The microbiome is far more likely to influence research than any bacteria routinely monitored in rodents today.
Bacteriology has changed dramatically since 1890, when German physician Robert Koch introduced four postulates that, in theory at least, were designed to establish a causative relationship between a microbe and disease.
The criteria specified that a pathogen: (1) should not be found in healthy organisms; (2) should be cultivable; (3) should cause disease when inoculated in a healthy, susceptible lab animal and; (4) must be re-isolated from the new host and shown to be identical to the disease-causing pathogen.
Nos. 1 and 2 were soon dropped due to the concept of latent infections—which covers most of what is monitored in rodents today—and the recognition that certain pathogens, such as Clostridium piliforme, were uncultivable. And if No. 1 was questionable, then so was No. 4, leaving No. 3 as the only postulate that still carried weight in modern bacteriology. Yet while this postulate fit most of what was included when rodent health monitoring was evolving in the 1950s, the only bacterium found in rodent bacteriology screenings today is Pasteurella pneumotropica. Funny thing is, 10 years after Charles River’s founder Henry Foster produced the world’s first health-monitored rodents in 1959, Patricia Brennan from the Argonne National Laboratory showed it was impossible to fulfill postulate No. 3 for P. pneumotropica without adding Mycoplasma pulmonis.
So, today enormous resources are spent on an agent that, strictly speaking, can’t really be regarded a pathogen. Call it my “gut instinct” but maybe time has come to spend these resources differently and more broadly.
Microbial hot spots
The gut microbiota contains a hundred trillion (1014) organisms dispersed on 500 to 1000 different species, only 10-20 % of which can be cultivated. However, molecular methods such as qPCR, gel electrophoresis (GGE), terminal restriction fragment length polymorphism analysis (T-RFLP) and, least but not least, high-throughput sequencing have evolved over the last decade, allowing a full characterization of the entire microbiome. This has shown the microbiota to have an essential impact on a wide range of animal models that apply to inflammatory bowel disease (IBD),[2-8] diabetes type 1 [9-11] and type 2[12, 13], obesity,[14-17] dermatitis and psychiatric disease.[19, 20].
Different bacterial species work in conjunction with one another, making it unclear just who is the pathogen, the co-pathogen or the symbiont.[13, 17] The level of the entire phylum Firmicutes correlates to leptin-deficiency, stress responses[20, 21] and vitamin D receptor function, and for some animal models the microbiota is responsible for between 35% to more than 80 %of the variation in some parameters.
Bacterial species with a strong impact on animal models, have been revealed, but can they be regarded as pathogens or symbionts, and should they be absent or present in rodents purchased to model disease? For instance, in mice a high abundance of Akkermansia muciniphila may protect against diabetes type 1, while a low abundance may protect against colorectal cancer. Segmented filamentous bacteria (SFB) drive arthritis development but also seems to protect mice against diabetes type 1. Stress, dietary fluctuations,[9, 27] and other factors may change the gut microbiota, and with this the animal model.
Different strategies may be pursued to control the variation caused by the gut microbiota. Standardization may be achieved by inoculation of tailor-made microbiotas or feeding animals certain prebiotic diets, but we would probably have to use different standards for different types of research.
Alternatively, animals for microbiota-sensitive studies could be screened to incorporate this information in data evaluation, thereby turning this uncontrolled variation into controlled variation. With rapidly declining prices for full sequencing we are reaching a state where, without additional cost, it is now possible to replace bacteriological screenings of little customer relevance with screenings of high value for the animal user.
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