Sotagliflozin pretreatment attenuates acute LPS-induced depression-like behavioral abnormalities and modulates the...

Inflammation-driven depression is increasingly recognized as a major therapeutic target, yet effective pharmacological strategies remain limited. Sotagliflozin (SOTA), a dual inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1/2), has demonstrated anti-inflammatory and metabolic benefits, but its neuropsychiatric effects remain unclear.

This study investigated whether SOTA pretreatment attenuates acute lipopolysaccharide (LPS)-induced depression-like behavioral abnormalities and modulates the gut microbiota-immune-brain axis.

Male mice received SOTA for 7 days before LPS injection. Behavioral outcomes were assessed using the open field test and forced swimming test. Systemic inflammation, hippocampal synaptic protein expression, and gut microbiota composition were evaluated using ELISA, Western blotting, and 16S rRNA sequencing, respectively.

SOTA pretreatment attenuated the LPS-induced reduction in open field center time and increase in forced swimming immobility time. SOTA also reduced LPS-induced splenomegaly and serum IL-6 and TNF-α levels. Western blotting showed that SOTA blunted the LPS-induced reductions in hippocampal GluA1 and PSD-95 expression. 16S rRNA sequencing demonstrated that SOTA partially normalized LPS-associated gut dysbiosis and modulated the relative abundance of genera including Enterococcus, Coriobacteriaceae UCG-002, and Parvibacter. Exploratory correlation and functional prediction analyses linked these taxa to behavioral and inflammatory markers and implicated predicted steroid and triterpenoid biosynthesis pathways.

SOTA pretreatment attenuates acute LPS-induced depression-like behavioral abnormalities in association with reduced systemic inflammation, blunted synaptic protein loss, and altered gut microbiota profiles. Dual SGLT1/2 inhibition warrants further investigation in inflammation-associated mood disorders.