LAUSR

Back in the 19th century, working with laboratory rodents was dangerous. There was a certain risk of catching hazardous zoonoses such as Yersinia pestis, Leptospira, Salmonella, and Streptobacillus moniliformis. It was, therefore, common, to decontaminate rodents with strong chemicals before studies. This progressed to efforts that were made to eliminate such infections from rodent colonies in the last half of the 19th century. In the beginning of the 20th century, scientists described some fatal rodent diseases, such as Bordetella bronchiseptica in guinea pigs and Clostridium piliforme in mice, which were not dangerous for humans, but were detrimental to research because of unanticipated loss of animals. Also in the early 20th century, it became evident that animals could be rendered free of all microbial organisms (germ-free, axenic) without fatal consequences if maintained in closed isolators. In 1947, Henry Foster founded the United States breeding company later known as Charles River. With the concurrent introduction of the 3Rs (refinement, reduction, replacement) to animal-based research, he started the use of cesarean section and barrier protection as a way to refine rodent models by producing them free of well-defined specific pathogens. Disease-provoking rodent infections were all eliminated, while new ones, such as Citrobacter rodentium and Filobacterium rodentium (cilia-associated respiratory bacillus) were described and subsequently also fully eliminated. Nowadays laboratory rodents are produced only behind barriers subjected to thorough health monitoring programs and, should any of the previously experienced bacterial agents be found, depopulation is often the only viable solution. Early attempts to move rederived germ-free rodents from isolators to barrier-protected facilities were often confounded by opportunistic infections. To circumvent this, Russell W. Schaedler explored whether limiting the number of commensal bacterial species could minimize clinical disease in reconstituted rodents. He selected known commensal (i.e. not associated with disease) bacteria, which could be cultivated, and this collection became known as the Schaedler flora. After a redesign it became ‘‘The altered Schaedler flora’’ (ASF), which today is the initial microbiota of most commercial laboratory rodent-breeding colonies. ASF bacteria can be recovered from rodents several years after the initial colonization. Although ASF provides a valuable tool for controlled studies of the role of microbes in models of disease, the translatability of such studies must be viewed with caution as ASF does not recapitulate the complexity of microbiota that exist in human populations. As a result, we must interpret such studies in combination with studies performed in rodents with complex microbiota. However, the latter are also potentially flawed as during 70 years of rederivation and barrier protection key microorganisms crucial to the function of the animals as models for human beings may have been lost, or at least found in only some rodent colonies. An example can be found with the anti-inflammatory bacterium Akkermansia muciniphila, whose presence in contemporary rodent colonies is now inconsistent and thus may be affecting reproducibility of inflammatory models of disease. This phenomenon is also well known in human medicine, in which it has been hypothesized that the ‘‘loss of old friends’’ has affected the incidence of a number of diseases, such as allergies and type 1 diabetes. To address this there is growing interest in using pet store or wild mice, which possess microbiota that have evolved in a more complex and antigen-experienced environment. While such studies may have merit, they are also complicated by lack of controlled microbiota and adventitious pathogens that most research facilities strive to exclude. A happy