Nature | Vol 585 | 24 September 2020 | 515routine diagnostics, as has been reviewed recently^30 ,^148. Therapeutics
that target the microbiota are also emerging—including selective elimi-
nation of oncomicrobes, faecal transplantation of anti-tumorigenic
species and skewing the microbiota by oral supplementations or tar-
geted bacteriophage therapy^30 ,^149 ,^150. However, careful consideration
of any therapeutic avenue is required owing to the numerous effects
of the microbiome on the biology of the host, many of which are cur-
rently unknown.
To uncover the desired clinical potential of the microbiome in
CRC, we must continue to distinguish correlation and causation by
systematically adding knowledge to the layers of complexity. For exam-
ple, CRC-associated mutations are known to affect the way in which
cells respond to stimuli—such as a mutation in KRAS that increases
responsiveness to IL-22^151 —but whether such mutations affect host
colonization, dysbiosis and intercellular communications is unclear.
Importantly, we must decipher whether characteristics of specific
strains or the collective capabilities of an ‘oncogenic’ microbiota—
which encompasses bacteria, fungi, viruses, archaea and their pro-
duced metabolites—alter disease. Owing to the vast intra-individual
heterogeneity in the microbiota, it is plausible that distinct strains in
different individuals will trigger a similar pathology through common
pathways. Therefore, targeting wide-spanning functions, rather than
specific taxa, might be the most effective strategy^152. Finally, although
we have focused on the microbiome in CRC, many of the underlying
mechanisms that we have discussed could be relevant to other diseases
such as IBD, in which certain bacteria—including E. coli and B. fragilis—
are similarly over-represented^153.
Conclusion
Various mechanisms have been revealed that begin to explain how
elements of the microbiota modulate tumorigenesis, broadly ranging
from alteration of the intestinal barrier and/or immune landscape to
reshaping the colonic ecological niche and the provision of genotoxic
insults (Fig. 1 ). Although host maladaptation and consequential barrier
breakdown is most probably critical in order to facilitate close proxim-
ity between the host and the microbiota, longitudinal multi-omics are
required to decipher the chronology of these ‘phases’ in tumour devel-
opment. To provide answers to the many open questions, an in-depth
understanding of how the microbiota mediates its effects in the context
of the tumour microenvironment—whether through direct effects on
DNA damage and inflammation or through other host-derived mecha-
nisms—is required. Fortunately, technological advances provide us
with revised tools to study the microbiota in the context of increasingly
physiological CRC model systems, in order to decipher the challenging
complexity of a colonic tumour microenvironment.
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