Neonatal Antibiotic Therapy, The Pulmonary Microbiome, and theCholinergic Anti-inflammatory Pathway

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 DESCRIPTION (provided by applicant): 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 α7 nicotinic acetylcholine receptors, inhibiting NF-κB activation and downregulating synthesis and release of inflammatory cytokines, primarily TNF, IL-1β, 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.