Effect of Antibiotics on Enteric Neurons and Glia
Condition: Antibiotic Enterocolitis
MeSH terms: Enterocolitis
Study type: Interventional
Phase: Phase 4

Summary: 
      The interactions between bacteria and their products with the intestinal tissue are important
      for maintaining a healthy and balanced system. Alterations in gut bacteria communities have
      been associated with various human pathologies. The investigators have found that mice
      treated with short and long-term antibiotics exhibit a transient yet profound loss of neurons
      in the more superficial submucosal and deeper muscularis plexi in the intestine accompanied
      by slow motility. Glia cells also depend on microbiota for their maintenance. In humans,
      antibiotic use has been associated with disorders of gut-brain interactions (DGBI) such as
      irritable bowel syndrome however whether there are changes in the enteric neurons and glia
      cells remain unknown. Therefore, the investigators propose to further characterize the
      neurons and glia populations in the human distal colon after a single antibiotic course. This
      study will reveal glia and neuronal subtypes that are susceptible to changes in the bacteria
      populations and depend on microbial products for their maintenance. These findings will guide
      future DGBI studies to ascertain the physiological effects that such loss has on intestinal
      healthy balance.
    

Detailed description: 
      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.
    

Intervention name(s): Amoxicillin Oral Capsule
Intervention type(s): Drug
Intervention description(s): Amoxicillin 875mg every 12 hours for 7 days.
Intervention MeSH terms: Amoxicillin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Glia; Enteric Neurons