More than 1·2 million patients are diagnosed with colorectal cancer every year, and more than 600,000 die from the disease. Incidence strongly varies globally and is closely linked to elements of a so-called western lifestyle. Incidence is higher in men than women and strongly increases with age; median age at diagnosis is about 70 years in developed countries. Despite strong hereditary components, most cases of colorectal cancer are sporadic and develop slowly over several years through the adenoma-carcinoma sequence. The cornerstones of therapy are surgery, neoadjuvant radiotherapy (for patients with rectal cancer), and adjuvant chemotherapy (for patients with stage III/IV and high-risk stage II colon cancer). 5-year relative survival ranges from greater than 90% in patients with stage I disease to slightly greater than 10% in patients with stage IV disease. Screening has been shown to reduce colorectal cancer incidence and mortality, but organised screening programmes are still to be implemented in most countries.

Several bacterial species have been implicated in the development of colorectal carcinoma (CRC), but CRC-associated changes of fecal microbiota and their potential for cancer screening remain to be explored. Here, we used metagenomic sequencing of fecal samples to identify taxonomic markers that distinguished CRC patients from tumor-free controls in a study population of 156 participants. Accuracy of metagenomic CRC detection was similar to the standard fecal occult blood test (FOBT) and when both approaches were combined, sensitivity improved > 45% relative to the FOBT, while maintaining its specificity. Accuracy of metagenomic CRC detection did not differ significantly between early- and late-stage cancer and could be validated in independent patient and control populations (N = 335) from different countries. CRC-associated changes in the fecal microbiome at least partially reflected microbial community composition at the tumor itself, indicating that observed gene pool differences may reveal tumor-related host–microbe interactions. Indeed, we deduced a metabolic shift from fiber degradation in controls to utilization of host carbohydrates and amino acids in CRC patients, accompanied by an increase of lipopolysaccharide metabolism.