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Of mice, men and microbes: the impact of the microbiome on immune responses
  1. David S Pisetsky1,2
  1. 1 Department of Medicine and Immunology, Duke University Medical Center, Durham, North Carolina, USA
  2. 2 Medical Research Service, VA Medical Center, Durham, North Carolina, USA
  1. Correspondence to Dr David S Pisetsky, Medical Research Service, VA Medical Center, Durham, NC 27705, USA; david.pisetsky{at}

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Rheumatic diseases are a diverse group of conditions in which the host and the environment interact to drive inflammation and autoreactivity. In this dyadic model, the strongest environmental influence is infection, with bacteria and viruses likely to trigger disease in a host predisposed by genetics; infection can either non-specifically stimulate the immune system to heighten the propensity for autoreactivity or specifically stimulate B and T cell autoreactivity by molecular mimicry. For many years, this venerable model has powerfully influenced the design of experiments in both the human and animal systems as well as their interpretation.

While the ‘one organism, one disease’ mechanism may pertain to at least some rheumatic diseases (eg, rheumatic fever following Streptococcus infection), for most other conditions, pathogenesis is more complicated, at least in part because one of the major sources of foreign organisms—bacteria, viruses, fungi and others—resides in or around the host as the microbiome. The microbiome is a huge biomass, with the mammalian host containing as many prokaryotic as eukaryotic cells; the number is in the trillions. Many studies have therefore addressed whether the microbiome can influence the occurrence of not only rheumatic diseases but also metabolic, cardiovascular and neuropsychiatric conditions, among others.1 2

As shown recently in a provocative study by Rosshart et al 3, the host and the environment are not truly distinct, with data presented suggesting that the microbiome and the host have coevolved to produce an optimal balance of positive and negative effects. In their drive to study disease in a more reductionist way, investigators have likely disrupted this balance by breeding genetically inbred mice in very clean environments. Although a clean environment would seemingly reduce potential ‘contaminating’ influences of infection, it is very much unnatural and leads to a microbiome that itself can alter host responses and skew …

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  • Handling editor Josef S Smolen

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.