Limosilactobacillus reuteri-Derived Tryptophan Metabolites Differentially Activate AhR Signaling: Implications for Neuroinflammation in Multiple Sclerosis
McManus, Caitlin
McManus, Caitlin
Citations
Altmetric:
License
License
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by inflammation, demyelination, and progressive neurodegeneration. Although current therapies reduce relapse rates, they do not effectively halt neurodegeneration or treat progressive MS, underscoring the need to identify new mechanistic drivers of CNS inflammation. Emerging evidence implicates the gut microbiome as a key environmental regulator of MS, with people with MS exhibiting altered microbial composition, reduced short?chain fatty acids, and broad disruptions in microbial metabolite profiles. Among these pathways, microbial metabolism of dietary tryptophan has gained attention for its ability to generate indole?derived metabolites that activate the aryl hydrocarbon receptor (AhR), a ligand?dependent transcription factor that regulates immune and neuroinflammatory responses. Limosilactobacillus reuteri is a prominent producer of AhR?active tryptophan metabolites, yet the specific microbial genes and pathways responsible for generating these ligands remain poorly defined. To address this gap, I used a dual?plasmid AhR luciferase reporter assay in HEK293T cells to quantify AhR activation in response to supernatants derived from wild?type L. reuteri R2lc and its ?pks and ?araT mutants. Bacterial strains were cultured under standardized conditions, and DMEM?conditioned supernatants were applied to transfected cells expressing both AhR and an AhR?responsive luciferase reporter. Luminescence was measured after 48 hours as a direct readout of AhR activation. Preliminary results show that wild?type L. reuteri induces robust AhR activation, whereas the ?pks mutant exhibits a near?complete loss of activity. The ?araT mutant displays an intermediate phenotype, producing significantly less activation than wild?type but more than ?pks. This activation hierarchy (WT > ?araT > ?pks) was consistent across independent experiments. These findings suggest that the pks pathway is the dominant contributor to AhR?active metabolite production, with araT playing a secondary modulatory role. Together, these data support a model in which microbial genotype shapes the inflammatory potential of tryptophan metabolites, with implications for understanding microbiome-CNS interactions in MS.
Description
Date
1/1/2026
Student Status
Junior (Graduating in 2027)
Journal Title
Journal ISSN
Volume Title
Type of presentation
Poster
Collections
Research Projects
Organizational Units
Journal Issue
Citation
DOI
Advisor(s)
Department
Program/Major
Molecular Genetics
College/School
College of Agriculture and Life Sciences
Organization
Research Category
Clinical Science