The dark side of antibiotics

Interactions in the gut between host cells and bacteria can determine a state of health or disease. A study investigates how antibiotic treatment can affect host cells in a way that drives growth of pathogenic bacteria. See Letter p.697

An unwanted side effect of antibiotics can be an increase in pathogenic gut bacteria. A study reported on page 697 by Faber et al.1 now shows that increased growth of the gut pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) after antibiotic treatment in mice is the result of sugar oxidation that is driven by a host enzyme.

The mammalian gastrointestinal tract is colonized by a dense community of resident microbes known as the gut microbiota that not only helps us to digest certain foods, but also helps to prevent colonization by invading and potentially hostile microorganisms — a property known as colonization resistance. Perturbations to the microbiota, such as those caused by the use of oral antibiotics, often lead to increased colonization by various gut pathogens, such as S. Typhimurium and Clostridium difficile2,3. Broad-spectrum antibiotics deplete the resident (commensal) microbiota, allowing pathogens to proliferate, which in turn can lead to gastrointestinal inflammation4. Antibiotic-associated diarrhoea and inflammation occurs in 5–25% of people treated with antibiotics and is considered a major health problem5.

Nutrient availability is a key factor in determining bacterial growth. It has been known for decades that pretreatment of mice with the antibiotic streptomycin increases the severity of colon inflammation induced by S. Typhimurium6, and in the inflamed gut there are multiple nutrients that can facilitate the replication of this bacterium. For example, S. Typhimurium and other members of the Enterobacteriaceae family can use ethanolamine derived from the degradation of cell membranes as a source of carbon and nitrogen7,8,9.

In addition, antibiotic-mediated disruption of the microbial food web can give rise to microbiota-liberated sugars in the gut that promote the growth of S. Typhimurium and C. difficile10. Moreover, antibiotics also increase expression of a host enzyme called inducible nitric oxide synthase (iNOS)11, but the link between iNOS and enhanced S. Typhimurium growth in the gut had not been previously established. The key advance in the paper by Faber and colleagues is to provide mechanistic insight into how antibiotic treatment leads to iNOS-dependent generation of oxidized sugars, which S. Typhimurium uses as a food source to grow rapidly in the gut.

The authors investigated the changes that occur after antibiotic treatment. After confirming that the treatment leads to overexpression of iNOS (by an unknown mechanism), the authors showed that host-driven iNOS-dependent oxidization of the sugars glucose and galactose in the gut leads to the generation of the sugars glucarate and galactarate, both of which can be metabolized by S. Typhimurium.

The researchers then characterized S. Typhimurium genes involved in metabolizing oxidized glucose and galactose (the gudT ygcY gudD STM2959 operon). The expression of these genes is induced by hydrogen, a fermentation product of the microbiota12, indicating that the production of the enzymes that they encode is tightly regulated, and probably restricted to a gut-like environment. Interestingly, related genes were found in other Enterobacteriaceae present in the resident bacterial community, such as Escherichia coli and Klebsiella oxytoca. The authors show that these genes are also important for E. coli to increase in numbers in the gut after antibiotic treatment.

Because S. Typhimurium probably competes with commensal bacteria for the oxidized sugars, it is tempting to speculate that it might have evolved specific mechanisms to outcompete resident bacteria for the same food source. The elucidation of such competition mechanisms would add a new layer of complexity to our understanding of the microbiota's response to antibiotics and will require further studies. Thus, the increase of S. Typhimurium in the gut after antibiotic treatment can be attributed to the microbiota-delivered nutrients sialic acid and fucose10 and to host-mediated oxidation of carbohydrates in the gut, providing diverse food sources for the pathogen (Fig. 1).

Figure 1: Gut changes after antibiotic treatment.

Faber et al.1 confirmed that treatment of mice with antibiotics increases the expression of the host enzyme inducible nitric oxide synthase (iNOS) by an unknown mechanism. iNOS can produce reactive oxygen species, and the authors propose that such species can oxidize glucose and galactose sugars to glucarate and galactarate, respectively. These oxidized sugars are metabolized by Salmonella enterica serovar Typhimurium (S. Typhimurium), as well as by other members of the Enterobacteriaceae family, such as resident Escherichia coli. Antibiotic treatment also results in the formation of sialic acid and fucose by the activity of resident bacteria; these nutrients can also be metabolized by S. Typhimurium10. Antibiotic treatment therefore ultimately creates a perfect mix of nutrients for S. Typhimurium to proliferate.

Antibiotics are useful for treating susceptible bacterial infections and certainly provide human health benefits. However, with the emergence of multidrug-resistant pathogens that are predicted13 to kill 10 million people a year by 2050, there is a dark side to antibiotics. The mechanism described by Faber et al. sheds light on another dark side. Indeed, increasing numbers of studies now describe mechanisms used by gut pathogens to take advantage of the post-antibiotic period to hyper-replicate within the gut and successfully infect the host. Faber and colleagues' work could lead to the development of new and better therapeutic approaches for preventing diseases that are a consequence of antibiotic treatment. Footnote 1


  1. 1.

    See all news & views


  1. 1

    Faber, F. et al. Nature 534, 697–699 (2016).

    CAS  ADS  Article  Google Scholar 

  2. 2

    Pavia, A. T. et al. J. Infect. Dis. 161, 255–260 (1990).

    CAS  Article  Google Scholar 

  3. 3

    Kelly, C. P., Pothoulakis, C. & LaMont, J. T. N. Engl. J. Med. 330, 257–262 (1994).

    CAS  Article  Google Scholar 

  4. 4

    Högenauer, C., Hammer, H. F., Krejs, G. J. & Reisinger, E. C. Clin. Infect. Dis. 27, 702–710 (1998).

    Article  Google Scholar 

  5. 5

    Bergogne-Bérézin, E. Int. J. Antimicrob. Agents 16, 521–526 (2000).

    Article  Google Scholar 

  6. 6

    Bohnhoff, M., Drake, B. L. & Miller, C. P. Proc. Soc. Exp. Biol. Med. 86, 132–137 (1954).

    CAS  Article  Google Scholar 

  7. 7

    Kofoid, E., Rappleye, C., Stojiljkovic, I. & Roth, J. J. Bacteriol. 181, 5317–5329 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Garsin, D. A. Nature Rev. Microbiol. 8, 290–295 (2010).

    CAS  Article  Google Scholar 

  9. 9

    Thiennimitr, P. et al. Proc. Natl Acad. Sci. USA 108, 17480–17485 (2011).

    CAS  ADS  Article  Google Scholar 

  10. 10

    Ng, K. M. et al. Nature 502, 96–99 (2013).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Songhet, P. et al. PLoS ONE 5, e13804 (2010).

    ADS  Article  Google Scholar 

  12. 12

    Lamichhane-Khadka, R., Benoit, S. L., Maier, S. E. & Maier, R. J. Open Biol. 3, 130146 (2013).

    Article  Google Scholar 

  13. 13

    Tackling Drug-Resistant Infections Globally: Final Report and Recommendations (Wellcome Trust/UK Gov., 2016).

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Correspondence to Thibault G. Sana or Denise M. Monack.

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Sana, T., Monack, D. The dark side of antibiotics. Nature 534, 624–625 (2016). https://doi.org/10.1038/nature18449

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