Preclinical study demonstrates selective FFAR2 activation ameliorates neuroinflammation in mice, indicating a gut-directed approach for multiple sclerosis.
Key Points
To determine the receptor-mediated mechanisms through which short-chain fatty acids and free fatty acid receptor 2 (FFAR2) modulate gut and central nervous system autoimmunity.
Treated established experimental autoimmune encephalomyelitis (EAE) in mice via selective oral administration of the synthetic FFAR2 agonist Cpd1.
Conducted transcriptomic analysis of intestinal CD4⁺ T cells to evaluate pathway suppression.
Utilized antibody-mediated neutralization of interleukin-22 (IL-22) to determine the mechanistic dependence of FFAR2-mediated protection.
Oral administration of Cpd1 promoted regulatory T cells and type 3 innate lymphoid cells in the intestine while suppressing inflammatory infiltration in the central nervous system.
Transcriptomic profiling of intestinal CD4⁺ T cells demonstrated broad suppression of signaling pathways governing T-cell activation and proliferation.
Antibody neutralization of IL-22 completely abolished Cpd1-driven disease protection, confirming that IL-22 is required for FFAR2-mediated suppression of CNS autoimmunity.