Fig. 6.

Models of the order of microbial effects on host social behaviour. Germ-free models, as well as studies involving antibiotic administration or disruptions to maternal physiology during pregnancy, have revealed the important contributions of the microbiome to host development in rodents. However, because many of the specific mechanisms by which microbes influence host physiological development are unknown, it is currently not possible to establish the order of these effects, and how they in turn affect social behaviour. This gives rise to several hypotheses about how these processes occur in relation to one another. (A) The microbiome influences the immune system, metabolism, and the brain independently, with microbial effects on the immune system and metabolism having little or no effect on the brain and social behaviour. (B) A sequential model in which a particular developmental sequence leads to the microbiome ultimately affecting host social behaviour. The microbiome influences the development of a single function, which in turn influences a second function, and so on. A and B are unlikely to occur in reality, but may represent useful null models for the generation of predictions and comparisons. (C) An interactive model which assumes that the microbiome makes core, parallel contributions to host metabolism and immunity that interact with one another, and which in turn influence brain development and function, contributing to the host’s social behaviour (in this case, effects on the brain follow sequentially from changes in host metabolism and immunity). (D) An interactive hybrid model. Apart from microbial effects on the brain via immunological and metabolic influences, brain development may also be affected by the microbiome more directly, perhaps via modulation of the vagus nerve or enteric nervous system. These models are highly simplified, and represent merely four possibilities. Many other combinations are of course possible, and may involve other physiological systems including the endocrine system and the olfactory system. Although this diagram only shows microbial effects on host physiological functions, the relationships are bidirectional, with the host’s metabolism, immunity, brain, and social behaviour exerting effects on the microbiome as well.