Genes alone cannot explain the current rise in colorectal cancer (CRC) and scientists are now trying to elucidate the gut microbiota’s contribution as an important player. Previous human research has shown mechanisms by which the bacteria miht affect tumorigenesis, especially in the early stages. However, gut microbiome signatures of CRC in association studies have not always been validated across different populations and are subject to biological and technical confounders.
Two articles on the involvement of gut microbiome in CRC were recently published in Nature Medicine.
The first study, led by researchers from the European Molecular Biology Laboratory in Heidelberg (Germany), the University of Copenhagen (Denmark) and the University of Trento (Italy), has identified a set of 29 species indicative of colorectal cancer across populations from seven countries.
By comparing fecal metagenomic data from case-control studies and using newly generated data, the researchers sought to establish robust gut microbiome signatures of CRC across seven cohorts from France, Austria, Italy, Germany, the United States, China and Japan.
Despite differences in geography, dietary patterns and lifestyles, the authors found a set of 29 species indicative of CRC that seem to be universal, rather than only disease-specific. Most of these core gut microbial markers were previously associated with CRC and were more driven by geographical and technical study differences than the disease itself, whereas 11 Clostridiales species were unknown until now.
Interestingly, metagenomic analyses among the core set of 29 species enriched in the CRC gut microbiome revealed 4 species clusters with different gut microbiota composition, which were also related to tumor location and patient sex. They were, however, in general, independent of tumor stage:
- Cluster 1: exclusively comprised Porphyromonas species and was enriched in rectal tumors.
- Cluster 2: contained species with intermediate prevalence in CRC cases and was more abundant in female CRC patients.
- Cluster 3: comprised species with higher prevalence in CRC cases.
- Cluster 4: only contained members of the Clostridiales
At a functional level across studies, the gut microbiome from CRC patients was enriched in metabolic pathways involved in the degradation of amino acids, mucins and organic acids. That is indicative of a metabolic shift towards amino acid metabolism secondary to a fat- and meat-rich diet. In contrast, genes for carbohydrate metabolism were depleted.
Moreover, some gut microbial virulence and toxicity mechanisms were found to be enriched in CRC patients, which suggests their role in colorectal carcinogenesis. They included the adhesion protein A by Fusobacterium nucleatum, the enterotoxin of Bacteroides fragilis, colibactin by Escherichia coli and conversion of primary to secondary bile acids by Clostridium species. The enrichment of genes that encoded for these virulence factors was validated across all study populations.
Wirbel and colleagues also succeeded in establishing CRC-specific microbiome signatures and separated them for other conditions such as type 2 diabetes, Parkinson’s disease and inflammatory bowel disease, with similar effects on the gut microbiome, based on previous research showing gut microbiome signatures driven by specific diseases.
The researchers used five available datasets and two new cohorts to explore the reproducibility of previous links between the gut microbiome and CRC. The findings were also validated in two additional cohorts.
The gut microbiome of CRC cases showed higher richness than controls, which was explained by the translocation of microbes from the oral cavity into the colon.
At a functional level, Maltez Thomas and colleagues showed an enrichment of gluconeogenesis and amino acid putrefaction and fermentation pathways associated with CRC. In contrast, complex carbohydrates, stachyose and galactose metabolism pathways were enriched in controls.
It is worth mentioning that the capacity of certain gut bacteria to degrade choline—found in meat and other foods—into trimethylamine (TMA) metabolite—previously involved in atherosclerosis—was more abundant in CRC. This was explained by a higher expression of genes related to TMA synthesis in the CRC-associated metagenomes. The close relationship between gut microbiome and choline metabolism adds to mechanisms described by Wirbel and colleagues in confirming potentially carcinogenic gut microbiota virulence in CRC.
On the whole, both studies show the potential of gut microbial signatures for predicting CRC. This is based on the availability of whole-metagenome shotgun datasets of CRC cohorts, with an accuracy similar to the fecal occult blood test used for CRC screening.
As the specific gut microbiome signatures were validated in early CRC stages and in different studies, these data suggest potential for use as candidate for developing non-invasive CRC screening. However, it should be acknowledged that stool microbiome could help with predicting CRC when pooled datasets, rather than using independent cohorts, are used. This may be explained by the heterogeneity of studies and population characteristics.
“In the future we hope we can use these signatures as biomarkers and as a diagnostic tool for colorectal cancer,” says author Manimozhiyan Arumugam in a press release from the University of Copenhagen.
Wirbel J, Theodor Pyl P, Kartal E, et al. Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nat Med. 2019. doi: 10.1038/s41591-019-0406-6.
Maltez Thomas A, Manghi P, Asnicar F, et al. Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation. Nat Med. 2019. doi: 10.1038/s41591-019-0405-7.