Differences in how male and female pigs respond to early-life adversity with regard to gastrointestinal nervous system development and function provides potential mechanistic clues into GI diseases in humans and animals.

The gut has a mind of its own, and scientists call it the “second brain.” With more than 100 million neurons—outnumbering those that surround the spinal column—this enteric, or intestinal, nervous system communicates directly with the spinal cord and the brain to heavily influence gastrointestinal health. While we understand the enteric nervous system’s central function in health, the ways in which early-life factors may disrupt the mechanisms of disease resistance remain unknown. Now, Dr. Moeser’s team has reported novel findings on how early-life adversity alters the development of the enteric nervous system, increasing intestinal permeability and contributing to GI disorders.

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 governs the function of the GI system, as well as changes in epithelial barrier function and microbiome colonization and structure. These changes allow the host to survive and thrive.

We know there is a clear brain-to-gut pathway, and early-life events and sex differences play important roles in GI disorders, such as irritable bowel syndrome (IBS), which affects about a quarter of the population and is up to four times more prevalent in females. In part because it is a disease that impairs bodily function, patients with IBS are more likely to undergo unnecessary procedures, including rates of hysterectomies or ovarian surgeries that are up to 50 percent higher than comparison groups, making IBS a major women’s health issue.

The adult onset and severity of IBS, inflammatory bowel disease, other GI diseases, and even allergies are associated with early-life adversity, such as the loss of a caregiver, emotional and physical abuse, or other physical injuries. While this link has been established, how it works is a mystery that Dr. Adam Moeser and his team are working to solve.

Dr. Moeser, director of the GI Stress Biology Laboratory and Matilda R. Wilson Endowed Chair, led the team in new research that shows how pigs respond to early-life adversity when it comes to the development and function of the GI nervous system. The team developed a porcine model to study stress-related GI diseases because when compared to humans, pigs suffer from similar GI diseases and have similar stress responses and intestinal tracts. The resulting research verified that early-weaning stress—a common swine production management protocol— simulates early-life adversity in humans and induces lasting hypersensitivity of cholinergic nerves. These nerves are abundant in the gut and produce the neurotransmitter acetylcholine, which controls a wide range of GI functions including motility, intestinal permeability, immune responses, and fluid secretion. Cholinergic nerves are key in regulating gut immunity and barrier functions, which are pivotal factors in health. Without proper function, leaky gut, diarrhea, inflammation, and other symptoms of GI disease are more likely to arise.

The Moeser Laboratory also found that early-life stress in female pigs induces developmental changes in the enteric nervous system that are lifelong and more pronounced than those found in males. This finding correlates with sex-related GI disease patterns found in humans and illustrates the importance of sex differences in different species. The identification of heightened nerve secretion responses in female compared with male pigs provides potentially important insights into the underlying sex differences that exist in human stress-induced GI disorders while also pointing toward an understanding of why females are more vulnerable.

These findings are the result of a project that began in 2013 with an NIH-funded grant. Dr. Moeser’s team has published more than 30 papers within the last 8 years that address early-life stress and gastrointestinal disorders. The team first identified current swine production management practices that were causing an increase in GI disease susceptibility later in life. This led to their investigation of enteric nervous system mechanisms and underlying biology that would link early-life stress and adult onset of severe GI disease together. These most recent findings, published in the journal Neurogastroenterology & Motility in September 2016, provide potential mechanistic clues into the differences in sex that are prevalent in diseases like IBS. The paper was selected as an editorial focus, and experts who reviewed the paper commended the novel use of a large animal model, which is more translatable to human disorders than rats or mice.

Dr. Moeser’s research has One Health implications. For pigs, early-weaning stress is a common swine production management practice. Piglets are weaned early, allowing for the sow to potentially be rebred sooner. While this method may increase the number of pigs produced, it also produces a higher number of unhealthy pigs with compromised gut health, poor digestive function, and disease susceptibility. These findings may facilitate the implementation of less-stressful production practices that result in healthier pigs.

In both pigs and humans, the research points to a better understanding of how early-life factors can lead to a lifetime of disease susceptibility. This understanding will provide researchers with targets to focus on when devising preventative measures against GI diseases. Additionally, as researchers learn more about the development of the gut, new therapeutic targets may be unveiled, which may even bridge into sex-specific treatments and other forms of precision medicine.

The next steps are to evaluate stressors, consequences, and sex differences more closely. Dr. Moeser’s team will research the components of stress in humans, breaking down causes and types of stress into separate components to see which may have a stronger impact when it comes to adult onset GI diseases. The team also will examine which other consequences, besides GI disease, an altered nervous system may lead to, particularly in regard to immune function. Additionally, the team will focus on sex differences to determine if sex hormones, physiology, or other factors are the reason why females are more vulnerable or males more resistant to the effects of early-life stress.