ABSTRACT
The gut-brain axis has been recognized as a highway sending beneficial and pathogenic signals in the gut in
milliseconds to the brain and the body. This gut-brain connection may explain the overlap in seemingly
different diseases, namely the overlap between autism spectrum disorder (ASD) and gastrointestinal
dysfunctions including inflammatory bowel disease (IBD). Specifically, individuals with ASD are more likely to
have gastrointestinal problems, and the incidence of IBD flare-ups in patients parallels severity of ASD.
Microbes in the gut utilize the gut-brain axis and evidence suggests they are part of the relationship between
ASD and gut inflammation. Importantly, as gut microbes can be orally delivered to the gut, they present a
therapeutic opportunity to mitigate disease while avoiding problems associated with drugs such as proper
delivery to the target location, off-target effects, and improper dosage. For example, the clinically tested and
commercially available microbe Limosilactobacillus reuteri promotes normal social behavior in six mouse ASD
models and reduces gut inflammation in humans and animals with colitis. Proper utilization of L. reuteri for
ASD and gut inflammation has been road-blocked by a critical unmet need: how does L. reuteri act on the gut
and the brain to mitigate these diseases and how can we optimize the usage of L. reuteri as a human therapy?
Efforts to understand L. reuteri’s mode of action in social behavior have pointed to a necessary role for the
hormone oxytocin release in the brain. Oxytocin is a multi-functional hormone promoting normal social
interaction and stress behaviors and acting as an anti-inflammatory hormone. How L. reuteri signals to release
oxytocin from the brain is unknown other than that the vagal nerve is required. We, therefore, hypothesized
that L. reuteri’s effects on the body begin with its interaction with the intestinal epithelium. Our efforts to
understand how L. reuteri might signal from the gut epithelium led us to make an unexpected finding: L. reuteri
increases the expression and secretion of oxytocin from intestinal epithelial cells. Oxytocin had not been
previously recognized as being produced in the gut epithelium.
These observations led us to ask the question, could gut stimulation of oxytocin be a pre-requisite of brain-
stimulated oxytocin and L. reuteri’s beneficial effects on ASD and gut inflammation? To begin to understand
the role of gut-derived oxytocin in mediating the beneficial effects of L. reuteri, the following specific aims are
proposed: Aim 1. Does intestinal epithelial oxytocin promote normal social and stress behaviors? Aim
2. Does intestinal epithelial oxytocin protect against gut inflammation and damage? The success of
these investigations will open therapeutic possibilities for safely and effectively treating social behavior and gut
dysfunction in ASD individuals.
