Effect of Antibiotics on Submucosal Enteric Neurons and Glia in the Lower Gastrointestinal

The enteric nervous system (ENS) has been recognized as the "second brain" as it can regulate enteric physiology without central nervous system input. Similar to the central nervous system, it is composed of multiple neuron populations whose main functions are gut motility, secretion, and absorption. In addition to the neurons, the ENS contains glia cells whose main role is neuroprotection but also contribute to normal gut motility. Several studies have demonstrated that the microbiota and the ENS have an intimate relationship that begins in utero, and it is critical for its normal development. Neurons can recognize bacteria and their products. Several investigators have shown neuronal loss after enteric infections and antibiotic (Ampicillin) treatment in the muscularis layer, that results in delayed transit time in animal models. Hence, communication between the microbiota and the ENS is important to maintain normal gut motility. Disorders of Gut-Brain Interactions (DGBIs) are quite common, among these are Irritable Bowel Syndrome (IBS) defined by Rome IV criteria as abdominal pain associated with a change in consistency and frequency of bowel movements and the constipation predominant subtype (less than 3 bowel movements per week) is the most prevalent, which is also the most common motility disorder that mouse models of infection and antibiotics treatment exhibit. IBS has been associated with dysbiosis and a recent study demonstrated that antibiotic use immediately before or after screening colonoscopy increased the risk of developing IBS. In addition, dysfunction of submucosal neurons in IBS has been previously reported but whether there are changes in neuron numbers or neuron characteristics has not been explored. While there have been prospective studies that have explored the effects of antibiotics in patients treated for Helicobacter Pylori, there have been other investigators who have focused on the long term effects of antibiotics in healthy volunteers.

Therefore, similar to animal models, investigators propose that humans experience a profound and transient loss/alteration of neurons in the setting of antimicrobial use associated dysbiosis that manifest as DGBIs, most notably the constipation subtypes. This proposal will address whether antimicrobial use leads to quantitative and qualitative changes in the populations of submucosal neurons and glia cells in human subjects.

This hypothesis will be tested in a prospective study in which healthy participants will be asked to take the commonly used antibiotic amoxicillin twice a day for 7 days, and colon tissue biopsies will be obtained before and after treatment. Human tissue will be processed and analyzed to visualize structural changes, and changes in gene expression, bacteria, metabolites will be determined through single nuclei RNA sequencing, 16S ribosomal bacteria RNA sequencing and metabolomics analysis respectively.