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Infect Immun. 2009 Jun;77(6):2367-75. Epub 2009 Mar 23.
Reproducible community dynamics of the
gastrointestinal microbiota following
antibiotic perturbation.
Antonopoulos DA, Huse SM, Morrison HG, Schmidt TM, Sogin ML, Young VB.
Source
Department of Internal Medicine, Division of Infectious Diseases, University of Michigan,
Ann Arbor, MI 48109-5623, USA.
Abstract
Shifts in microbial communities are implicated in the pathogenesis of a number of
gastrointestinal diseases, but we have limited understanding of the mechanisms that lead to
altered community structures. One difficulty with studying these mechanisms in human
subjects is the inherent baseline variability of the microbiota in different individuals. In an
effort to overcome this baseline variability, we employed a mouse model to control the host
genotype, diet, and other possible influences on the microbiota. This allowed us to determine
whether the indigenous microbiota in such mice had a stable baseline community structure
and whether this community exhibited a consistent response following antibiotic
administration. We employed a tag-sequencing strategy targeting the V6 hypervariable region
of the bacterial small-subunit (16S) rRNA combined with massively parallel sequencing to
determine the community structure of the gut microbiota. Inbred mice in a controlled
environment harbored a reproducible baseline community that was significantly impacted by
antibiotic administration. The ability of the gut microbial community to recover to baseline
following the cessation of antibiotic administration differed according to the antibiotic
regimen administered. Severe antibiotic pressure resulted in reproducible, long-lasting
alterations in the gut microbial community, including a decrease in overall diversity. The
finding of stereotypic responses of the indigenous microbiota to ecologic stress suggests that a
better understanding of the factors that govern community structure could lead to strategies
for the intentional manipulation of this ecosystem so as to preserve or restore a healthy
microbiota.
Supplemental Content
Gut Microbes. 2010 Jul;1(4):279-284. Epub 2010 May 24.
Antibiotic administration alters the
community structure of the gastrointestinal
micobiota.
Robinson CJ, Young VB.
Source
Department of Internal Medicine; Division of Infectious Diseases; University of Michigan;
Ann Arbor, MI USA.
Abstract
We recently demonstrated that antibiotic administration has a reproducible effect on the
community structure of the indigenous gastrointestinal microbiota of mice. In this addendum
we report on additional experimentation using the antibiotic vancomycin. In accord with our
previous findings, vancomycin administration results in consistent alteration of the microbiota
of the cecal contents and the cecal mucosa. These alterations are largely reversed by a threeweek period of recovery without antibiotics. In contrast to our previous results using other
antibiotics, the alterations in community structure associated with vancomycin occured
without a significant decrease in the overall bacterial biomass. These results indicate that
different antibiotics have specific effects on the gut microbiota. This points the way towards
targeted, therapeutic alteration of the gut bacterial community as a whole.
Supplemental Content
Microbiol Mol Biol Rev. 2010 Sep;74(3):453-76.
From structure to function: the ecology of
host-associated microbial communities.
Robinson CJ, Bohannan BJ, Young VB.
Source
Department of Internal Medicine, Division of Infectious Diseases, University of Michigan,
4618D Medical Sciences II, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5623, USA.
Abstract
In the past several years, we have witnessed an increased interest in understanding the
structure and function of the indigenous microbiota that inhabits the human body. It is hoped
that this will yield novel insight into the role of these complex microbial communities in
human health and disease. What is less appreciated is that this recent activity owes a great
deal to the pioneering efforts of microbial ecologists who have been studying communities in
non-host-associated environments. Interactions between environmental microbiologists and
human microbiota researchers have already contributed to advances in our understanding of
the human microbiome. We review the work that has led to these recent advances and
illustrate some of the possible future directions for continued collaboration between these
groups of researchers. We discuss how the application of ecological theory to the humanassociated microbiota can lead us past descriptions of community structure and toward an
understanding of the functions of the human microbiota. Such an approach may lead to a shift
in the prevention and treatment of human diseases that involves conservation or restoration of
the normal community structure and function of the host-associated microbiota.
Supplemental Content
PLoS One. 2010 Mar 24;5(3):e9836.
Short-term antibiotic treatment has
differing long-term impacts on the human
throat and gut microbiome.
Jakobsson HE, Jernberg C, Andersson AF, Sjölund-Karlsson M, Jansson JK, Engstrand L.
Source
Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.
Abstract
Antibiotic administration is the standard treatment for the bacterium Helicobacter pylori, the
main causative agent of peptic ulcer disease and gastric cancer. However, the long-term
consequences of this treatment on the human indigenous microbiota are relatively unexplored.
Here we studied short- and long-term effects of clarithromycin and metronidazole treatment, a
commonly used therapy regimen against H. pylori, on the indigenous microbiota in the throat
and in the lower intestine. The bacterial compositions in samples collected over a four-year
period were monitored by analyzing the 16S rRNA gene using 454-based pyrosequencing and
terminal-restriction fragment length polymorphism (T-RFLP). While the microbial
communities of untreated control subjects were relatively stable over time, dramatic shifts
were observed one week after antibiotic treatment with reduced bacterial diversity in all
treated subjects in both locations. While the microbiota of the different subjects responded
uniquely to the antibiotic treatment some general trends could be observed; such as a dramatic
decline in Actinobacteria in both throat and feces immediately after treatment. Although the
diversity of the microbiota subsequently recovered to resemble the pre treatment states, the
microbiota remained perturbed in some cases for up to four years post treatment. In addition,
four years after treatment high levels of the macrolide resistance gene erm(B) were found,
indicating that antibiotic resistance, once selected for, can persist for longer periods of time
than previously recognized. This highlights the importance of a restrictive antibiotic usage in
order to prevent subsequent treatment failure and potential spread of antibiotic resistance.
Supplemental Content
Microbiology. 2010 Nov;156(Pt 11):3216-23. Epub 2010 Aug 12.
Long-term impacts of antibiotic exposure
on the human intestinal microbiota.
Jernberg C, Löfmark S, Edlund C, Jansson JK.
Source
Department of Bacteriology, Swedish Institute for Infectious Disease Control, SE-171 82
Solna, Sweden. [email protected]
Abstract
Although it is known that antibiotics have short-term impacts on the human microbiome,
recent evidence demonstrates that the impacts of some antibiotics remain for extended periods
of time. In addition, antibiotic-resistant strains can persist in the human host environment in
the absence of selective pressure. Both molecular- and cultivation-based approaches have
revealed ecological disturbances in the microbiota after antibiotic administration, in particular
for specific members of the bacterial community that are susceptible or alternatively resistant
to the antibiotic in question. A disturbing consequence of antibiotic treatment has been the
long-term persistence of antibiotic resistance genes, for example in the human gut. These data
warrant use of prudence in the administration of antibiotics that could aggravate the growing
battle with emerging antibiotic-resistant pathogenic strains.
Supplemental Content
http://mic.sgmjournals.org/content/156/11/3216.full.pdf+html FREE
Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4554-61. Epub 2010 Sep 16.
Incomplete recovery and individualized
responses of the human distal gut
microbiota to repeated antibiotic
perturbation.
Dethlefsen L, Relman DA.
Source
Department of Microbiology and Immunology, Stanford University School of Medicine,
Stanford, CA 94305, USA.
Abstract
The indigenous human microbiota is essential to the health of the host. Although the
microbiota can be affected by many features of modern life, we know little about its responses
to disturbance, especially repeated disturbances, and how these changes compare with
baseline temporal variation. We examined the distal gut microbiota of three individuals over
10 mo that spanned two courses of the antibiotic ciprofloxacin, analyzing more than 1.7
million bacterial 16S rRNA hypervariable region sequences from 52 to 56 samples per
subject. Interindividual variation was the major source of variability between samples. Dayto-day temporal variability was evident but constrained around an average community
composition that was stable over several months in the absence of deliberate perturbation. The
effect of ciprofloxacin on the gut microbiota was profound and rapid, with a loss of diversity
and a shift in community composition occurring within 3-4 d of drug initiation. By 1 wk after
the end of each course, communities began to return to their initial state, but the return was
often incomplete. Although broadly similar, community changes after ciprofloxacin varied
among subjects and between the two courses within subjects. In all subjects, the composition
of the gut microbiota stabilized by the end of the experiment but was altered from its initial
state. As with other ecosystems, the human distal gut microbiome at baseline is a dynamic
regimen with a stable average state. Antibiotic perturbation may cause a shift to an alternative
stable state, the full consequences of which remain unknown.
Supplemental Content
J Clin Microbiol. 2004 Mar;42(3):1203-6.
Antibiotic-associated diarrhea accompanied
by large-scale alterations in the composition
of the fecal microbiota.
Young VB, Schmidt TM.
Source
Department of Microbiology and Molecular Genetics, Infectious Diseases Unit, National
Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan
48824, USA. [email protected]
Abstract
Alterations in the diversity of the gut microbiota are believed to underlie the development of
antibiotic-associated diarrhea (AAD). A molecular phylogenetic analysis was performed to
document temporal changes in the diversity of fecal bacteria of a patient who developed
AAD. Antibiotic administration was associated with distinct changes in the diversity of the
gut microbiota, including a marked decrease in the prevalence of butyrate-producing bacteria.
Following the discontinuation of the antibiotic, resolution of diarrhea was accompanied by a
reversal of these changes, providing the first direct evidence linking changes in the
community structure of the gastrointestinal bacteria with the development of AAD.
Comment in

Rev Gastroenterol Disord. 2004 Fall;4(4):216-7.
Supplemental Content
Benef Microbes. 2010 Sep;1(3):211-27. doi: 10.3920/BM2010.0009.
Homeostatic impact of indigenous
microbiota and secretory immunity.
Brandtzaeg P.
Source
Department and Institute of Pathology, Laboratory for Immunohistochemistry and
Immunopathology (LIIPAT), Centre for Immune Regulation (CIR), Oslo University Hospital,
Rikshospitalet, Norway.
Abstract
In the process of evolution, the mucosal immune system has generated two layers of antiinflammatory defence: (1) immune exclusion performed by secretory IgA (and secretory IgM)
antibodies to modulate or inhibit surface colonisation of microorganisms and dampen
penetration of potentially dangerous antigens; and (2) suppressive mechanisms to avoid local
and peripheral hypersensitivity to innocuous antigens, particularly food proteins and
components of commensal bacteria. When induced via the gut, the latter phenomenon is
called 'oral tolerance', which mainly depends on the development of regulatory T (Treg) cells
in mesenteric lymph nodes to which mucosal dendritic cells (DCs) carry exogenous antigens
and become conditioned for induction of Treg cells. Mucosally induced tolerance appears to
be a rather robust adaptive immune function in view of the fact that large amounts of food
proteins pass through the gut, while overt and persistent food allergy is not so common. DCs
are 'decision makers' in the immune system when they perform their antigen-presenting
function, thus linking innate and adaptive immunity by sensing the exogenous mucosal impact
(e.g. conserved microbial molecular patterns). A balanced indigenous microbiota is required
to drive the normal development of both mucosa-associated lymphoid tissue, the epithelial
barrier with its secretory IgA (and IgM) system, and mucosally induced tolerance mechanisms
including the generation of Treg cells. Notably, polymeric Ig receptor (pIgR/SC) knock-out
mice that lack secretory IgA and IgM antibodies show reduced epithelial barrier function and
increased uptake of antigens from food and commensal bacteria. They therefore have a hyperreactive immune system and show predisposition for systemic anaphylaxis after sensitisation;
but this development is counteracted by enhanced oral tolerance induction as a homeostatic
back-up mechanism.
Supplemental Content
http://wageningenacademic.metapress.com/content/x054308538p3k787/fulltext.pdf FREE
J Immunol. 2010 Feb 1;184(3):1218-26. Epub 2010 Jan 4.