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Cholesterol sulfate alleviates functional dyspepsia in juvenile mice via modulating the gut microbiota-derived
Aitong Liu1, Guangtao Yan1, Jun Xie2
1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China.
Insights
Cholesterol sulfate (CHS) effectively treats pediatric functional dyspepsia (FD) in mice by improving gut motility and reducing inflammation. CHS works by modulating gut microbiota and lactate metabolism, offering a potential therapeutic for children with FD.
Area of Science:
- Gastroenterology
- Pharmacology
- Microbiome research
Background:
- Functional dyspepsia (FD) affects 8.4% globally, with no specific pediatric treatments.
- Cholesterol sulfate (CHS), from sea cucumber, may protect the gut.
- Pediatric FD treatment remains a significant unmet need.
Purpose of the Study:
- To evaluate the pharmacological effects of CHS on a juvenile mice model of FD.
- To investigate CHS's impact on gastrointestinal motility, inflammation, and gut microbiota in pediatric FD.
- To elucidate the mechanism of CHS action, particularly its role in lactate metabolism.
Main Methods:
- Induced FD in juvenile mice using repeated low-dose cisplatin.
- Administered CHS and assessed gastrointestinal motility, serum and intestinal biomarkers (gastrin, motilin, IL-4, IL-1β, lactate, LDH).
- Analyzed gut microbiota composition (F/B ratio, Lactobacillus), gene expression (GPR81, AChE), and neurotransmitter levels (ghrelin, 5-HT).
Main Results:
- CHS significantly enhanced gastrointestinal motility and reduced inflammation in FD mice.
- CHS modulated gut microbiota, decreasing the F/B ratio and Lactobacillus dominance.
- CHS lowered lactate and LDH levels, downregulating GPR81 and upregulating ghrelin, 5-HT, and AChE, indicating a mechanism involving gut microbiota-derived lactate metabolism.
Conclusions:
- CHS demonstrates significant therapeutic potential for pediatric FD by enhancing gut motility and alleviating inflammation.
- The mechanism involves regulating gut microbiota metabolism, specifically reducing lactate production.
- CHS represents a promising novel therapeutic agent for pediatric functional dyspepsia.
Abstract:
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.
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