One integrated system: the immune system and microbiome

Antibiotics cause damage to the microbiome because they are usually insufficiently selective. By this, we mean that antibiotics inhibit or kill most bacteria that they interact with, whether that bacterium is pathogenic or helpful. We see at least three distinct mechanisms whereby indiscriminate antibiotic action is harmful for a patient’s ability to fight infection, working at cross purposes with killing the pathogens:

• i
  Removing beneficial competitors.
• ii
  Preventing the adaptive immune response from “learning” the pathogen, a phenomenon called arrested immunity.
• iii
  Interrupting the gut-immune axis.

First, antibiotics deplete our natural bacterial flora. Commensal (non-pathogenic) bacteria serve many beneficial roles, helping in metabolism and competing for nutrients and adhesion sites. Antibiotics inhibit susceptible bacteria, but not resistant bacteria present in our microbiomes. After antibiotic treatment, the niches once occupied by commensals are now free for resistant and often pathogenic species to colonize.^121–123

Infection by Clostridioides difficile is the most striking example of this phenomenon. C. difficile is itself considered a CDC urgent threat pathogen, causing over 223,000 infections annually,³⁴ perhaps as many as 460,000.¹²⁴ Unlike other threat pathogens, C. difficile infection happens almost exclusively after antibiotic use, in particular, clindamycin, fluoroquinolones, and cephalosporins,¹²⁵ precisely because these antibiotics decolonize the gut of competitors. When appropriate competitors are restored to patients after antibiotics, they are protected from C. difficile.¹²² Similarly, women who take antibiotics have triple the risk of vaginal yeast infections, as bacteria which normally compete with fungi are removed by antibiotics.^126,127

In another manifestation of this problem, after commensal depletion by antibiotics, patients are more at risk for invasive bloodstream infections from resistant bacteria, previously present in the gut and greatly expanded after susceptible competitors were killed. In particular, vancomycin-resistant Enterococcus (VRE) can bloom in the gut after a course of antibiotics, prior to bloodstream invasion.¹²⁸

In the second mechanism, antibiotics interrupt the process of adaptive immunity in a phenomenon called arrested immunity. Antibiotic treatment prevents the adaptive immune system from fully learning how to defend against the pathogen, which means that the risk of reinfection is higher than when the immune system clears the infection on its own. Reinfection is much more likely after antibiotic treatment than when infection resolves naturally. Antibiotics short-circuit the antigen exposure that is necessary to train T cells and develop antigen specific antibodies. It appears that for successful antigen recognition, the adaptive immune system requires exposure to an antigen for a certain period of time, which is cut short when antibiotics kill pathogens early in the infection cycle.^129–131

Finally, antibiotics impair the immune response via the gut-immune axis. Damaging the healthy microbiome impairs immune function. While the specific mechanisms remain an area of intense, active investigation, it is clear from emerging laboratory, animal model, and clinical evidence that broad-spectrum antibiotics and the resulting gut dysbiosis disrupt proper immune response. The microbiome is particularly involved in instructing the adaptive immune response, including the differentiation and balance of effector and regulatory T cells and antibody responses.^132,133 The largest body of evidence links the healthy microbiome to lung immunity. Gut-damaging antibiotics impair alveolar immune function and reduce the ability to fight infection.^134–136 A clear, clinical example is that healthy adults given a 5-day course of broad-spectrum antibiotics develop gut dysbiosis and measurable blunting of antibody response to influenza vaccine.¹³⁷

Antibiotics are, to be sure, wonder drugs. The net benefits of antibiotics are most clear in response to acute, severe infection where the immune system has been overrun. However, in cases where infections are more likely to be chronic, or less likely to be immediately life-threatening, or where antibiotics are likely to fail, or where the goal is infection prevention, killing bacteria indiscriminately with antibiotics—pathogens and healthy microbiome alike—is probably not the best strategy. As the scientific community has come to appreciate the harmony in which the immune system and microbiome work, we see bacterial defense disablers as a therapeutic strategy that contributes to the harmony in fighting infection, rather than disrupts it.