These observations are consistent with previous reports
demonstrating that whether
a harmful response occurs
when microbiota interact with
host immune systems is determined by host genetic factors
(1, 3). The findings of Atarashi
et al. uncover a bacterial strain
from oral microbiota that ectopically colonize inflamed
intestine, providing a resource
to study mechanisms of pathogenic gut inflammation.
Gut microbiota regulate the
development and function of
cells from the two arms of immunology—innate and adaptive
immune responses—and even
determine host responsiveness
to certain kinds of treatments,
including cancer immuno-therapeutics (6–8). Induction
of different T cell subsets with
the capacity to control or mediate inflammatory immune
responses can be polarized by
the signals from the commensal microbiota or pathobionts.
Interestingly, intestinal colonization of Kp-2H7 did not affect
T cell generation but preferentially induced inflammatory TH1
cell generation in the intestine,
indicating a unique mechanism
by which Kp-2H7 ectopically
induces TH1-mediated intestinal inflammation. Increasing evidence demonstrates
that the oral and intestinal microbiota
have substantial effects on the onset and/
or progression of nonintestinal inflammatory diseases such as cardiovascular diseases, autoimmune encephalomyelitis, and
arthritis, by inducing the generation of inflammatory immune cells that can migrate
to distant, inflamed tissues and mediate
damage (9–11). To investigate the mechanisms for the observed TH1-mediated inflammation by Kp-2H7, Atarashi et al. used
several mouse models deficient in certain
innate and adaptive immune responses.
They found that Klebsiella antigen-specific
TH1 responses were induced by dendritic
cells (DCs) via Toll-like receptor 4 (TLR4)
signaling, indicating that intestinal DCs
act as antigen-presenting cells to sense the
signals from pathobionts and then produce cytokines to initiate T cell responses.
Moreover, epithelial cells, activated by
TLR4 signaling, produced interleukin-18
(IL-18), which further amplified the TH1
response. The expression of interferon-g
(IFN-g) and IFN-inducible genes in DCs
and epithelial cells is important in their
interactions with T cells for sustained accumulation of TH1 cells in the inflammatory immune response (see the figure).
The authors showed that other Klebsiella
strains—Ka-11E12 from the saliva sample of
a patient with active ulcerative colitis, and
surprisingly, Kp-40B3 from a saliva sample
of a healthy individual—can also induce
substantial TH1-mediated inflammatory
responses in the intestine. These data suggest that additional Klebsiella strains or
other previously undescribed pathobiont
strains may be identified if more samples
and more pathological phenotypes are systematically analyzed.
What is the clinical relevance of these
findings? Atarashi et al. analyzed fecal mi-
crobiome data sets of patients with Crohn’s
disease, primary sclerosing cholangitis,
and alcoholism. They found that the aggre-
gated relative abundance of Klebsiella spe-
cies was significantly higher
in these patients compared
with healthy controls, and the
induction of TH1-associated
genes was accordingly en-
riched in most fecal samples of
the patients with inflammatory
disease who carried Klebsiella
species. These data strongly
indicate the pathogenic role of
oral cavity–derived Klebsiella
strains in inflammatory dis-
eases, although so far the data
Location does matter. Atarashi et al. highlight a way in
which ectopic intestinal colonization of TH1-inducing oral
bacteria (i.e., Klebsiella strains)
induce intestinal inflammation
once they are translocated and
colonize the intestine through
swallowing saliva. These findings outline the potential
preventive or therapeutic approaches for intervening in
chronic intestinal inflammation by targeting the oral-derived bacteria, particularly
Klebsiella strains, by deleting
the pathobiont or blocking the
colonization or TH1-mediated
pathogenesis of oral Klebsiella
strains. It would be interesting to investigate what the major components of normal gut
microbiota are in individuals
in whom intestinal colonization was prevented. It remains unclear how important
the genome–microbiome interaction is in
the pathogenesis of inflammatory diseases
induced by ectopically colonized pathobionts. The major innate sensors to recognize
ectopically colonized bacteria and consequently drive T cell–mediated inflammation need further identification to better
understand the pathological process. j
REFERENCES AND NOTES
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2. M. Schirmer et al., Cell 167, 1125 (2016).
3. J. M. Pickard etal .,
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X.C. is a recipient of grants from the National Natural Science
Foundation of China (81788104) and CAMS Innovation Fund for
Medical Sciences (2016-12M-1-003).
Strains of Klebsiella spp.
from the oral cavity can
colonize a dysbiotic gut
lumen, but not a
DCs and epithelial cells
via TLR to produce IL-18,
which recruits and activates
TH1 cells and thus in.ammation.
Department of Immunology and Center for Immunotherapy,
Institute of Basic Medical Sciences, Peking Union Medical
College, Chinese Academy of Medical Sciences, Beijing
100005, China. Email: firstname.lastname@example.org
20 OCTOBER 2017 • VOL 358 ISSUE 6361 309
Intestinal colonization by oral bacteria
induces chronic inflammation
Under certain circumstances, such as antibiotic-induced dysbiosis, ingested
oral bacteria, especially Klebsiella strains, colonize the intestine
and activate TH1 cells, leading to intestinal inflammation.