It is well established that the microbiome plays a role in regulating systemic and mucosal inflammation, but the mechanism underlying this recognized phenomena remains unclear. Diseases associated with microbiome disruptions including allergies and asthma, diabetes and metabolic syndrome, heart disease, arthritis, ulcerative colitis, sepsis, and Alzheimer's disease. Increased cytokine-driven inflammation is also believed to play a causative role in these same diseases. We propose that these two phenomena are linked by the function of acetylcholine-producing lymphocytes, which develop in response to interactions with byproducts of the microbiome and which act to regulate inflammatory cytokines. Inflammatory cytokine production is regulated by the brain via the cholinergic anti-inflammatory pathway. Secreted acetylcholine binds to ?7 nicotinic acetylcholine receptors, inhibiting NF-?B activation and downregulating synthesis and release of inflammatory cytokines, primarily TNF, IL-1?, and IL-6. There is growing recognition that the acetylcholine in the cholinergic anti-inflammatory pathway is not secreted directly by the nervous system. In the spleen and peritoneal cavity, the critical acetylcholine-secreting cells are lymphocytes. Splenic CD4 T cells and peritoneal B-1 and B-2 cells secrete acetylcholine in response to signals from the vagal nerve, controlling the inflammatory response to factors as varied as TLR agonists, hemorrhagic shock, and tissue ischemia. Loss of these cholinergic lymphocytes leads to uncontrolled inflammation in response to inflammatory stimuli. These cholinergic (i.e., acetylcholine-producing) lymphocytes develop post- natally, in response to interaction with byproducts of the intestinal microbiome. The cholinergic anti- inflammatory pathway also functions in the lungs, but the mechanics of acetylcholine secretion in response to inflammation is unknown. We propose that the pulmonary compartment possesses a cohort of cholinergic lymphocytes similar to those of the peritoneal cavity. We further propose that these pulmonary cholinergic lymphocytes are regulated in response to interactions with byproducts of the recently-described pulmonary microbiome. Finally, we propose that early life disruption of the mucosal microbiome by neonatal antibiotic therapy leads to permanent disruption of these critical cholinergic lymphocytes. Using antibiotic treatment to reduce intestinal and systemic microbial load, TNF as a biomarker of inflammation, and LPS stimulation as the prototypic inflammatory stimulus, we propose to confirm cholinergic lymphocytes as the link between neonatal antibiotic treatment and inflammatory-associated disorders in adulthood.

Public Health Relevance

A number of diseases, including allergies and asthma, diabetes and metabolic syndrome, heart disease, arthritis, ulcerative colitis, sepsis, and Alzheimer's disease, have been associated with uncontrolled, ongoing inflammation, and have also been associated with neonatal antibiotic therapy. We propose to uncover the link between neonatal antibiotics and uncontrolled inflammation later in life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI119929-01A1
Application #
9038022
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Dong, Gang
Project Start
2016-01-01
Project End
2017-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
1
Fiscal Year
2016
Total Cost
$187,500
Indirect Cost
$62,500
Name
San Diego State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
073371346
City
San Diego
State
CA
Country
United States
Zip Code
92182