THE ROLE OF IN UTERO ENDOTOXIN EXPOSURE IN THE POSTNATAL IMMUNE RESPONSE IN MICE
Embargo until
2021-05-01
Date
2020-03-13
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Johns Hopkins University
Abstract
In this body of work, we were interested in both the temporary state of endotoxin tolerance and the gastrointestinal diseases known collectively as inflammatory bowel disease (IBD). Endotoxin tolerance is a state of muted immune response to bacterial endotoxins after an initial, sub-lethal exposure to an endotoxin. It has been observed primarily in sepsis patients of all ages and can lead to secondary infection and mortality. Conversely, IBD is a disease associated with increased inflammation and tissue damage within the gastrointestinal tract. Although early environmental influences are thought to influence disease development in IBD, little is known about the role of the uterine environment on subsequent early life endotoxin tolerance or IBD risk. We hypothesized that prenatal exposure to bacterial lipopolysaccharide (LPS), an endotoxin, could decrease responses to subsequent inflammatory triggers in early childhood. We also hypothesized that this exposure could modify the subsequent development of dextran sulfate sodium (DSS)-induced ulcerative colitis in adulthood by influencing the associated cellular and genetic immune response. To test our hypotheses, we exposed developing mice in utero to LPS or saline at embryonic day 17.5 (E17), and then induced either a second intraperitoneal exposure to LPS or saline in early life or colitis at 5 weeks and assessed inflammation and disease severity using a variety of metrics. In order to define the developmental impact of any LPS effect on colitis development, we also exposed one week old mice to either LPS or saline. Surprisingly, mice exposed to LPS at E17 were protected from subsequent colitis development, and maintained intestinal barrier and tight junction function similar to that of control mice that were not exposed to DSS. By contrast, mice exposed to either LPS or saline at postnatal day 7 both developed severe colitis upon DSS exposure. These results identify a critical time window during fetal development during which exposure to an otherwise pro-inflammatory agent like LPS could protect against an inflammatory state in both early life and adulthood.
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Keywords
Inflammatory bowel disease, endotoxin, prenatal exposure