. 2021 Dec 2;53(12):1821–1833. doi: 10.1038/s12276-021-00703-x

Table 1.

Regulation of CNS diseases in animal models by gut microbial metabolites.

Diseases in animal models	Metabolites	Effects of metabolites on disease	Effects of metabolites on cells and molecules	Ref
EAE and related demyelinating diseases	SCFAs	Exacerbation	GPCR-mediated immune cell activation; Increased Th17 polarization	¹⁸
	SCFAs	Suppression	IL-10 production; Induction of regulatory T and B cells; Decreased MAPK activation; Th1 suppression; HDAC inhibition; Increased glycolysis and AKT/mTOR; Oligodendrocyte maturation	^{18,27,102,104,105}
	LCFA	Exacerbation	MAPK activation; Increased Th17 and Th1 activity; Decreased Treg activity	^104,216
	Trp metabolites (3.4-DAA I3S, I3C, DIM, IPA, IAld)	Suppression	STAT1-mediated suppression of antigen presenting cells; Activation of microglial AhR; Decreased NF-κB activity; Th17 suppression; Treg expansion; Increased SOCS2 activity	^116,150,217
	PSA	Suppression	Increased activity of CD103⁺ DCs; Induction of IL-10⁺ T cells; TLR2-dependent increase in CD39⁺CD4⁺ T cell activity	^94,217
	2^ND BA (TUDCA)	Suppression	Suppression of inflammatory responses in astrocytes and microglia cells in a GPBAR-dependent manner	¹⁴³
PD models	SCFAs	Exacerbation	Microglia activation; Increased αSyn-mediated motor dysfunction; Activation of microglial and astrocytes; Higher expression of TLR4, Increased activity of TBK1, NF-κB, and TNF-α.	^71,218
	SCFAs	Suppression	GPR41 activation; Suppression of dopaminergic neuronal loss; Enrichment of C4-producing bacteria; Increased gut occludin expression	^163,164
	2^ND BA (UDCA, and TUDCA)	Suppression	Increased intracellular ATP levels; Enhanced contrast response function; Suppressed JNK activity; Suppressed ROS production	^179,183
AD models	SCFAs	Exacerbation	Microglial activation; Increased amyloid β plaque deposition via apoE-TREM2	¹⁹⁹
AD models	SCFAs	Suppression	Increased neuronal activity with hippocampal c-Fos expression; Decreased polymerization of amyloid β; Suppression of NF-κB and COX-2 in microglia	^73,188,195
ASD models	SCFAs	Exacerbation	Astrocyte activation; Increased TNF-α production; Altered hippocampus structure	²¹³
ASD models	SCFAs	Suppression	Increased excitatory/inhibitory balance in the prefrontal cortex	²¹⁵

AhR aryl hydrocarbon receptor, BDNF brain-derived neurotrophic factor, COX-2 cyclooxygenase-2, CREB cyclic AMP response element binding protein, GPBAR G-protein-coupled bile acid receptor, GPCR G-protein-coupled receptor, DAA digestible amino acid, DI diindolylmethane, DIM 3,3’-diindolylmethane, HDAC histone deacetylases, IAld indole aldehyde, IPA indole-3-propionic acid, I3C indole-3-carbinol, I3S 3-indoxyl sulfate, JNK c-Jun N-terminal kinase, MAPK mitogen-activated protein kinase, mTOR mechanistic target of rapamycin, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, PSA polysaccharide A, ROS reactive oxygen species, SOCS suppressor of cytokine signaling, STAT signal transducer and activator of transcription, TBK1 TRIF-TANK binding kinase, TREM-2 triggering receptor expressed on myeloid cells-2, Trp tryptophan, TUDCA tauroursodeoxycholic acid, UDCA ursodeoxycholic acid.