish Medical Research Council, Swedish Cancer Society, J.D. Kempe Memorial Foundation, Wallenberg Foundation, Lundberg Foundation, ALF grant Lund University Hospital and grants from the Uniformed Services University of the Health Sciences, the National Institutes of Health and Washington University.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.