Early-life adversity, including abuse, neglect and illness, is linked to leading causes of morbidity and mortality across the lifespan and represents a major health concern.
Three Michigan State University researchers—Adam Moeser AJ Robison and Cynthia Jordan—have received a five-year $2.26 million National Institutes of Health, or NIH, grant to help determine lifetime disease risk for people who have experienced early-life adversity. Their project, “Neuro-Immune Mechanisms in Early Life Stress-Induced Gastrointestinal Disease,” is funded by the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development.
The innovative research team brings together expertise in gastrointestinal, or GI, biology, immunology, stress, sex differences, epigenetics and agricultural animal health and production to fill a knowledge gap with dual biomedical and agricultural importance.
“The overall aim of the project is to understand the biology and mechanisms by which early-life adversity influences disease risk across the lifespan,” said Moeser, Matilda R. Wilson Endowed Chair in the Department of Large Animal Clinical Sciences in the College of Veterinary Medicine. Moeser, who is also an associate professor and leads the Gastrointestinal Stress Biology Laboratory at MSU, is project director.
Moeser’s previous NIH-funded research showed that early-life adversity causes a specific immune cell—the mast cell—to become hyperactive in adulthood. Moeser’s lab also identified a novel sex difference in mast cells, in that mast cells from adult females who previously experienced early-life stress induced more severe inflammation and GI disease in females than in males. In collaboration with Jordan, a neuroscientist who is an expert in sex differences biology, it’s become clear that male androgens play a role. In humans, females are often more at risk for stress-related immune and GI disorders. This may be due to the mast cell programmed by androgens to protect males from such stress-related disorders.
“It’s well known that early-life adversity in the form of emotional and physical abuse and trauma in childhood increases your risk for developing a wide number of diseases in adulthood, including functional bowel disorders, food allergies, depression and other debilitating disorders,” said AJ Robison, an associate professor with joint appointments in the MSU Department of Physiology and the Neuroscience Program in the College of Natural Science, or NatSci.
“Many of these diseases are also sex-biased and likely depend on sex differences in hormones,” said Jordan, a professor in NatSci’s Neuroscience Program. Jordan will work with Moeser and Robison to better define how the mechanisms of sex differences operate in the mast cell and how that contributes to a sex bias or prevalence with disease risk later in life.
“My lab has studied this phenomenon using pigs and other animal models, we believe hyperactive mast cells are central players in chronic lifelong inflammation induced by early-life stress, which is central to many diseases including IBS, allergy and autoimmune disease,” Moeser said. “Pigs, whose GI tracts are extremely similar to those of humans, may be one of the clearest windows we have into researching stress, disease and new therapies and preventatives—both for people and animals.
“With this new project, our goal is to define the cellular mechanisms by which early-life stress alters the development of the immune system and how this, in turn, contributes to lifelong risk for a number of disorders that are associated with stress and the brain-gut axis in people and animals,” Moeser said.
Robison, a neuroscientist whose research focuses on how the structure of DNA can be altered to make specific genes more or less likely to be expressed, is investigating how early-life stress can cause epigenetic changes, or external modifications to DNA that turn genes "on" or "off," in the mast cell, which results in long-term function. Understanding how hormones inside the body interact with stress to have long-lasting effects on mast cells is new and a major goal of the project.
“What will certainly come out of this work is a better understanding of the etiology of these diseases — what’s the mechanism, what’s driving bowel diseases and food allergies, and perhaps even identify big implications for psychiatric disorders,” Robison said. “Our hope is that a better understanding of these factors will give us insight into new therapeutic opportunities, especially sex-specific and age-specific therapeutic opportunities, including direct manipulation of mast cells.”
“We’re specifically studying the role of early-life adversity and how it interacts with sex differences in perinatal androgens to program mast cells to respond differently to stress in males and females, and how this may give rise to resilience or susceptibility to disease,” Jordan said. “This is really the next frontier in sex difference research.”
Based on their findings, the scientists hope to better determine biological targets and interventions to mitigate lifetime risk of disease associated with early-life adversity. These interventions may benefit humans and include the potential for biological sex-specific therapies and preventatives, as well as management strategies and medical therapies for animals.