Schisantherin A: Remodeling Gut Microbiota to Activate the Gut–Immune–Neural–Adipose Axis for Thermogenesis

The global obesity epidemic necessitates safe and effective strategies to enhance energy expenditure. Schisantherin A (Sin A), a lignan derived from Schisandra chinensis, has demonstrated metabolic benefits, yet its systemic mechanism remains unclear. A recent study published in Nature Communications by researchers from Shanghai University of Traditional Chinese Medicine reveals that Sin A alleviates diet‐induced obesity by remodeling the gut microbiota and activating a multi‐organ “gut‐immune‐neural‐adipose” axis. In diet‐induced obese (DIO) mice, Sin A inhibits bile salt hydrolase (BSH)‐expressing Lactobacillus species, elevating circulating conjugated bile acids, which activate the Takeda G protein‐coupled receptor 5 (TGR5) on adipose tissue macrophages. This triggers a TGR5‐p‐CREB‐STAT6 signaling cascade, promoting M2‐like macrophage polarization and the secretion of the cytokine SLIT3. SLIT3 then binds to its receptor ROBO1 on sympathetic nerve terminals, stimulating norepinephrine release, which acts via β3‐adrenergic receptors to upregulate uncoupling protein 1 (UCP1)‐dependent thermogenesis in white adipose tissue. Genetic ablation of TGR5 in myeloid cells, global deletion of STAT6, or local knockdown of SLIT3 or ROBO1 abolishes Sin A's metabolic effects, confirming the pathway's necessity. The study establishes Sin A as a microbiota‐modulating agent that activates an integrated neuroimmune circuit in adipose tissue to promote thermogenesis and improve metabolic health, highlighting the therapeutic potential of targeting the gut–immune–neural–adipose axis in obesity.