Nature - USA (2020-09-24)

512 | Nature | Vol 585 | 24 September 2020

Review

this receptor on myeloid cells increased bacterial invasion and IL-17A
secretion, as well as the number and size of proliferating tumours^84.
To add further complexity, many cytokines display pleiotropic func-
tions within CRC^25. For example, IL-22—which is known to be triggered
by the microbiome^85 ,^86 and produced by T cells and innate lymphoid
cells^87 —can sustain IEC proliferation and induce anti-apoptotic proteins
during inflammation (pro-tumorigenic), but can also promote barrier
integrity and induce the repair of DNA damage after genotoxic insults
(anti-tumorigenic)^87 –^90. It should be noted that some of these mecha-
nistic insights are derived from model systems using mouse-adapted
pathogens such as Helicobacter hepaticus^87. Such disparate roles for
cytokines in carcinogenesis depend on their concentration and their
temporal dynamics during disease progression, as well as the context
of other cell types, cytokines and mutations—variables that are often
overlooked in more reductionist studies.

Inflammation-driven bacterial niche
Studies of IBD^91 —and now the CRC models discussed below—have illus-
trated that uncontrolled inflammation creates a different ecological
niche within the colon, leading to the outgrowth of bacterial species
that are better adapted. Although this is typically regarded as detrimen-
tal, such a nuanced process may be evolutionarily important. When
studying putatively harmful species, it should therefore be considered
that the shift towards a microbiota that has adapted to cope with the
new harsh environment might be critical for host regeneration.

The abundance of specific ‘oncogenic’ species seems to depend in

part on the anti-inflammatory cytokine IL-10, illustrating the detrimen-

tal consequence of immune maladaptation during carcinogenesis.

Indeed, increased amounts of genotoxic pks+ E. coli were observed

in the intestine of IL-10-knockout mice, and tumour multiplicity was

dependent on unrestrained inflammation^92 ,^93. IL-10 deficiency is also

reported to coincide with increased abundance of the Bacteroides,

Prevotella and Rikenella genera^94. The combined inhibition of IL-10 and

the bacterial scavenger protein lipocalin in vivo leads to the colonic

outgrowth of Alistipes spp., a microorganism that induces spontane-

ous colitis-associated cancer in an IL-6-dependent manner^95 and is

over-represented in cohorts of patients with CRC^96. Importantly, the

microbial community can feed back to alter levels of IL-10, for exam-

ple through the production of butyrate. Signalling downstream of

butyrate-specific receptor GPR109A suppressed inflammatory-driven

carcinogenesis and enabled macrophages and dendritic cells to skew

CD4+ T cells into IL-10-producing T regulatory cells^66. Additionally,

Clostridium butyricum, a butyrate-producing strain that is used clini-

cally for its anti-inflammatory effects in IBD, can supress IEC prolifera-

tion in tumour-bearing ApcMin/+ mice by decreasing expression of the

Wnt pathway component β-catenin^97.

Like IL-10, a lack of IL-33 also enhances susceptibility to

inflammation-driven colon cancer. Genetic ablation of IL-33 coin-

cides with an early increase of pro-inflammatory IL-1α, preceding a

later wave of inflammation driven by IL-6, IL-17 and IL-1β in the mouse

colon. In vivo, IL-33 triggered production of immunoglobulin (Ig)A,

MDSC

CXCL1

CXCL2

CXCL5

NK cell

TAN

TAM

IgA

FFAR2 ATG7

CCL5

CCL20

?

Homeostasis Maladaptation Barrier dysfunction Inammation Hyperplasia Tu mour

H. hepaticus

IL-1β

IL-23a

IL-6 IL-17a

IL-22

NOD

1/2

Alistipes

spp.

A. muciniphila

pks+

E. coli

FOXP3+ Treg cell

IL-10

SCFAs

Plasma cell

Ty pe 17

lymphoid cells

(CD4+ TH17 cells

and ILC3s)

CD4+ TH1 cell

CD4+ T cell

Enterotoxigenic P. anaerobius

B. fragilis

F. nucleatum

CD8+ T cell

Pro-inammatory

myeloid cells

IL-33

Microbiota

Mucus

ab

e

f

c

d

Fig. 2 | Known inf lammatory mechanisms by which the microbiota
contributes to CRC. The microbiota contributes to CRC pathogenesis via a
range of emerging mechanisms. a, Microbiota-derived SCFAs induce IL-10,
which can dampen inf lammation. IL-33 upregulates the production of IgA,
which limits the activity of mucus-degrading A. muciniphila. b, Inf lammation
triggered by IL-10 deficiency enables the outgrowth of harmful (Alistipes spp.),
genotoxic (pks+ E. coli) and other undefined species that further enhance
inflammation and contribute to genomic instability. c, Increased epithelial
permeability enables the inf lux of various species that stimulate
pro-inf lammatory cytokine production, affecting epithelial cell proliferation
and promoting CD4+ TH17 responses. Altered innate immunity is permissive for

H. hepaticus-induced IL-22 production by ILC3 and leads to epithelial cell

proliferation. d, Biofilms containing ETBF, pks+ E. coli and F. nucleatum coat

tumours and polyps and coincide with increased mRNA levels of IL6, IL23A and

I L 1 7A. e, Specific species alter the immune-cell composition of the tumour

microenvironment. For example, ETBF and P. anaerobius trigger the secretion

of chemokines that recruit immunosuppressive MDSCs, tumour-associated

macrophages (TAMs) and tumour-associated neutrophils (TANs), whereas

F. nucleatum can directly inhibit the cytotoxic activity of natural killer (NK)

cells. Elements of the microbiota can be protective in CRC, such as certain

Clostridia species, which promote CD4 TH1 and CD8 T cell responses (f). ILC,

innate lymphoid cell.