the gut microbiome. However, across host species,
a handful of Bacteria and Archaea, with known
importance for health, have emerged as heritable
and associate with host genes related to immunity
and diet. These interactions may be fairly sensitive
to diet, making the gut microbiome a tractable
therapeutic target. The field of microbiome GWAS
is in its infancy. Developments in sample acquisition, data generation, and analysis will continue to
reveal informative and biologically relevant associations between taxa and host genetic variants.
These associations, which underlie interactions yet
to be described, are the signatures of an ongoing
coevolution between host and microbiome.
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We thank T. Spector, J. Bell, and C. Ober. This work was funded by
NIH RO1 DK093595, a David and Lucile Packard Foundation
Fellowship (R.E.L.), The Cornell Center for Comparative Population
Genomics (R.E.L. and J.K.G.), and a National Science Foundation
Graduate Fellowship (J.K.G.)
Resurrecting the intestinal microbiota
to combat antibiotic-resistant pathogens
Eric G. Pamer
The intestinal microbiota, which is composed of diverse populations of commensal
bacterial species, provides resistance against colonization and invasion by pathogens.
Antibiotic treatment can damage the intestinal microbiota and, paradoxically, increase
susceptibility to infections. Reestablishing microbiota-mediated colonization resistance
after antibiotic treatment could markedly reduce infections, particularly those caused by
antibiotic-resistant bacteria. Ongoing studies are identifying commensal bacterial species
that can be developed into next-generation probiotics to reestablish or enhance
colonization resistance. These live medicines are at various stages of discovery, testing,
and production and are being subjected to existing regulatory gauntlets for eventual
introduction into clinical practice. The development of next-generation probiotics to
reestablish colonization resistance and eliminate potential pathogens from the
gut is warranted and will reduce health care–associated infections caused by highly
Antibiotic treatment has saved millions of lives. Penicillins, sulfa drugs, macrolides, ami- noglycosides, quinolones, cephalosporins, and carbapenems are used to “target” path- ogens that cause potentially lethal infections,
resulting in marked reductions in morbidity and
mortality. None of these antibiotics, however, are
selective for pathogens, and their administration
leads to collateral destruction of commensal bacterial populations constituting the microbiota. Furthermore, many pathogens have acquired resistance
to antibiotics, reducing treatment options and cure
rates in a broadening range of clinical settings. The
impact of broad-spectrum antibiotics on commensal inhabitants of our mucosal surfaces, in particular the gastrointestinal tract, has increasingly
been the focus of laboratory investigation (1–3).
It is well appreciated that a side effect of antibiotic treatment is increased susceptibility to a
range of bacterial infections (4). An intact microbiota can exclude invading bacteria by direct and
indirect mechanisms that, in aggregate, provide
Although not a new idea, administration of live
bacteria to compensate for loss of commensal
microbes and colonization resistance after anti-
biotic treatment is becoming increasingly plau-
sible, largely because the bacterial species that
promote high-level colonization resistance to in-
fection are being defined (5–9). The effectiveness
of these bacterial species is impressive, and (for
the most part) these organisms are not asso-
ciated with disease states, nor do they express
virulence factors associated with pathogenic bac-
teria. This review summarizes recent studies iden-
tifying protective commensal bacterial species and
discusses the need for a development path for
these potential next-generation probiotics that
demonstrates their effectiveness, ensures their
safety, and promotes their eventual production,
distribution, and affordability.
Colonization resistance mediated by
Not long after antibiotics were introduced for the
treatment of bacterial infections, investigators
noted that antibiotic administration to animals
markedly reduced colonization resistance against
a range of pathogens. Early studies demonstrated
that antibiotic administration to mice or hamsters
rendered these animals more susceptible, by as
much as six orders of magnitude, to infection by
common enteric pathogens (10–13). More than
50 years ago, it was found that loss of obligate
anaerobic bacterial populations from the lower
gastrointestinal tract strongly correlated with susceptibility to infection, which suggests that these
commensal organisms were providing colonization resistance (13). Compositional analyses of
colonic microbial populations in humans after
antibiotic treatment demonstrated that loss of
obligate anaerobes frequently results in expansion
of g-proteobacteria and enterococci; these findings suggest that the complex, pre-antibiotic commensal microbiota suppresses the expansion of
the oxygen-tolerant bacterial species (14, 15).
Microbiota destruction and
Increasing antibiotic resistance, according to the
World Health Organization, is one of the most important threats to human health ( www.who.int/
entity/drugresistance/en). Bacterial resistance to
antibiotics has become a formidable problem for
the treatment of many infections. A subset of these
infections—indeed, some of the most antibiotic-resistant forms—occur in hospitalized patients,
where they achieve very high densities that facilitate patient-to-patient spread. Extended-spectrum
b-lactamase (ESBL)–producing Enterobacteriaceae,
Infectious Diseases Service, Department of Medicine,
Immunology Service, and Lucille Castori Center for Microbes,
Inflammation and Cancer, Sloan Kettering Institute, Memorial
Sloan Kettering Cancer Center, New York, NY 10065, USA.