Thus
far development of synthetic microbial communities has
been
guided by ability to grow organisms in culture, considerations
for
antibiotic sensitivity, and serendipity in terms of ability to control
CDI. In fact, a relatively simple mix of bacteria has already been
described
in a murine model of RCDI [47]. Similarly, defined microbial
communities capable of abrogating the cycle of CDI recurrence
in
patients were described by Tvede and colleagues in the late
1980s
[48], as well as more recently [49]. These mixtures appear
to
engraft promptly, but become relatively minor constituents of
total
microbiota over time. This pattern is reminiscent of successive
microbial colonization following birth, a period of gradually
increasing
microbial diversity until maturity at approximately 2–3
years
of age. Interestingly, newborns are commonly colonized with
toxigenic
C. difficile, although they typically remain asymptomatic
[50–53]. As their microbiota and the immune system mature, C.
difficile
usually disappears. It is hypothesized that newborns lack
the
receptor for C. difficile toxins, although it is also plausible that
early
commensal organisms are able to contain C. difficile patho-
genicity
via mechanisms that have not yet been recognized [53]. It
is
certainly possible that specific defined microbiota even with very
limited
diversity can perform some critical functions such as activation
of immune-mediated colonization resistance, reconstitution
of
secondary bile acid metabolism, or even provision of minimal
microbial community-building scaffolding that allows further
diversification
and maturation. One of the anticipated challenges
for
synthetic microbiota manufacturing will be ensuring that critical
activities needed for therapeutic efficacy will not be lost during
laboratory
or industrial culture growth, as the organisms adapt
to
life outside the human host. Ultimately, functionally relevant
assays
will be needed in addition to monitoring of precise composition
ofdefinedmicrobiotaintherapeuticproductdevelopment.