Oral administration of indole-3-lactic acid alleviates activity-based anorexia in female mice

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by extreme dietary restriction, pronounced weight loss, and disturbed energy metabolism. In recent years, increasing attention has been given to the role of the gut microbiota and its tryptophan-derived metabolites in modulating host neural function and feeding behavior via the gut-brain axis. Indole-3-lactic acid (ILA), one of the major tryptophan metabolites produced by the gut microbiota has been shown to exert neuroprotective and anti-inflammatory effects. However, its role in central appetite regulation remains unclear. In this study, we systematically evaluated the therapeutic potential and underlying mechanisms of ILA using an activity-based anorexia (ABA) mouse model. Oral administration of ILA significantly mitigated weight loss, reduced food intake, and hyperactivity in ABA mice. Pharmacokinetic analysis revealed that ILA was efficiently absorbed from the gastrointestinal tract, crossed the blood-brain barrier, and maintained a relatively stable concentration in the brain. Transcriptomic profiling of the hypothalamus identified 457 differentially expressed genes (DEGs), which were significantly enriched in pathways related to neuroactive ligand-receptor interactions, PI3K-Akt signaling, and MAPK signaling. Notably, the expression of the orexigenic neuropeptide Qrfp and its receptor Gpr103 was markedly upregulated following ILA treatment. These findings were further validated in vitro and in vivo, confirming that ILA activates the Qrfp-Gpr103 signaling axis. Additionally, ILA significantly restored dopamine and serotonin (5-HT) levels in the striatum of ABA mice. Collectively, our results demonstrate that ILA, as a microbiota-derived tryptophan metabolite, holds promise for improving energy deficits through modulation of central neural circuits, suggesting its potential as an adjunctive intervention for anorexia nervosa and related metabolic disorders.