Stress, sex, and the enteric nervous system

Abstract

Made up of millions of enteric neurons and glial cells, the enteric nervous system (ENS) is in a key position to modulate the secretomotor function and visceral pain of the gastrointestinal tract. The early life developmental period, through which most of the ENS development occurs, is highly susceptible to microenvironmental perturbation. Over the past decade, accumulating evidence has shown the impact of stress and early life adversity (ELA) on host gastrointestinal pathophysiology. While most of the focus has been on alterations in brain structure and function, limited experimental work in rodents suggest that the enteric nervous system can also be directly affected, as shown by changes in the number, phenotype, and reactivity of enteric nerves. The work of Medland et al. in the current issue of this journal demonstrates that such alterations also occur in pigs, a larger mammalian species with high translational value to human. This work also highlights a sex-differential susceptibility of the ENS to the effect of ELA, which could contribute to the higher prevalence of GI disorders in women. In this mini-review, we will discuss the development and composition of the ENS and related gastrointestinal sensory motor and secretory functions. We will then focus on the influence of stress on the enteric nervous system, with a particular emphasis on neurodevelopmental changes. Finally, we will discuss the influence of sex on those parameters.

Keywords: development; early life adversity; enteric nervous system; sex differences; stress.

Figure 1. Pathways involved in the influence of early life adversity (ELA) on enteric nervous system plasticity (phenotype, number, chemical codes, activity)

Both the brain and the gut are affected by ELA. Centrally, ELA can modulate the HPA axis and the ANS which can in turn impact on the ENS plasticity. ELA also affects the HPG axis. Age and sex affect brain and gut development, as well as the HPA axis, HPG axis and ANS. While sex hormones (estradiol, progesterone, testosterone) are absent from the body from birth to puberty, the HPG axis is active in neonates (GNRH/LH secretion) in a sex-dependent manner. The ENS expresses sex hormones and gonadotropin hormones receptors supporting its direct modulation by the HPG axis.