Feature Review
Antibiotic-Induced Changes in the Intestinal Microbiota and Disease

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The gut microbiota contains trillions of bacteria belonging to hundreds, possibly thousands, of species and is crucial for optimal maintenance of host physiological processes.

The microbiota protects against infections and other pathologies by directly inhibiting invading microbes or by orchestrating appropriate immune responses; conversely, metabolites produced by some gut commensals can promote a variety of diseases such as atherosclerosis or cancer.

Antibiotics alter the microbiota composition, resulting in an increased risk of disease, secondary infections, allergy, and obesity. In addition, they promote the spread of drug-resistant pathogens, making the search for alternative clinical approaches imperative.

Novel strategies are being developed to substitute or complement antibiotic therapies, attempting either to selectively target pathogens without perturbing the microbiota and/or to re-establish commensal communities together with the protective and beneficial effects they confer to the host.

The gut microbiota is a key player in many physiological and pathological processes occurring in humans. Recent investigations suggest that the efficacy of some clinical approaches depends on the action of commensal bacteria. Antibiotics are invaluable weapons to fight infectious diseases. However, by altering the composition and functions of the microbiota, they can also produce long-lasting deleterious effects for the host. The emergence of multidrug-resistant pathogens raises concerns about the common, and at times inappropriate, use of antimicrobial agents. Here we review the most recently discovered connections between host pathophysiology, microbiota, and antibiotics highlighting technological platforms, mechanistic insights, and clinical strategies to enhance resistance to diseases by preserving the beneficial functions of the microbiota.

Section snippets

Beneficial Roles of the Microbiota

The gut microbiota exerts many beneficial functions for the host, to a level that it can be considered an additional organ [8]. For example, commensal bacteria convert primary bile acids into secondary bile acids and they also produce vitamins of the B and K groups, and ferment otherwise indigestible plant-derived fibers producing short-chain fatty acids (SCFAs) that feed enterocytes and modulate immune functions 2, 3. Furthermore, the microbiota drives intestinal development by promoting

Gut Microbiota and Pathogenesis

The microbiota can contribute to a variety of diseases through different mechanisms, including the production of noxious catabolites and the capacity to overgrow, to sustain inflammation, or to provide support for pathogens. Many factors, such as diet, underlying inflammation, and dysbiosis, can modulate such pathogenic potential. In the next section we discuss recent literature on the role of gut commensal bacteria in disease pathogenesis.

Antibiotic Treatment Induces Long-Lasting Changes in the Microbiota that Correlate with Disease

Numerous studies have confirmed that antibiotics have a tremendous impact on the composition and functionality of the human microbiota. One study documented that healthy volunteers treated for 1 week or less with antibiotics reported effects on their bacterial flora that persisted 6 months to 2 years after treatment, including a dramatic loss in diversity as well as in representation of specific taxa, insurgence of antibiotic-resistant strains, and upregulation of antibiotic resistance genes

Generation of Antibiotic Resistance: The Driving Forces

Antibiotic-resistant pathogens are a major public health burden. However, ARGs are highly represented not only in such pathogens but also among human commensal bacteria. An early survey suggested that a sizable fraction of the anaerobe compartment within the microbiota of healthy subjects is resistant to one or multiple antibiotics, with the proportion of such bacteria increasing following antibiotic treatment [92]. A more recent metagenomic analysis of the gut microbiota obtained from two

Antibiotic Resistance Generation: De Novo Mutations

As previously discussed, antibiotics exert a selective pressure that drives rapid development of resistant strains. This process generally requires multiple DNA mutations. To understand how such mutations are acquired, in one study E. coli cultures were challenged with increasing doses of three different antibiotics for 20 days in vitro [107]. Antibiotic resistance was found to arise following similar or identical mutational patterns in replicate experiments; mutations affecting the same, or

Resistance Genes Are Spread via HGT

Bacteria can exchange ARGs via HGT. Specifically, HGT includes: (i) transformation, the acquisition of DNA fragments from the environment; (ii) conjugation, the delivery of genetic material from one cell to another through a pilus; and (iii) transduction, an exchange mediated by bacteriophages 97, 110. All three mechanisms have been implicated in the transfer of ARGs (Figure 3) 97, 110.

Generally speaking, HGT can take place among commensals, environmental bacteria or, importantly, between the

Moving Beyond Antibiotics

Considering the important roles of the microbiota in regulating host physiology, and the multiple drawbacks of antibiotic use discussed above, finding alternative or complementary strategies to fight infections is imperative. Different promising approaches have been proposed to tackle this problem (Figure 4).

First and foremost, reforming or establishing a set of complementary public health measures can greatly diminish the need for antibiotic use. As pointed out by Laxminarayan [116], improving

Concluding Remarks

Recent evidence demonstrates the fundamental role of the gut microbiota in directing host physiology. In particular, the development of a fully functional immune system requires key induction and maintenance signals from the commensal community, many of which are likely still to be discovered (see Outstanding Questions). Antibiotics, to which we are increasingly exposed, disrupt the equilibrium among commensal populations, and lead to a decreased or altered communication between the human

Acknowledgments

We thank members of the laboratory of E.G.P., particularly Sejal Morjaria and Sohn G. Kim, for critical reading of the manuscript and valuable suggestions. S.B. is supported by a Swiss National Science Foundation Early Postdoc Mobility Fellowship. Y.T. is supported by the National Institutes of Health (NIH; grant 1K23 AI095398-01 to Y.T.), the Lucille Castori Center for Microbes, Inflammation, and Cancer, and the Tow Foundation. E.G.P. has received funding from NIH grants RO1 AI095706, AI042135,

Glossary

Antimicrobial peptides (AMPs)
small peptides with bactericidal activity, mainly positively charged, that are produced by microorganisms and host myeloid and epithelial cells.
Bacteriocins
toxins, largely proteins, secreted by bacteria to kill other bacteria.
β-Lactams
antibiotics containing a β-lactam ring in their molecular structure; this class includes penicillins, cephalosporins, and carbapenems.
B1 cells
subset of B cells activated by innate sensor triggering that produce the vast majority of

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