Helicobacter pylori is a bacterium well-adapted to colonize the hostile, acidic human stomach. Roughly half of all people in the world are infected with H. pylori, and the bacterium is spread through bodily fluids and poor hand hygiene. While many people infected with H. pylori are asymptomatic, some go on to develop stomach pain, peptic ulcers, or, in the most severe cases, stomach cancer. H. pylori infection causes inflammation in the stomach lining which can lead to the loss of the acid- and digestive enzyme-producing cells in the stomach. Researchers hypothesize that the chronic inflammation and changing pH contribute to the development of stomach cancer, but the exact mechanisms underlying this process are unclear.
Stomach acid usually destroys any bugs trying to sneak their way into the body. Destruction of the acid-producing cells in the stomach by H. pylori infection ultimately makes the stomach less acidic, causing a dramatic shift in the type and number of bacteria present. As the stomach becomes less acidic, bacteria from the mouth can colonize the stomach. “Only a small percentage of people with H. pylori infection get stomach cancer, so we’ve always been thinking about what the other missing stuff is, and another microbe could be [contributing to cancer development],” explains Dr. Nina Salama, a pioneering H. pylori researcher. Of these oral bacteria, Fusobacterium species are associated with a wide range of cancers including stomach and colon cancer. Still, the precise role of Fusobacteria in stomach cancer remained elusive. In a new preprint, researchers in the Salama lab, led by Dr. Camilo Gómez-Garzón, sought to characterize how Fusobacterium species colonize stomach tissue and how stomach cancer change these interactions.
The team began by determining whether Fusobacterium animalis could invade stomach cancer cells. Cell invasion requires bacteria to adhere to and invade a cell. They incubated the bacteria with a common cancer cell line and quantified the bacteria that stuck to or invaded the cells. Under low oxygen conditions (like those in the stomach), they found that F. animalis adhered to and invaded cancer cells. Next, they compared the ability of F. animalis and F. nucleatum, another cancer-associated Fusobacterium species, to invade stomach cancer cells under hypoxic conditions. They found that both bacteria were able to invade cultured cells, but invasion by F. animalis was more robust.
“Fusobacterium is called a sticky bug because it has a diverse arsenal of adhesins…that have a role in cell invasion and adherence,” explains Gómez-Garzón. One adhesin in this arsenal targets the Gal-GalNAc sugar motif on the surface of cells. Previous work has shown that F. animalis can use Gal-GalNAc to invade cells, and Gal-GalNAc is upregulated in gastric cancer. To test if Gal-GalNAc mediated F. animalis cell invasion, the team incubated F. animalis with free floating Gal-GalNAc and quantified cell invasion. They found that Gal-GalNAc impaired the ability of the bacteria to invade stomach cancer cells. In parallel, they confirmed that stomach cancer cells express Gal-GalNAc on their surface. Together, these results suggest that Gal-GalNAc contributes to cancer cell invasion by F. animalis.
Before H. pylori infection induces stomach cancer, the bug can create a precancerous state in the tissue. Precancerous stomachs are less acidic than healthy stomachs, and their cells display different sugars on their surfaces. To understand how Fusobacteria may interact with non-cancerous cells, the group investigated whether Fusobacteria could colonize healthy and precancerous stomach tissue. They infected mice with normal or precancerous stomachs with F. animalis or F. nucleatum and quantified the amount of bacteria present over time. They found that neither bacterium was able to colonize healthy stomach tissue, and F. nucleatum was unable to colonize the precancerous stomach. In contrast, F. animalis heavily colonized the precancerous stomach. Precancer in stomach tissue occurs in different stages over time. To assess the impact of precancer stages on F. animalis colonization, the team infected precancerous stomachs with F. animalis at different timepoints and saw that F. animalis loads increased at later precancer stages.
To determine the impact of acidity changes in F. animalis colonization, the group gave mice with precancerous stomachs acidified or non-acidified drinking water and measured F. animalis loads over time. Mice drinking less acidic water had higher F. animalis loads, indicating that the low acidity in precancerous stomachs promotes F. animalis colonization. Despite this, lowering the acidity of healthy stomach tissue with omeprazole, a common drug for gastritis and heartburn, did not lead to F. animalis colonization. They next examined the contribution of cell surface sugars to F. animalis colonization by quantifying Gal-GalNAc expression in precancerous and normal stomachs. Precancerous stomachs expressed higher levels of Gal-GalNAc, but when the team analyzed samples from patients with stomach cancer, they did not find a significant correlation between F. animalis infection and Gal-GalNAc production. Together, these results indicate that neither acidity nor Gal-GalNAc expression are sole drivers of F. animalis infection during precancer.
It is well established that H. pylori infection changes the bacterial populations present in the stomach, but whether H. pylori and F. animalis could coexist in the same stomach was unclear. “Clinical data shows that usually H. pylori and Fusobacterium seem to be mutually exclusive,” says Gómez-Garzón. They put these clinical findings to the test by coinfecting precancerous stomachs with F. animals and H. pylori. Surprisingly, the team found that both bacteria could colonize the same stomach. “There could be some kind of collaboration, or maybe [each bacteria] are just doing their own thing,” continues Salama.
Taken together, these results show that F. animalis can colonize precancerous stomach environments. This work challenges the previous notion that F. animalis is only found in cancerous stomach tissue. While Gal-GalNAc and reduced acidity are important for F. animalis growth in the precancerous tissues, other mechanisms underlie bacterial invasion. The team hopes that future work can further elucidate these factors that contribute to infection.
This work was supported by funding from the Gastric Cancer Foundation, the National Institutes of Health, the Fred Hutch Cancer Center Microbiome Research Initiative Pilot Grant, and a Washington Research Foundation Postdoctoral Fellowship to CGG.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Nina Salama contributed to this work.
Gómez-Garzón C, Chen Q, O’Brien VP, Salama NR. 2026. Metaplasia Enables Stomach Colonization by Fusobacterium animalis. bioRxiv. 2025 Dec 19:2025.12.16.694801. doi: 10.64898/2025.12.16.694801.
Kelsey Woodruff is a PhD candidate in the Termini Lab at Fred Hutch Cancer Center. She studies how acute myeloid leukemia cells remodel the sugars on their membranes to reprogram cancer cell signaling. Originally from Indiana, she holds a bachelor's degree in Biochemistry from Ball State University. Outside of lab, you can find her crocheting and enjoying the Seattle summers.
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