Cholesterol sulfate alleviates functional dyspepsia in juvenile mice via modulating the gut microbiota-derived lactate.

The overall global pooled prevalence of functional dyspepsia (FD) was 8.4 %, affecting 3-27 % of children. Currently, no specific medication exists for FD, especially in pediatric cases. Cholesterol sulfate (CHS), a bioactive compound derived from sea cucumber, shows potential in protecting the gastrointestinal tract, but its effects on pediatric FD remain unknown. This study assessed the pharmacological effects of CHS using a juvenile mice model of FD induced by repeated low-dose cisplatin. Results indicated that CHS significantly enhanced gastrointestinal motility and alleviated inflammation, marked by increased serum gastrin (GAS) and motilin (MTL), elevated interleukin-4 (IL-4), and reduced interleukin-1β (IL-1β) in intestines of FD juvenile mice. CHS restrained FD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidotas (F/B) ratio and suppressing Lactobacillus dominance. Notably, CHS decreased lactate and lactate dehydrogenase (LDH) levels in serum and the intestines of FD juvenile mice. Elevated lactate suppresses ghrelin production through G protein-coupled receptor (GPR81) receptor signaling, impairing intestinal motility, which highlights the significance of reducing lactate levels. Ghrelin enhances gastrointestinal motility by activating intestinal cholinergic neurons and potentiating serotonin (5-HT) signaling. After CHS treatment, GPR81 expression was downregulated while acetylcholinesterase (AChE) expression, ghrelin and 5-HT levels were upregulated in intestines, as well as heightened serum AChE activity. The co-administration of CHS with antibiotics(ABX) significantly attenuated its therapeutic efficacy, confirming that CHS alleviates FD in juvenile mice by inhibiting gut microbiota-derived lactate metabolism. In conclusion, our study provides evidence to support the utilization of CHS for regulating gastrointestinal motility for pediatric FD patients.