Gut microbiome study challenges established cancer biomarkers, identifies new bacterial links to colorectal cancer

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In a recent study published in the journal Nature Medicine, a European team of researchers quantitatively characterized the microbiome profile to study the association between gut microbiota and malignant colonic transformations in colorectal cancer. They also aimed to identify the covariates related to the microbiome that could be obscuring the biological phenomena involved in the association between the gut microbiome and colorectal cancer.

Study: Microbiome confounders and quantitative profiling challenge predicted microbial targets in colorectal cancer development. Image Credit: FOTOGRIN / Shutterstock

Background

The incidence of colorectal cancer is on the rise, especially among individuals below the age of 50 years. It is the third most prevalent form of cancer and has the second highest rate of cancer-associated mortality. However, early detection and treatment can effectively decrease the progression of colorectal cancer and reduce the risk of mortality. Timely detection through colonoscopies and the removal of adenomas and polyps are known to reduce the risk of colorectal cancer by 90%.

Recent research on the gut microbiome has revealed that shifts in the gut microbiota have been linked to various disease phenotypes. Studies have also reported an association between bacterial markers, such as an increase in  Fusobacterium in the stool and lesions of patients with colorectal cancer. However, the ascertainment of risk factors of colorectal cancer and the role of confounding variables, which can improve population-wide screening, remains a challenge.

About the study

The present study quantitatively characterized the microbiota profile to determine its associations with malignant transformations in the colon. The researchers examined close to 600 microbial profiles of patients whose clinical presentations necessitated a colonoscopy, some of whom were colorectal cancer patients. These microbial profiles were then compared with those from previous studies and existing datasets, which included colorectal cancer patients and controls.

The researchers also aimed to identify covariates that could potentially obscure or confound the biological phenomena underlying the association between gut microbiota and the risk of colorectal cancer. They believe that although it is known that multiple variables can influence the gut microbiome profiles, the control for these covariates has not been standardized. Factors such as moisture content, known to impact the overall variation in the gut microbiome significantly, are not controlled for in numerous studies.

Furthermore, the approach of relative microbiome profiling, which expresses taxon abundance in percentages and is the predominantly used method in microbiome studies, presents various issues related to microbial compositions and relative profile interpretations. Therefore, a quantitative microbiome profiling approach, which uses normalized comparisons of profiles across differing conditions or samples, helps lower the rates of false negatives and false positives.

In the present study, the researchers used clinical and colonoscopic assessments to categorize the participants into three groups: those with no evidence of colon lesions, patients with precancerous lesions or polyps between 6 mm and 10 mm in size and less than 10 in number, and patients in various stages of colorectal cancer. Flow cytometry was used to measure the microbial load of the stool samples collected from the participants.

Additionally, the loss of mass after lyophilization of the stool samples was used to determine the moisture content and fecal concentrations of calprotectin were also measured. Deoxyribonucleic acid (DNA) was extracted from the stool samples, and the 16S ribosomal ribonucleic acid (RNA) sequence was amplified using polymerase chain reaction (PCR) for the microbial profiling.

Results

The results showed that established biomarkers of colorectal cancer, such as Fusobacterium, were not significantly associated with colorectal cancer diagnosis after controlling for covariates such as body mass index (BMI), fecal calprotectin (an indicator of intestinal inflammation), and transit time (measured using moisture content as proxy).

However, the study found robust associations between colorectal cancer risk and bacterial species such as Prevotella intermedia, Porphyromonas asaccharolytica, Peptostreptococcus anaerobius, Parvimonas micra, Dialister pneumosintes, and Anaerococcus vaginalis. The researchers believe these bacteria should be targeted as potential biomarkers for colorectal cancer risk.

Additionally, individuals who did not have lesions in the colon but whose fecal immunochemical tests justified the need for a colonoscopy were enriched for the Bacteroides2 enterotype, indicating all the hallmarks of gut microbiome dysbiosis such as low microbial richness, low cell count, a decrease in butyrate-producing bacteria, higher abundance of proinflammatory bacteria, and higher concentrations of fecal calprotectin. These findings also highlight the uncertainties involved in determining healthy controls for research related to cancer microbiome.

Conclusions

Overall, the quantitative characterization of the microbial profiles of patients with colorectal cancer, precancerous polyps, or lesions revealed that established biomarkers of colorectal cancer risk were not significant when adjusted for covariates such as moisture content, BMI, and fecal calprotectin. However, robust associations were found between numerous other bacterial species and colorectal cancer, which can potentially be targeted as biomarkers.

Additionally, the findings revealed that individuals with no colonic lesions but with positive fecal immunochemical tests show enrichments of the enterotype for microbiome dysbiosis, highlighting the complex nature of cancer microbiomes.

Journal reference:
  • Tito, R. Y., Verbandt, S., Vazquez, A., Lahti, L., Verspecht, C., LlorénsRico, V., VieiraSilva, S., Arts, J., Falony, G., Dekker, E., Reumers, J., Tejpar, S., & Raes, J. (2024). Microbiome confounders and quantitative profiling challenge predicted microbial targets in colorectal cancer development. Nature Medicine. DOI: 10.1038/s41591024029632, https://www.nature.com/articles/s41591-024-02963-2 
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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