Saturday, May 17, 2014

How antibiotics can make us vulnerable

   Since birth human [infant] immune system is constantly exposed to environmental antigens. These antigens are either of harmless or harmful nature. In general, there are two ways for immune system to learn the difference between harmless and harmful antigens.

   First detection system is a genetically fixed trait programmed to detect evolutionary stable signature associated with presence of harmful microorganisms, like endotoxin (LPS).

   Second detection system is a de novo acquired phenotypic trait involving collaboration between commensal microbiota, dendritic cells and T cells. It complexity, especially its dependency on commensal microbiota renders it more prone to errors.

  Until very recent times, humans used to spend their entire lives in a farm-like environment, being exposed to diverse set of environmental antigens and microorganisms. However, urbanization and non-discriminate use of antibiotics changed the playing field, especially undermining the proper development of second detection system. This led to the increase in frequency of allergic or autoimmune inflammatory disorders and several types of cancer.

    To specifically show how non-discriminatory use of antibiotics could lead to immune deficiencies, lets review recent paper published in Nature Medicine.

    This study by Deshmukh H, et al. (1), examined the effect of broad spectrum antibiotics treatment on mice neonates.

    As expected continued treatment of pregnant female mice and neonates (- day 5 / + day 14)  with combination of 3 or 5 broad-spectrum antibiotics resulted in significant (20X-50X) reduction of gut microbiota. This in turn led to reduction of circulating and bone-marrow residing neutrophils. Plasma level of G-CSF, a cytokine responsible for neutrophil mobilization were also reduced. Analysis of germ-free mice confirmed that these effects were due to reduction of microbiota.

   To understand how this reduction of neutrophils affected neonatal mice, the authors injected antibiotic-treated neonatal mice with pathogenic strains of E. Coli or K. Pneumoniae. Compared to control mice, antibiotic-treated neonatal mice became highly susceptible to infections. Similar effect was seen with neonatal mice treated with neutrophil-depleting antibody. However, neonatal mice simultaneously treated with either G-CSF or transplanted with gut microbiota showed improved survival and resistance to infection.

    To further elucidate the mechanism of susceptibility, the authors examined the role of IL-17. It has been recognized that IL-17 plays a role in G-CSF induction and in neutrophil biology. It turned out that antibiotic-treated neonatal mice or germ-free mice have reduced level of IL-17. Alternatively, treatment of mice with anti-IL-17 antibody or use IL-17R alpha KO mice confirmed that IL-17 was critical factor in neutrophil mobilization.

   Finally, the authors showed that TLR4 and MyD88 pathways were involved in microbiota-driven neutrophil mobilization. Importantly, injection of low dose of LPS could restore IL-17 and G-CSF level in antibiotic-treated mice and improve neutrophil mobilization in blood and bone-marrow. This effect was again IL-17 dependent. However, the authors did not examine if injection of low dose of LPS could improve survival of antibiotic-treated mice.

   In summary, the authors' proposed model suggests that early post-natal colonization of neonatal mice with microbiota activates innate immune system leading to IL-17 production that in turn induces G-CSF secretion and neutrophil mobilization. This process prepares neonatal mice to resist harmful effect of pathogenic microorganisms.

   One relevant finding is that injection of G-CSF or low dose of pure LPS could improve neutrophil mobilization in neonatal mice treated with antibiotics. This could have clinical application for human neonates.

   One things that is really confusing about this study is the fact that antibiotic-treated neonatal mice were highly susceptible to pathogenic microorganisms which are it turn supposedly susceptible to the effects of broad-spectrum antibiotics used to treat mice. I have no idea how to interpret these particular experiments.


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