Oral GAD65-L. lactis Vaccine Halts Diabetes Progression in NOD Mice by Orchestrating Gut Microbiota–Metabolite Crosstalk and Fostering Intestinal Immunoregulation

TL;DR

An oral vaccine using Lactococcus lactis expressing GAD65 halts diabetes progression in mice by altering gut bacteria and metabolism to boost immune regulation.

Contribution

The study introduces an oral GAD65-L. lactis vaccine that modulates gut microbiota-metabolite interactions to prevent diabetes in NOD mice.

Findings

The vaccine delays diabetes onset and preserves pancreatic function in NOD mice.

Gut microbiota diversity increases with enrichment of beneficial bacteria.

Metabolic pathways like pyrimidine and arachidonic acid metabolism are altered over time.

Abstract

This study successfully developed an oral vaccine for Type 1 Diabetes utilizing recombinant Lactococcus lactis expressing the GAD65 autoantigen. We conducted an in-depth investigation into its protective mechanisms in NOD mice, with a particular focus on its effects on the gut microbiota and metabolome. The administration of the GAD65-L. lactis vaccine resulted in a significant delay in diabetes onset and the preservation of pancreatic function. Our analyses revealed notable alterations in the gut microbial ecosystem, enhancing its diversity and the abundance of beneficial bacteria. Metabolomic profiling indicated time-dependent changes in metabolic pathways, with a marked enrichment of pyrimidine metabolism at 16 weeks and arachidonic acid metabolism at 24 weeks after vaccination by both GAD65-L. lactis and NZ9000-L. lactis. Integrated correlation analysis identified specific microbiota–metabolite interactions, including associations between Ruminiclostridium and lipid species in the GAD65-L. lactis group. These modifications in the microbial community and metabolic landscape were accompanied by enhanced immunoregulatory responses in intestinal LPLs, including expanded Treg populations and suppressed CD8+ T cells, a rising trend in IL-10-producing naive dendritic cells, and increased concentrations of TGF-β.

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