Characterizing gut microbial structural variation reveals strain heterogeneity and metabolic dysfunction in colorectal cancer.

Authors

Ying Cui, Qintian Qiu, Yongqiu Chen, Tao Ding

Published in

mSystems. Pages e0110926. Nov 13, 2026. Epub Nov 13, 2026.

Abstract

Previous studies investigating gastrointestinal (GI) diseases have primarily focused on the composition, gene expression, and specific strains of gut microbiota. However, the impact of genetic variations, especially structural variations (SVs) in microbial genomes, on the development of GI tumors has been largely overlooked. In this study, we analyzed 1,027 fecal metagenomes from seven data sets and identified 8,278 coverage-defined SVs across 51 bacterial species in the gut microbiomes. We found that SVs were prevalent in the gut microbiota of studied cohorts. Surprisingly, the genetic makeup of SV-based clusters differed significantly between healthy individuals and those with colorectal cancer (CRC), indicating substantial intra-specific diversity within these populations. By integrating taxonomic-SV markers, we achieved optimal accuracy in early CRC detection, and the SVs also displayed regional heterogeneity. Microbial genetic variation provides additional insights into taxonomy and functionality, allowing us to have a more precise understanding of the microbiota associated with CRC. Notably, our study uncovered potential links between microbial SVs and metabolic disorders of CRC, including SV regions that encode glycoside hydrolases associated with disordered carbohydrate metabolism in CRC. We integrated a framework called MicroSVsProfiler to identify and classify SVs in individuals diagnosed with CRC, as well as in healthy controls. Our findings underscore the importance of considering SVs in microbiome studies, especially in the absence of strain-specific differences in abundance. Future research should explore the deeper layer of the microbiota's structural variantome for a better understanding of the occurrence and characteristics of CRC across different stages.IMPORTANCEMost microbiome studies of colorectal cancer focus on which bacterial species are more or less abundant, potentially overlooking genetic differences among strains of the same species. By analyzing 1,027 fecal metagenomes from seven independent cohorts, we show that large-scale changes in bacterial genomes, known as structural variations, provide disease-related information that is not captured by species abundance alone. These strain-level SV signatures distinguished healthy individuals from patients with colorectal cancer, improved early-cancer classification when combined with taxonomic markers, and varied across geographic populations. We also found that cancer-associated structural variations were linked to altered microbial metabolic functions, particularly carbohydrate metabolism and glycoside hydrolases. Together, these findings establish microbial structural variation as a complementary dimension of the gut microbiome and provide a framework for developing more precise, population-aware biomarkers and for investigating how strain-level genetic changes may contribute to metabolic disturbances associated with colorectal cancer.

PMID:
43023736
Bibliographic data and abstract were imported from PubMed on 13 Nov 2026.

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