University of Colorado
Department of Biochemistry and Molecular Genetics

Author Of 1 Presentation

Microbiome Poster Presentation

P0674 - “Lactobacillus species differentially alter CNS autoimmunity via distinct immunomodulatory genomic loci and modulation of gut microbial composition.” (ID 1561)

Speakers
Presentation Number
P0674
Presentation Topic
Microbiome

Abstract

Background

The etiology of multiple sclerosis (MS) is complex, multifactorial, and polygenic with approximately 30% of disease susceptibility attributed to genetics, and only modest increase in risk attributed to any singular allele. The remaining 70% of risk is attributed to environmental influences, including diet, vitamin D intake, smoking, and stress, all of which can contribute to an imbalance in the gut microbiome as a central emerging risk factor. Recent studies have shown that MS patients harbor altered gut microbial content as compared to healthy controls, including depletion of the Lactobacillus genus, however the mechanism by which these changes impact disease pathogenesis remains unclear.

Objectives

The purpose of this study was to identify commensal members of the gut microbiome sufficient to alter CNS autoimmunity and begin to discern their mechanism of action.

Methods

Using a multipronged approach involving gut microbiome transplantation and colonization of germ-free mice, commensal microbiota associated with exacerbation of a murine model of MS, experimental autoimmune encephalomyelitis (EAE) where identified bioinformatically upon 16S sequencing. Commensal isolation and colonization studies were used to validate computational predications coupled with mechanistic studies utilizing immune profiling strategies and whole genome sequencing of bacterial isolates.

Results

We demonstrate that disparate gut microbiomes in genetically identical hosts confer differential susceptibility to EAE correlating with the abundance of several commensal Lactobacillus species, including Lactobacillus reuteri (L. reuteri), which unexpectedly is associated with exacerbation of neuroinflammation. Functionally, colonization with L. reuteri was sufficient to exacerbate EAE and elicit higher proportions of CD4+ effector T cells and higher GM-CSF production by CD4+ and CD8+ T cells in the CNS during chronic EAE. Mechanistically, whole genome sequencing of commensal Lactobacillus isolates, including L. reuteri, revealed alterations in the enzymatic machinery necessary to catabolize dietary tryptophan into indole derivatives with known immunomodulatory capacity, as well as species-specific bacteriocin production, with the capacity to shape the peripheral immune system and alter gut microbiome community structure. Consistent with the latter, we show that introduction of L. reuteri significantly remodels existing gut microbial communities.

Conclusions

These data highlight the need for further mechanistic study of host-microbe interactions as dictated by bacterial species-specific differences in commensal microbiota to discern their role in MS pathogenesis.

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