There are trillions of bacteria in the human digestive tract. In the mouth, bacteria help initiate the breakdown of food. In the intestines, they process complex molecules into nutrients that human cells can absorb. These bacteria are essential for proper digestion. Bacteria in the stomach, however, are often not so beneficial.
While the stomach plays a critical role in digestion – mechanically and chemically breaking down food by churning it with acidic, enzyme-filled gastric juices – its function is not improved by bacteria. Rather, part of its function is to kill bacteria, preventing pathogens in food from reaching the intestines.
A species of bacteria called Helicobacter pylori, however, thrives in this inhospitable environment – it infects the stomachs of approximately 40% of the world’s population. Chronic H. pylori infection can cause stomach ulcers and gastric cancer. But in most people, chronic infection does not cause any harm. It is unclear why and how disease develops in some people but not others.
Researchers in Dr. Nina Salama’s lab in the Fred Hutch Human Biology Division are investigating how H. pylori infection leads to gastric cancer. The genetics of the infecting H. pylori strain contribute to the risk of cancer development, but the ability of an H.pylori strain to adapt to a changing host environment and maintain robust stomach colonization may also lead to disease.
“We are interested in looking at the evolution at the scale of years, within a single host as H. pylori causes disease and changes the environment it must live in,” said graduate student Jacob Frick, leading author on a recent study available as a preprint on BioRvix. “We approached this from the surface of the bacteria, looking at genetic factors that influence direct interactions with host cells and proteins.”
The team worked with Aaron Ring in the Fred Hutch Translational Science and Therapeutics Division and Noah Palm at Yale University to perform a genome wide association study of 48 distinct H. pylori strains to identify regions in the bacterial genome where genetic diversity correlates with binding strength between the bacteria and human stomach cell surface proteins. They identified many genes that affect the bacterial cell surface, including genes for enzymes involved in the biosynthesis of lipopolysaccharide (LPS), the molecules that coat the bacterial outer membrane.
To understand how the bacteria evolve during infection, the researchers infected mice with H. pylori and compared the genetics and adherence traits of the bacteria used for the infection (parental strain) and the bacteria recovered from the stomach post-infection (passaged strain). They found that H. pylori evolves stronger adherence to stomach tissue during infection. The structure of LPS also changes – the molecules, which are made of long chains of sugars, become shorter. This led the team to hypothesize that genetic adaptation in the genes involved in LPS synthesis affects LPS structure and influences its ability to bind to host stomach tissue.
The researchers then focused in on one bacterial gene, futB, that encodes an enzyme that adds the sugar fucose to the growing LPS chain. Sequencing of the futB gene in parent and passaged H. pylori strains revealed that the gene (and the enzyme it encodes) becomes shorter during infection. Additional experiments confirmed that H. pylori strains with shorter futB enzymes have improved adherence to stomach tissue.
These results suggest a model in which bacterial genetics impact adherence phenotype and bacterial fitness. Shorter futB enzymes lead to shorter LPS chains, improved binding to human proteins, stronger adherence to stomach tissue, and enhanced bacterial colonization and survival.
Frick noted, “We identified these naturally occurring changes in lipopolysaccharide genes that have a profound effect on adherence and colonization, but we still don't know the selective pressure driving the mutations or mechanism of how they alter adherence.” Understanding this will be critical to elucidating how H. pylori persists and drives disease.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Aaron Ring and Nina Salama contributed to this research.
The spotlighted research was funded by the National Institutes of Health and The Leona M. and Harry B. Helmsley Charitable Trust.
Frick JP, Sonnert ND, Snow JA, Overly M, Yang H, Stoppler MN, Ring AM, Ernst RK, Palm NW, and Salama NR. 2026. Helicobacter pylori allelic variation in cell surface genes influences human exoproteome binding and stomach adherence. BioRxiv. doi: 10.64898/2026.03.06.710112
Science Spotlight writer Ashley Person is a PhD candidate in the Cohn lab in the Vaccine and Infectious Disease Division at Fred Hutch. She studies how HIV-infected cells persist over time in people living with HIV on long term treatment.
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