Hidden Bacteria Inside Stomach Tumors May Signal How Aggressive Gastric Cancer Will Be

Deep inside stomach tumors, an ecosystem of bacteria appears to be rewiring itself as cancer takes hold — and the pattern of that rewiring may hold clues to how aggressive the disease will become. A new study from researchers at Nantong University in China, published in the Journal of Translational Medicine, offers one of the most detailed portraits yet of the microbial communities living within gastric cancer tissue, and it suggests these microscopic residents are far more than passive bystanders.

Gastric cancer remains one of the most lethal malignancies worldwide, and its burden is particularly heavy in China, where it ranks among the leading causes of cancer death. For decades, one bacterium has dominated the conversation about stomach cancer: Helicobacter pylori, the spiral-shaped microbe notorious for driving chronic inflammation and ulcers. But scientists increasingly recognize that the stomach is home to entire communities of microbes, and that tumors themselves — once thought to be sterile — harbor their own distinctive microbiota. What those intratumoral communities look like, and whether they matter clinically, has remained murky.

The Nantong team, led by Haonan Zhou, Wei Feng, Yuxi Li and senior authors Wei Zong and Yan Huang, set out to resolve that ambiguity by combining two complementary DNA-sequencing approaches. The first, 16S ribosomal RNA sequencing, is the workhorse of microbiome research: it reads a conserved genetic marker present in all bacteria, allowing researchers to identify which microbial groups are present in a sample. The second, a technique called 2bRAD-M, takes a different route. Instead of targeting a single marker gene, it uses a restriction enzyme to slice the entire genomes in a sample into tiny, standardized fragments, which are then sequenced and mapped back to reference genomes. That gives the method the power to profile not just bacteria but also fungi and archaea, and to reach species-level resolution even when microbial DNA is scarce or degraded — a common problem in tumor tissue.

By running both methods on the same samples, the researchers could cross-validate their findings and capture a fuller picture than either technique alone could provide. They analyzed sixty paired samples: tumor tissue and adjacent normal tissue taken from the same patients with gastric cancer. Sequencing the pairs side by side allowed the team to control for each patient’s individual background and isolate the microbial changes specifically tied to the tumor itself.

The results revealed a clear signature of dysbiosis — a destabilized, imbalanced microbial community — within the tumors. At the phylum level, the firmicutes, a broad group of mostly Gram-positive bacteria, were markedly enriched in cancer tissue, while proteobacteria and several other major phyla declined. Zooming in to the genus and species levels, the team found that Lactobacillus, a genus usually considered benign or even beneficial in the gut, was enriched in tumor tissue, as was Streptococcus pneumoniae, a pathogen better known for causing pneumonia. Strikingly, Helicobacter pylori — the microbe most famously associated with stomach cancer — was actually reduced in the tumor samples relative to adjacent normal tissue.

That last finding is a reminder that the microbiology of established tumors may differ fundamentally from the microbiology of cancer initiation. H. pylori is a powerful driver of the chronic inflammation that sets the stage for gastric cancer, but once a tumor has formed, the microenvironment it creates — altered oxygen levels, changed acidity, disrupted immune surveillance — may favor entirely different microbial colonizers. The enrichment of Lactobacillus in particular raises intriguing questions: some studies have suggested that certain lactobacilli can promote tumor cell survival and proliferation, while others report protective effects. The new data add weight to the idea that in gastric tumors, this genus is part of a disease-associated community rather than a harmless passenger.

Critically, the microbial shifts were not just statistical noise. The team found that the abundance of specific microbial taxa correlated with clinical features of the disease, including TNM stage — the standard system for describing how far a tumor has grown and spread — and levels of carcinoembryonic antigen, or CEA, a protein biomarker routinely measured in patients with gastrointestinal cancers. In other words, the composition of the tumor microbiome tracked with measures of disease severity, raising the possibility that microbial profiles could one day complement existing biomarkers in assessing patients.

To verify that the sequenced DNA was not simply contamination introduced during sample handling, the researchers turned to independent methods. Fluorescence in situ hybridization, or FISH, uses fluorescently labeled probes that bind to specific bacterial RNA sequences, allowing intact microbial cells to be visualized directly inside tissue sections under the microscope. Immunohistochemistry for lipopolysaccharide, a molecule embedded in the outer membrane of many Gram-negative bacteria, provided a second line of visual confirmation. Together, these techniques demonstrated that bacteria genuinely reside within the tumor tissue, bolstering the sequencing results and addressing one of the most persistent criticisms of intratumoral microbiome studies.

Beyond cataloguing which microbes are present, the team used computational prediction tools to infer what the tumor-dwelling communities might be doing. Functional profiling suggested that microbial pathways related to metabolism and proliferation were significantly upregulated in gastric cancer tissue compared with normal tissue. While such predictions are indirect — they extrapolate function from the genes carried by the detected microbes rather than measuring activity directly — they hint that the intratumoral microbiota could be metabolically active participants in the tumor microenvironment, potentially supplying metabolites, modulating inflammation, or interacting with immune cells in ways that influence tumor behavior.

The study’s authors are careful to frame their conclusions appropriately. The work confirms that intratumoral microbiota dysbiosis exists in patients with gastric cancer and links specific taxa and functional pathways to clinical characteristics, but it stops short of proving causation. Whether the altered microbial communities help drive tumor progression, merely reflect it, or do some of both remains an open question that will require larger prospective cohorts and direct experimental studies. Still, the findings provide a foundation for future therapeutic strategies — from microbiome-based biomarkers that could refine risk assessment to interventions that might one day reshape the tumor’s microbial residents as part of cancer treatment. As the science of intratumoral microbiomes matures, gastric cancer is emerging as a prime example of how deeply intertwined microbes and malignancy can be.

Subject of Research: Intratumoral microbiota dysbiosis and its clinical associations in gastric cancer

Article Title: Integrated 2bRAD-M and 16S rRNA sequencing reveals intratumoral microbiota dysbiosis and clinical associations in gastric cancer

Article References: Zhou, H., Feng, W., Li, Y., Xu, Y., Zong, W., & Huang, Y. (2026). Integrated 2bRAD-M and 16S rRNA sequencing reveals intratumoral microbiota dysbiosis and clinical associations in gastric cancer. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09025-w

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09025-w

Keywords: gastric cancer, intratumoral microbiota, 2bRAD-M, 16S rRNA sequencing, dysbiosis, Helicobacter pylori, Lactobacillus, tumor microenvironment, biomarkers, CEA, TNM stage, Journal of Translational Medicine