Early life adverse psychosocial experiences, such as loss of a parent, abuse, or neglect, are linked with debilitating diseases in adult life. This paradigm of “early life origins of disease” is a rapidly growing field of research in human and animals. The gastrointestinal (GI) system, or gut, is particularly sensitive to early life stressors and increased stress during this time is linked with the adult onset and severity of major human GI diseases. Similarly, stressful early life production practices in livestock, such as early weaning, result in long-term disease susceptibility and are economically devastating.
Chronic GI disorders in humans and animals, such as irritable bowel syndrome and inflammatory bowel disease are linked to high stress levels early in life. Our laboratory is leading studies that investigate how these events may change the GI tract leading to increased susceptibility to these diseases later in life.
Our research has previously demonstrated that early life stress in laboratory rodent and large animal models triggers a stress response that is directly responsible for long-lasting harmful influences on GI health as well as increased susceptibility to infectious diarrheal diseases later in life. Moreover, we have demonstrated that a hallmark consequence of early life stress is long-lasting impairment in intestinal epithelial barrier function, also known “leaky gut.”
Intestinal permeability is a primary cause of GI diseases such as irritable bowel syndrome, inflammatory bowel disease, and food allergies, and is one of the primary reasons these diseases persist.
We know that early life stress and elevated intestinal permeability play a central role in GI diseases in human and agricultural animals, but we still do not understand the basic mechanisms. This is a major gap in knowledge that has profound implications for the well being of humans and animals, as well as serious economic implications for US health care and agriculture.
In order to understand how stress might influence long-term GI development and disease susceptibility, it is first important to consider the major intestinal developmental changes and adaptations occurring in the postnatal period.
Into the postnatal environment
In the weeks following birth, the gut undergoes major developmental changes as it adjusts to the postnatal environment. This includes development of the immune and enteric nervous systems, which govern the function of the GI system, as well as changes in epithelial barrier function and microbiome colonization and structure. The changes occurring in these systems allow the host to survive and thrive in the extra-uterine environment. Stress-induced perturbations in normal developmental processes during early life, when changes in neural connections occur, can lead to a deviation in long-term function of the GI system and increased disease susceptibility.
Our research has revealed that early weaning stress in a pig model induces permanent changes in the enteric nervous and immune systems. Pigs are a natural model for the study because they suffer similar GI diseases as humans and have similar stress responses and intestinal systems.
Interactions: enteric nervous and immune systems
A major finding resulting from this research is that early life stress leads to increased abundance and activity in the enteric nerves and mast cells in the intestine. We believe this “rewiring” of the intestinal system induced by early life stress is responsible for increased intestinal permeability and disease susceptibility.
Intriguingly, sex appears to play a major role in nervous system and mast cell changes with female animals showing more reactivity to the effects of stress. Therefore, this research has the potential to lead to an understanding of why females are more prone to certain diseases compared with males. This is expected to lead to the development of targeted innovative therapies centered upon modulation of the nerve-mast cell axis.
Modulating the gut-brain axis to develop new targeted therapies for GI diseases and allergies
A greater understanding of how stress adversely impacts our GI systems will have a number of clinically relevant applications for human and animal health and will be important to the therapeutic management of major debilitating GI diseases such as irritable bowel syndrome, enteric infections, and food allergies. In agricultural animals such as pigs, a more fundamental understanding of mechanisms of stress-induced GI disease will lead to innovative and practical management solutions, including nutritional and management interventions that promote long-term gut health and disease resistance.
If we can understand how stress affects cellular interactions within the gut, we will be able to better protect or treat humans and animals affected by these diseases.