New methodologies to find microbiome biomarkers

 Researchers from VIB-KU Leuven, UZ Leuven, Janssen Pharmaceuticals and multiple international collaborators have used quantitative methods and confounder control for the first time, to identify microbiome biomarkers in colorectal cancer development.

Cancer microbiome research has advanced significantly in the past decade, resulting in novel insights into cancer-associated biomarkers. However, previous research has concentrated on non-quantitative, descriptive biomarker discovery methods. The new study reveals the risks of adhering to these methods, which may have resulted in incorrect associations.

The team combined Quantitative Microbiome Profiling (QMP) with extensive patient phenotyping from a group of 589 patients at various stages of colorectal cancer. Additionally, they reanalysed the data from 15 published studies encompassing a total of 4439 patients and controls. The study showed that without confounder control, the results are equivalent to those stated by the authors of the published cohorts. Conversely, when confounder control and absolute quantitative methods are integrated, some previously claimed microbial biomarker associations are shown to be driven by other factors rather than cancer diagnosis.

Dr Jeroen Raes, PI and Vice-Director at VIB-KU Leuven Center for Microbiology and Rega Institute, Faculty of Medicine, KU Leuven, explained: “By implementing confounder control and quantitative profiling, we were able to reveal potential misleading associations between microbial markers and colorectal cancer development, for example driven by intestinal inflammation.”

Transit time, faecal calprotectin, and BMI were identified as primary microbial covariates, surpassing the variance explained by traditional CRC diagnostic groups. Surprisingly, well-established microbiome-CRC targets, like Fusobacterium nucleatum, failed to notably associate with CRC diagnostic groups when controlling for these covariates. Instead, robust associations of Anaerococcus vaginalis, Dialister pneumosintes, Parvimonas micra, Peptostreptococcus anaerobius, Porphyromonas asaccharolytica, and Prevotella intermedia with CRC were identified, suggesting their potential as future targets.

First author and postdoc at the Raes Lab Dr Raul Yhossef Tito-Tadeo added: “This research underscores the importance of rigorous methodologies in unravelling complex disease-microbiome associations. Many of the discovered targets have been mostly ignored until now.”

The findings have great clinical implications, as there is a requirement for quick, non-invasive colon cancer diagnostics. Current screening tools lack specificity and require many unnecessary colonoscopies, putting a burden on the healthcare system. 

“Fast, specific stool tests will allow a much larger number of individuals to be screened early, avoiding many unnecessary colon cancer deaths,” concluded Dr Sabine Tejpar, Gastro-enterologist at UZ Leuven, head of the Digestive Oncology group, and professor at the Faculty of Medicine KU Leuven. 

This study was published in Nature Medicine.