Reducing the group size in studies of dermatitis by standardization of the gut microbiota

Contact: Axel Kornerup Hansen

During the last decade it has become increasingly clearer that the composition of the gut microbiota has severe impact on disease expression in laboratory mice. The more the mice differ in this aspect, the more variation will be observed, and the more animals will be used. It is, therefore, reasonable to assume that if the mice could be made more uniform in their gut microbiota this would enable a reduction in the group sizes of mouse experiments.

The oxazolon induced mouse model of atopic dermatis is such a model in which the largest differences have been observed in relation to gut microbiota composition, and this model is the target of this project. However, the issues is also relevant for models of diabetes, obesity, Morbus Chrohn, as well as other diseases. Germ free mice are inoculated with a gut microbiota from mice with a high or a low response in the atopic dermatitis model, and it is hypothesized that the response when inducing the model in inoculated mice will mimic the donor.

Therefore, it may be possible in future development and test of products against atopic dermatitis in children to use mice made responding more precisely, because they have been inoculated with high responder microbiota. In subsequent projects it is the hope that the method can also be applied in other fields of research.

Project status at January 2017

The main idea behind the project was that over the past 5–10 years, it has been demonstrated in a number of research areas that the more diverse the gut microbiota in the animals, the less homogenous their reaction is in tests and the greater the number of animals that are consequently required. For this reason, it can be assumed that if you either make the gut microbiota in the mice more homogenous or provide them with a gut microbiota that ensures a high response, you can reduce the number of mice to be tested.

One of the disease models showing the greatest correlation is a mouse model for children’s eczema – also known as atopic dermatitis – which is why this model was chosen for this project. However, the issue is also relevant for other disease models such as models for diabetes, obesity and Crohn’s disease. The
project has now been completed it its entirety and is awaiting final approval for publication. Mice that are born germ-free were inoculated with the gut flora of mice with either a high or low susceptibility to children’s eczema. The mice inoculated with bacteria from high-response donors exhibited a significantly higher clinical score, enlarged ear thickness and elevated levels of the important transmitter substances IL-1β, TNF-alpha, IL-4, IL-5 and IL-6 compared with mice inoculated with bacteria from lowresponse
donors.

The inter-individual variation was generally not affected by this increase in effect. Non-inoculated germ-free mice exhibited high, but also highly variable, disease activity, which suggests that the missing response in some mice is due to the protective characteristics of certain bacteria. Mathematically speaking, the higher effect may possibly reduce the group size, but it is important to conduct further studies – both to show that efficient treatment for testing of mice will still be able to reduce this increased disease level to the usual low level, which is necessary for reducing the group size, and to make an attempt at finding the protective bacteria so that mice with these bacteria can be sorted out before the test as they cannot contribute to the conclusion of a test, anyway.

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