ORIGINAL ARTICLE
Ecobiotherapy Rich in Firmicutes Decreases Susceptibility to
Colitis in a Humanized Gnotobiotic Mouse Model
Jane M. Natividad, PhD,* Maria I. Pinto-Sanchez, MD,* Heather J. Galipeau, PhD,* Jennifer Jury, MSc,*
Manel Jordana, MD, PhD,
†
Walter Reinisch, MD,* Stephen M. Collins, MD,* Premsyl Bercik, MD,*
Michael G. Surette, PhD,* Emma Allen-Vercoe, PhD,
‡
and Elena F. Verdu, MD, PhD*
Background: Alterations in the intestinal microbiota, characterized by depletion of anti-inflammatory bacteria, such as Firmicutes, in patients with
ulcerative colitis (UC) have prompted interest in microbiota-modulating strategies for this condition. The aim of this study was to evaluate the role of
fecal and synthetic human microbial ecosystems, low or enriched in Firmicutes, on colitis susceptibility and host immune responses.
Methods: The microbiota of selected healthy and UC human donors was characterized by culture method and 16S rRNA-based sequencing. Germ-free
mice were colonized with fecal or a synthetic ecosystem enriched (healthy donors) or low (UC donors) in Firmicutes. Experimental colitis was induced
using dextran sodium sulfate. Colon transcriptome and colon lamina propria cells were evaluated in mice postcolonization by RNA-seq and flow
cytometry, respectively, and T helper (T
H
) 17 differentiation was assessed in vitro.
Results: Mice colonized with microbiota from patients with UC low in Firmicutes had increased sensitivity to colitis compared with mice colonized
with fecal or synthetic ecosystems rich in Firmicutes. Microbiota low in Firmicutes increased expression of T
H
17-related genes and expansion of
interleukin-17A–expressing CD4
+
cells in vivo. Supplementation with bacterial isolates belonging to the Firmicutes phylum abrogated the heightened
T
H
17 responses in vitro.
Conclusions: A microbiota rich in Firmicutes derived from fecal samples of a healthy human donor, or assembled synthetically, downregulated colonic
inflammation and T
H
17 pathways in mice. The results support the use of ecobiotherapy strategies, enriched in Firmicutes, for the prevention or treatment
of UC.
(Inflamm Bowel Dis 2015;21:1883–1893)
Key Words: ulcerative colitis, microbiota, T
H
17, Firmicutes
O
ver the past decade, the intestinal microbiota has become
one of the most studied areas in biomedical research.
Gnotobiotic studies have provided key evidence on how specific
bacterial strains influence the development and maturation of host
physiology and immunity, including secondary lymphoid devel-
opment, antimicrobial peptide maturation, and induction of
T helper (T
H
) cells, such as T regulatory (T
REG
) and proinflam-
matory T
H
17 cells.
1–3
Components of the intestinal microbiota
have differential capacity to influence host responses.
4
For
instance, experimentally defined communities, such as the
altered Schaedler flora (ASF), Clostridium species, or the poly-
saccharide A–expressing Bacteroides fragilis predominantly
induce T
REG
in the colon, whereas pathobionts Bilophila wad-
sworthia and segmented filamentous bacteria are potent inducers
of T
H
1 and T
H
17 cells, respectively.
5–8
Others have shown that
colonization with an enterotoxigenic B. fragilis worsens exper-
imental colitis in mice compared with a nontoxigenic strain.
9
Altogether, this suggests that the host-microbiota interaction sits
in a continuum between mutualism and pathogenicity, and the
composition of the microbiota is one factor that could potentially
upset this delicate balance.
Disturbed microbiota, termed dysbiosis, which is a state
in which the homeostatic balance between the microbiota and
the host is shifted toward a proinflammatory state, has been
described in a number of autoimmune and intestinal inflamma-
tory conditions.
10,11
It is currently accepted that ulcerative coli-
tis (UC), one of the 2 forms of inflammatory bowel disease
(IBD), results from the development of abnormal immune re-
sponses to the colonic microbiota.
12
Although therapies for UC
currently aim at modulating the immune response, there has
been increasing interest in microbiota-modulating therapies,
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of this
article on the journal’s Web site (www.ibdjournal.org).
Received for publication February 12, 2015; Accepted March 5, 2015.
From the *Farncombe Family Digestive Health Research Institute, McMaster
University, Hamilton, ON, Canada;
†
Department of Pathology, and Molecular Med-
icine, McMaster Immunology Research Centre, McMaster University, Hamilton,
ON, Canada; and
‡
Department of Molecular and Cellular Biology, University of
Guelph, Guelph, ON, Canada.
Supported by CCFC and CIHR (MOP 123282) grants to E.F.V. and E.A.-V. J.M.N.
was awarded CCFC/CAG student award.
The authors have no conflicts of interest to disclose.
Reprints: Elena F. Verdu, MD, PhD, Room HSC 3N4A, 1200 Main Street
West, Hamilton, ON L8N 3Z5, Canada (e-mail: verdue@mcmaster.ca).
Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc.
DOI 10.1097/MIB.0000000000000422
Published online 29 April 2015.
Inflamm Bowel Dis Volume 21, Number 8, August 2015 www.ibdjournal.org
|
1883
Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
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