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Protective effect of L-pipecolic acid on constipation in C57BL/6 mice based on gut microbiome and serum metabolomic
Huan Li1,2, Hong-Yun Xiao1,2, Li-Ping Yuan3
1Department of Pediatrics, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
Insights
L-pipecolic acid (L-PA) levels are decreased in children with functional constipation (FC). Supplementing L-PA in mice with loperamide-induced constipation improved gut health and motility by regulating key genes and neurotransmitters.
Area of Science:
- Gastroenterology and Gut Microbiome Research
- Pediatric Health and Metabolism
- Pharmacology and Drug Discovery
Background:
- Functional constipation (FC) in children significantly impacts growth, development, and quality of life.
- Reduced levels of L-pipecolic acid (L-PA) observed in FC children linked to gut microbiome and serum metabolomic alterations.
- Previous findings suggest a potential role for L-PA in the pathophysiology of pediatric constipation.
Purpose of the Study:
- To investigate the therapeutic effects of L-pipecolic acid (L-PA) on constipation.
- To evaluate the impact of L-PA on gut microbiota, serum metabolites, and intestinal function in a mouse model of constipation.
Main Methods:
- Recruited 26 FC children and 28 healthy controls for stool and serum sample analysis (16S rDNA sequencing, UPLC-Q/TOF-MS).
- Established a loperamide-induced constipation mouse model, divided into control, loperamide (Lop), and L-PA treatment (Lop + L-PA) groups.
- Assessed fecal parameters, intestinal motility, serum 5-HT, colon 5-HT expression, and mRNA levels of AQP3 and 5-HT4R.
Main Results:
- FC children exhibited altered gut microbiota diversity and identified 45 differential metabolites and 18 significantly different microbiota.
- Serum L-PA levels were significantly reduced in FC children, with associations found between L-PA, Ochrobactrum, and Phascolarcrobacterium.
- In constipated mice, L-PA administration improved fecal water content, intestinal transit rate, increased serum 5-HT, upregulated 5-HT4R, downregulated AQP3, and modulated constipation-related genes.
Conclusions:
- Significant alterations in gut microbiota and serum metabolites characterize functional constipation in children.
- Decreased abundance of Phascolarctobacterium and Ochrobactrum, along with reduced serum L-PA, are key findings in FC.
- L-PA demonstrates a therapeutic potential for constipation by enhancing fecal water content, intestinal transit, and modulating 5-HT and AQP3 expression.
Background:
Functional constipation (FC) in children affects their growth, development and quality of life. L-pipecolic acid (L-PA) was decreased in FC children based on gut microbiome and serum metabolomic. In this study, loperamide-induced constipation in mice was used to evaluate the effects of L-PA on constipated mice.
Method:
26 FC and 28 healthy children were recruited. Stool samples and serum samples were subjected to 16S rDNA sequencing and ultra-performance liquid chromatography/quadrupole time of flight (UPLC-Q/TOF-MS) approach, respectively. A loperamide-induced mouse constipation model was developed, and all mice were randomly divided into control (Con), loperamide (Lop) and L-PA (Lop + L-PA) treatment groups (6 mice per group). The mice in the Lop + L-PA group were given L-PA (250 mg/kg, once a day) and loperamide; the Lop group was given loperamide for 1 week, and the Con group was given saline. The fecal parameters and intestinal motility of mice in each group were detected. serum 5-HT levels and colon 5-HT expression were detected by ELISA and immunohistochemistry, respectively; qRT-PCR was used to detect the expression of AQP3 and 5-HT4R mRNA in each group.
Results:
45 differential metabolites and 18 significantly different microbiota were found in FC children. The α and β diversity of gut microbiota in FC children was significantly reduced. Importantly, serum L-PA was significantly reduced in FC children. The KEGG pathway enrichment were mainly enriched in fatty acid biosynthesis, lysine degradation, and choline metabolism. L-PA was negatively associated with Ochrobactrum, and N6, N6, N6-trimethyl-l-lysine was positively associated with Phascolarcrobacterium. In addition, L-PA improved the fecal water content, intestinal transit rate, and increased the serum 5-HT levels in constipated mice. Moreover, L-PA increased the expression of 5-HT4R, reduced AQP3, and regulated constipation-associated genes.
Conclusions:
Gut microbiota and serum metabolites were significantly altered in children with FC. The abundance of Phascolarctobacterium and Ochrobactrum and serum L-PA content were decreased in FC children. L-PA was found to alleviate the fecal water content, increase intestinal transit rate and the first black stool defecation time. L-PA improved constipation by increasing 5-HT and 5-HT4R expression while down-regulating AQP3 expression.
