Sex and gender as critical and distinct contributors to the human brain-gut-microbiome axis

The brain-gut-microbiome axis (BGMA) is a pivotal contributor to human health. A large body of research, especially from animal models, has revealed bidirectional, causal relationships between the BGMA and sex. In particular, sex steroids appear to be affected by the BGMA, to influence the BGMA, and to moderate environmental effects on the BGMA. However, animal research on the relationship between sex and the BGMA has not translated well to human models. We contend that this is due in part to an oversimplified approach to sex: although BGMA researchers have traditionally approached sex as a unidimensional, dichotomous variable, it is in fact multidimensional and is comprised of both multi-categorical and continuous dimensions. We also contend that research on the BGMA in humans should approach gender as a variable that is distinct from sex and that gender may influence the BGMA through pathways that are independent from the effects of sex alone. Research practices that consider the complexity and distinctiveness of sex and gender in relation to the human BGMA will not only yield improved understanding of this consequential system, but will also enhance the development of treatments for adverse health outcomes with BGMA-related etiologies. We conclude with recommendations for the implementation of such practices.