Nature | Vol 585 | 24 September 2020 | 509Review
Host–microbiota maladaptation in
colorectal cancer
Alina Janney^1 , Fiona Powrie^1 ✉ & Elizabeth H. Mann^1Colorectal cancer (CRC) is a heterogeneous disease of the intestinal epithelium that is
characterized by the accumulation of mutations and a dysregulated immune
response. Up to 90% of disease risk is thought to be due to environmental factors such
as diet, which is consistent with a growing body of literature that describes an
‘oncogenic’ CRC-associated microbiota. Whether this dysbiosis contributes to disease
or merely represents a bystander effect remains unclear. To prove causation, it will be
necessary to decipher which specific taxa or metabolites drive CRC biology and to
fully characterize the underlying mechanisms. Here we discuss the host–microbiota
interactions in CRC that have been reported so far, with particular focus on
mechanisms that are linked to intestinal barrier disruption, genotoxicity and
deleterious inflammation. We further comment on unknowns and on the outstanding
challenges in the field, and how cutting-edge technological advances might help to
overcome these. More detailed mechanistic insights into the complex CRC-associated
microbiota would potentially reveal avenues that can be exploited for clinical benefit.Colorectal cancer (CRC) is the second leading cause of cancer-related
death worldwide, and its incidence is increasing, particularly in indi-
viduals under 50 years of age^1 ,^2. As such, new diagnostic and treatment
options are needed. Unlike the well-described causal role of Helico-
bacter pylori in gastric cancer, a specific microorganism that triggers
CRC has not been identified. Nevertheless, an emerging strategy is to
target the altered—and putatively oncogenic—microbiota that has been
reproducibly identified in patients with disease. However, we must
first better understand what underlies the microbiota associations
that are observed in CRC, as well as their functional consequences.
Here we review published mechanisms pertaining to host–microbiota
interactions in CRC, and examine how microorganisms and metabolites
can elicit the hallmarks of cancer. We further consider host maladap-
tations that promote tumorigenesis by enabling the penetration of
microorganisms through the gut wall and deleterious inflammation.
Throughout this Review, we discuss potential explanations for seem-
ingly contrasting data and identify unresolved questions. We finish by
outlining technological advances that can be harnessed to accelerate
progress.
The intestinal host–microbiota interface
The mammalian colon co-evolves with a diverse microbial ecosystem,
in which symbiotic interactions facilitate the development of both host
and microbiota, in part by shaping a robust immune system in the host^3.
Complex dialogue between the host and the microbiota ensures peace-
ful coexistence with dietary components and beneficial commensals,
as well as defence against potentially harmful pathogens^4 ,^5. Central
to sustaining this balance are intestinal epithelial cells (IECs), which
form a single-layer physical barrier at the host–microbiota interface
that is continuously replenished by multipotent intestinal stem cells
residing in intestinal crypts^6 (Fig. 1 ). IEC proliferation is regulated by a
stem cell niche and involves paracrine signalling from the underlying
mesenchyme^7 , whereas the integrity of the barrier is further reinforced
by inter-epithelial tight-junction proteins alongside the secretion of
protective mucins^6.
In addition to their function as a physical barrier, IECs sense the
microbiota through pattern recognition receptors. Stimulation of
these receptors promotes epithelial cell repair and the upregulation
of tight-junction proteins, and triggers the production of various
cytokines that signal to cells in the lamina propria^6. Critically, the epi-
thelium does not stand alone, but rather as a triad with immune cells and
the mesenchyme (Fig. 1 ). If epithelial barrier defences are breached by
microorganisms or their products, immune and mesenchymal cells act
as a second line of defence by initiating a cascade of signalling networks
that uphold epithelial integrity^6 ,^8. For example, activation of the NF-κB
and STAT3 pathways can trigger the production of growth factors and
cytokines, which support homeostatic tissue repair^9. Such responses
simultaneously shape the microbiota by exerting a selective pres-
sure for particular microorganisms and by triggering the secretion of
epithelial-derived factors such as mucins and antimicrobial peptides^8.
Although mesenchymal cells are dynamic and are critical in maintain-
ing homeostasis^10 , further work is required to determine whether they
interact directly with the microbiota. Nevertheless, tight-knit regula-
tion of these interconnected pathways is essential, because excessive
stimulation can transform a well-balanced network into an inflamed
wound that will not heal^11.The aetiology of CRC
CRC is a disease of the intestinal stem cells that is characterized by
dysregulation of multiple components within the intestine (Fig. 1 ).
Although the underlying cause is often unclear, inflammation asso-
ciated with inflammatory bowel disease (IBD) is a known risk factorhttps://doi.org/10.1038/s41586-020-2729-3
Received: 7 May 2020
Accepted: 29 July 2020
Published online: 23 September 2020
Check for updates(^1) Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. ✉e-mail: [email protected]