Laboratory Animals - June Issue - 245

Lundberg
microbial diversity in the host prior to antibiotic
depletion.6
To the best of the author's knowledge, there are no
published reports regarding animal welfare issues
related to the transfer of human GM to animals.
However, though not experienced by the author, anecdotally people have experienced transient morbidity or
even mortality following oral gavage with human feces
to GF mice. It seems logical that an inflammatory reaction can happen in response to the intense load of foreign microorganisms, potentially leading to cytokine
storm and death-a risk that is likely to be higher in
young and immunological naı¨ ve GF animals compared
with older and antibiotic-treated animals. The procedure of oral gavage implies a risk in itself, for example,
volume-related lung obstruction was observed in GF
mouse pups after gavage of infant feces.7 Increased
monitoring following transplantation with human
GM is recommended, and publishing of morbidity
and loss of animals related to the procedure is encouraged in order to increase awareness and set directions
for possible improvements.

245
elucidating mechanistic pathways and possible new
therapeutic targets. A famous example of phenotype
transfer is that GF mice with GM from an obese twin
gain more weight than mice having the GM from the
lean counterpart twin.12 Studies like this have helped
improve our understanding of how the microbiome can
be causal in the development of metabolic disorders.
Linkage of GM composition to phenotype is not
restricted to conditions in the gastrointestinal tract.
GF mice colonized with GM from patients with multiple sclerosis (MS) had exacerbated symptoms of
experimental autoimmune encephalitis compared with
mice with GM from healthy controls, indicating a
causative role of the GM in MS which was supported
by fewer IL-10þ regulatory T cells (Tregs) in the mesenteric lymph nodes of these MS mice.13 The opportunity to unravel such immunological host-microbiota
effects is the strongest argument for using animal
models, yet the host-microbiota interface is the most
questioned feature of the GM humanized mouse
concept.

Challenges
Opportunities
The transfer of single organisms, simplistic communities or complex microbiota from humans to GF animals is a simple procedure usually undertaken by oral
gavage of a microbial suspension. Once the human GM
is established in the new hosts, it remains stable over
time when the hosts are housed in isolators or individually ventilated cage systems.8,9 It is less simple to understand how the physiology of the new host is affected
and what that means to the study purpose.
Nevertheless, the concept has undoubtedly helped
advance our understanding of the capabilities of the
microbiome. Table 1 exemplifies recent studies using
mice with human GM where model features were
deemed relevant to the purpose. There is robust evidence that a human GM in mice responds ecologically
and metabolically to dietary changes. The translational
value of dietary interventions was demonstrated by
identifying modules of bacterial genera allied with
intake of a Western diet in mice with human GM and
subsequently investigating these genera in a human
trial. The preclinically observed changes correctly predicted changes observed in the human study.10 Within
the area of infectious disease, human GM in mice also
seem to be relevant, as shown by the ability to protect
against Salmonella infection.11 A Clostridium difficile
infection model functioned similarly to mice with a
mouse GM, but the human GM model was expected
to be more ecologically relevant.9
For discovering associations between host phenotype and GM, animals with human GM aid in

Several reports describe an abnormal immunophenotype of mice with a human GM. The number of intraepithelial lymphocytes (IELs) was lower in GF mice with
rat or human GM compared with mice colonized with a
mouse GM. Furthermore, only the mouse GM was able
to change histological characteristics of the IELs and
epithelial cells.14 GF mice with human GM had low
levels of CD4þ and CD8þ T cells and antimicrobial
peptide in the small intestine.15 Splenocytes of GF
mice with infant microbiota produced lower amounts
of cytokines involved in Th1, Th2 and Treg
responses.16 Comparable to GF mice, a human GM
could not induce Tregs in the small intestine, whereas
Tregs were higher in the colon compared with GF control mice.17 Hence, human-derived bacteria may have a
higher affinity or colonization preference to the murine
large intestine compared with the small intestine.
The immunological defects are hypothesized to be
caused by lack of evolutionary adaptation to the host.
It is well known that only a portion of human GM is
successfully transferred to mice. In GF mouse experiments, the colonization efficiency typically varies
between 44% and 70%,15,18,19 though in one case it
was as successful as 90%.20 A study using antibiotictreated mice reached a 57-68% recovery of bacterial
genes in recipients compared with the donor sample.5
Mouse-to-mouse GM transfer is generally more successful, with a colonization efficiency up to 93%.15
Interestingly, rats may be better suited recipients of a
human GM compared with mice. Wos-Oxley et al.
transferred the same human GM to GF rats and mice



Laboratory Animals - June Issue

Table of Contents for the Digital Edition of Laboratory Animals - June Issue

Contents
Laboratory Animals - June Issue - Cover1
Laboratory Animals - June Issue - Cover2
Laboratory Animals - June Issue - Contents
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Laboratory Animals - June Issue - Cover3
Laboratory Animals - June Issue - Cover4
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