Yunpi Xiaoji Formula Restores Gut-Brain Axis Homeostasis in Infantile Anorexia by Targeting the SCFAs-GPR43 Signaling...

Infantile anorexia (IA) represents a complex feeding disorder with limited therapeutic options currently available. The traditional Chinese medicine (TCM) formula Yunpi Xiaoji Formula (YPXJF) has demonstrated clinical efficacy in ameliorating IA symptoms; however, its underlying mechanisms, particularly those associated with the gut-brain axis, remain to be systematically elucidated.

This study aimed to determine the association between anorexia and the SCFAs-GPR43-PYY/GLP-1 pathway, to investigate whether YPXJF ameliorates IA via modulation of this pathway, and to elucidate its role in gut-brain axis crosstalk.

The phytochemical profile of YPXJF and its absorbed serum constituents was characterized using UHPLC-MS. An integrative approach combining in vivo IA rat models and in vitro cell systems was employed. Interventions included the GPR43 agonist 4-CMTB and antagonist GLPG0974. Genetic techniques involved GPR43 knockdown and overexpression in GLUTag L-cells. Gut-brain axis communication was modeled using a Transwell co-culture system of GLUTag L-cells and POMC neurons. Analytical methods comprised H&E staining, immunohistochemistry, immunofluorescence, Western blotting, RT-PCR, and ELISA.

A total of 883 compounds were detected in YPXJF, with 130 absorbed constituents (82 prototypes and 48 metabolites) identified in serum, primarily phenolic acids, alkaloids, and flavonoids. The pathogenesis of IA was driven by aberrant activation of the gut-brain axis. In IA rats, elevated levels of fecal SCFAs (acetate, propionate, and butyrate) activated G protein-coupled receptor 43 (GPR43) on colonic L-cells, leading to excessive secretion of the anorexigenic hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). These hormones subsequently acted on the hypothalamus to upregulate anorexigenic POMC/CART neurons and downregulate orexigenic NPY/AGRP neurons, ultimately resulting in anorexia. YPXJF treatment effectively reversed this dysregulation by normalizing fecal SCFA profiles and downregulating colonic GPR43 expression, which reduced GLP-1 and PYY secretion. Consequently, YPXJF suppressed hypothalamic POMC neuronal activity and enhanced NPY neuronal activity, restoring appetite and body weight. These findings were confirmed by molecular assays showing that YPXJF efficacy was blunted by GPR43 overexpression or agonist co-administration.

YPXJF ameliorates IA by modulating the SCFAs-GPR43 pathway and restores gut-brain axis homeostasis by attenuating pathological anorexigenic signaling and restoring physiological appetite regulation. This study provides a mechanistic basis for YPXJF's clinical application and identifies GPR43 as a promising therapeutic target.