The microbiome and rodent models of immune mediated diseases

Abstract

Over the last six decades production of laboratory rodents have been refined with the aim of eliminating all pathogens, which could influence research results. This has, however, also created rodents with little diversity in their microbiota. Until 10 years ago the impact of the microbiota on the outcome of rodent studies was ignored, but today it is clear that the phenotype of rodent models differs essentially in relation to the environment of origin, i.e. different breeders or different rooms. In this review, we outline the mechanisms behind gut bacterial impact on rodent models of immune mediated diseases, and how differences in environment of origin leads to phenotypic model differences within research areas such as infectious diseases and vaccine development, the metabolic syndrome, gut immunity and inflammation, autoimmunity and allergy. Finally, we sum up some tools to handle this impact to increase reproducibility and translatability of rodent models.

Fig. 1

Immune activation by bacteria in the gut. In the gut the immune cells and the enterocytes possess different types of Toll-like receptors (TLR), which can be stimulated by different types of microbial associated molecular patterns (MAMP), which dependent on cell type and TLR will cause different forms of innate immune activation and cytokine production. MAMPS are such as peptidoglycan, lipoproteins, lipoteichoic acid, polysaccharide A and zymosan from Gram positive bacteria, lipopolysaccharides and profillin from Gram negative bacteria, and flagellin from bacterial flagellas. Epitopes, which are different parts of bacterial molecules with an adaptive immune stimulatory potential, will be presented by antigen presenting cells (yellow arrows), such as the dendritic cells, to T and B cells. The cytokine production initiated by the innate MAMP-TLR stimulation will upscale (blue arrows) or downscale (red arrows) the differentiation (green arrows) of T and B cells into effector cells. Stimulation by IL-12 secreted by the dendritic cells as a response to MAMP stimulation will facilitate the differentiation of naïve T cells, into T helper cells type 1 (Th1) on the cost of T helper cells type 2 (Th2), while this process is downscaled by IL-10 from the regulatory T cells (T-reg). IL-12 will also stimulate the natural killer T (NKT) cells. The B cells will present the antigen for the Th2s, which will respond back with IL-4 and IL-5 to turn the B cell into an antigen producing plasma cell. This process is upscaled by IL-6 caused by the MAMP-TLR stimulation of the macrophages, and B cells will be stimulated by IL-10 from T-regs and Th2, while TGF-β from the T-regs will downscale activities of both B cells and macrophages. TGF-β will upscale the activity of Th17 cells. The activated macrophages will produce TNF-α, which will stimulate a number of different T cells. There are far more cytokines and cell types than this, there are other pattern recognition receptors than the TLRs, and in relation to gut virus infections cytotoxic T cells will also be relevant