Their findings suggest that the gut microbes may serve as noninvasive biomarkers to help identify subtypes of CRC and guide personalized treatment recommendations.
“Our new work contributes to the growing body of evidence highlighting the significance of microbiota-driven mechanisms in cancer pathogenesis,” lead investigator Weizhong Tang, MD, with Guangxi Medical University Cancer Hospital in Nanning, China, said in a statement.
The research was recently published online in Microbiology Spectrum.
The onset and growth of CRC has been linked both to imbalances in the gut microbiome and to mutations in the KRAS gene — about 40% of people with CRC have a KRAS mutation. Yet, the interplay between gut dysbiosis and KRAS mutations in CRC remains unclear.
To investigate further, Dr. Tang and colleagues used 16s rRNA sequencing to analyze stool samples from 94 patients with CRC, including 24 with KRAS-mutated CRC and 70 with KRAS wild-type (nonmutated) CRC.
The researchers identified 26 distinct types of gut microbiota with statistically significant differences in abundance between the KRAS mutant and KRAS wild-type CRC patients.
At the genus level, Fusobacterium, Clostridium, and Shewanella were all abundant in the KRAS mutant group.
Fusobacterium is a Gram-negative microbe found in the gastrointestinal tract and the oral cavity. Recent studies have established a strong link between Fusobacterium and CRC development. Other work found elevated levels of Fusobacterium nucleatum were not only closely associated with KRAS mutation but also correlated with chemoresistance in CRC.
Clostridium produces metabolites in the large intestine, which are known to cause DNA damage and trigger inflammatory responses, thereby increasing the risk of CRC development.
Similarly, Shewanella has been proven to be a contributor to CRC development.
The researchers say it’s “plausible” to consider all three as potential noninvasive biomarkers for identifying KRAS mutation in CRC patients.
In contrast, Bifidobacterium and Akkermansia were abundant in the KRAS wild-type group.
Bifidobacterium is a probiotic with antitumor activity and Akkermansia is a Gram-negative anaerobic bacterium abundant in the gut and currently recognized as a potential probiotic.
The researchers speculated that CRC patients may have a reduced likelihood of developing KRAS mutation in the presence of Bifidobacterium and Akkermansia.
Analyses of biological pathways of gut microbiota associated with KRAS mutation status in CRC revealed a significantly higher abundance of the isoflavonoid biosynthesis pathway in the KRAS wild-type group compared with the KRAS mutant group.
“In comparison to KRAS mutant CRC, it is postulated that KRAS wild-type CRC may be less aggressive due to the upregulation of the isoflavonoid biosynthesis pathway, which may inhibit CRC development and progression,” the authors wrote.
Promising Predictive Model
Dr. Tang and colleagues also developed a machine learning model to predict KRAS mutation status in CRC patients based on the gut microbiota signature in KRAS mutant CRC.
The initial results underscore the model’s predictive efficacy and suggest that it has “considerable potential for clinical application, offering a novel dimension in the prediction of KRAS mutation status among CRC patients in a clinical setting,” the authors wrote.
They caution that the model requires data from a larger cohort to improve its efficacy, and they plan to do larger studies to validate the findings.
The study had no commercial funding. The authors declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
