Beyond species-level profiles: Connecting microbial communities, strain differences and colorectal cancer

Understanding the gut microbiome in colorectal cancer requires more than tracking which species increase or decrease. Researchers also need to examine how microbes interact, how strains within the same species differ genetically, and how these features influence metabolism and host responses.

A review by researchers from Fudan University and Tongji University brings these dimensions together. Published in Microbiology China, “Advances in multi-kingdom microecological dysbiosis and strain-level variations in colorectal cancer” connects microbial community changes and genetic variations with disease mechanisms, biomarker development and potential interventions.

“Knowing which microbes are present is only the starting point,” said Na Jiao, corresponding author and a principal investigator at Fudan University. “Understanding their relevance to cancer requires connecting community interactions and strain differences with the functions that affect the host.”

The review describes colorectal cancer-associated dysbiosis as a restructuring of microbial communities involving bacteria, archaea, fungi and viruses. Alongside changes in resident gut microbes, bacteria originating in the mouth can establish themselves in the intestine. Cooperation and competition among microbial groups may further influence colonization and community function. For example, research discussed in the review shows that Candida albicans, a fungus, can facilitate colonization of the colonic mucosa by Fusobacterium nucleatum, a bacterium implicated in colorectal cancer.

Within individual species, genetic differences provide another important layer of information. Strains can differ in tissue colonization, metabolic activity and interactions with host cells. The review highlights a distinct lineage within F. nucleatum subsp. animalis that is enriched in colorectal tumors and exhibits greater tumor-promoting potential. Changes ranging from individual DNA positions to gene acquisition or loss can help explain why species-level measurements may overlook biologically important differences.

The article connects these ecological and genetic features to three functional routes: microbial molecules, metabolic remodeling and signaling interactions with host cells. Toxins and adhesins can affect DNA integrity, tissue colonization and immune defenses. Microbial metabolites can support intestinal homeostasis or favor tumor development, depending on the molecule and biological context. Direct interactions with epithelial, tumor and immune cells can also influence cell proliferation, inflammation and antitumor immunity. Together, these mechanisms help explain how microbial changes may translate into host effects.

These insights support two broad avenues for translation. Biomarker research is expanding beyond individual species toward signatures combining multiple microbial groups, genetic variants and functional genes. Such approaches are being investigated for colorectal cancer and precancerous lesion detection, prognosis and treatment-response prediction. Microbiome-based interventions, including selected beneficial microbes, fecal microbiota transplantation, engineered bacteria and bacteriophages, are also under investigation, although most remain experimental and require further validation.

A central challenge is distinguishing cause from consequence. Microbes enriched in tumors may contribute to disease, adapt to the altered environment, or play different roles at different stages. Diet, medication and other factors can confound associations. Relative abundance measurements also cannot establish whether a microbe has increased in absolute number.

The authors therefore call for longitudinal studies, careful control of confounding factors, absolute microbial quantification and higher-resolution strain analysis. Integrating microbial genes, gene activity, proteins and metabolites with host responses, alongside experimental testing of candidate mechanisms, could build stronger evidence for translation.

“The goal is to establish which microbial functions influence disease, when they matter, and whether they can be measured or modified reliably,” Jiao said. “That evidence is essential for developing useful biomarkers and targeted interventions.”

This work was supported by the National Natural Science Foundation of China (Grant No. 32470098).