Host-microbe interactions are paramount for maintaining normal physiology of the human host, including the brain and behavior. Bacterial colonization of the gastrointestinal (GI) tract, formation of GI mucosal barrier function, and neurogenesis all occur during a critical developmental window in early life. Thus, exposure to trauma such as stress, infection or inflammation during neonatal life could detrimentally impact the developing microbiota, gut and brain (MGB) axis. Disrupted MGB axis signaling, including dysbiosis, mucosal barrier defects and/or changes in behavior, occur in multiple diseases, including inflammatory bowel disease (IBD), autism spectrum disorder, major depressive disorder, and obesity. Antibiotics (Abx) are administered to children more frequently than adults, due to increased susceptibility to bacterial pathogens. Since the MGB axis is developing during this critical time, Abx administration may have long-lasting effects. Administration of probiotic organisms can ameliorate numerous pathologies, including dysbiosis, mucosal barrier dysfunction, inflammation and behavioral defects. We have demonstrated that Lactobacillus-containing probiotics can prevent stress-induced MGB axis deficits following infection with a bacterial pathogen. We hypothesize that administration of specific probiotics can prevent neonatal Abx- induced deficits in the adult MGB axis. Therefore, our primary objective is to address the effects of neonatal dysbiosis on the development of the MGB axis using a model of neonatal Abx administration. Our overall goal is to determine whether intestinal dysbiosis disrupts the gut-brain axis, and whether administration of probiotics beneficially modulates the MGB axis. This goal will be accomplished by the following Specific Aims: (1) neonatal dysbiosis disrupts the developing MGB axis, (2) NOD-like receptors (NLR) are critical for MBG axis development; and (3) selective probiotics can restore MBG axis deficits via NLR. Taken together, these proposed studies will demonstrate whether neonatal dysbiosis disrupts the developing MGB axis, impacting the microbiota composition, altering NLR signaling, and causing behavioral deficits in adulthood. Furthermore, we will determine whether administering select probiotics ameliorates these effects, in part via NLR signaling and thereby support use of select probiotic strains therapeutically for altered MGB axis. Finally, our results may promote use of probiotics concomitantly with Abx administration to prevent development MGB axis deficits, particularly in children and neonates.

Public Health Relevance

The overall goal of this project is to understand how the microbiota-gut-brain (MGB) axis is impacted by dysbiosis of the intestinal microbiota, during the neonatal period of life. Alterations in the MGB axis are present in individuals suffering from major depressive disorder, irritable bowel syndrome, inflammatory bowel disease, autism spectrum disorder and obesity. Induction of dysbiosis, by administration of antibiotics in neonates, to decipher the mechanisms mediating these pathways will lead to better understanding of the role of the intestinal microbiota in early life programming of the gut-brain axis and novel therapeutic targets for treatment with select strains of probiotics.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT009365-02
Application #
9392537
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Duffy, Linda C
Project Start
2016-12-01
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Heeney, Dustin D; Gareau, Mélanie G; Marco, Maria L (2017) Intestinal Lactobacillus in health and disease, a driver or just along for the ride? Curr Opin Biotechnol 49:140-147