Exposure to early life adversity (ELA) during critical periods of prenatal and postnatal development is an
important risk factor for the later life onset of highly prevalent gastrointestinal (GI) diseases, including irritable
bowel syndrome (IBS) and inflammatory bowel disease (IBD). The precise mechanisms linking ELA and GI
disease susceptibility are unknown and thus management and therapeutic targets and biomarkers are lacking.
Our studies using a porcine model demonstrated that ELA alters the normal course of GI development resulting
in lifelong intestinal barrier dysfunction or “leaky gut', neuroimmune dysregulation and increased GI disease that
recapitulates much of the pathophysiology and clinical features of human stress-related GI disorders. We
recently identified two factors associated with ELA-induced GI disease susceptibility and severity in adulthood:
(1) heightened and persistent intestinal mast cell hyper-activity and (2) biological sex with females at increased
risk and males protected. Furthermore, we have identified novel sex-differences in the mast cell phenotype in
that mast cell from female animals exhibit enhanced synthesis storage and stress-induced release of mediators
such as histamine, proteases and serotonin which have known roles in GI neuroimmune disorders. Our
hypothesis is that mast cells and biological sex interact to organize the development of GI barrier and
neuroimmune systems, consequently determining the lifetime risk to disease following exposure to ELA. We
have designed three specific aims to accomplish this objective. Aim 1 will test the hypothesis that hyper-activation
of GI mast cells during early postnatal development lead to GI barrier and neuroimmune dysfunction in adulthood.
Aim 2 will test the hypothesis that the heightened vulnerability of females to ELA-induced GI disease depends
on androgens acting during early development. Aim 3 will test the hypothesis that ELA and perinatal androgens
program mast cells, via epigenetic and transcriptional mechanisms, resulting in mast cell hyperactivity which
drives GI barrier and neuroimmune dysfunction into adulthood. Together, the studies proposed in the grant
application are expected to result in a major paradigm shift in the understanding the origins of ELA-induced and
sex-biased GI neuroimmune diseases which could ultimately unveil new therapeutic targets to protect the GI
system during vulnerable periods of stress and to therapeutically modulate adult diseases in both sexes.