Efficacy and Mechanism of Synbiotics in Relieving Functional Constipation: Optimized by Generation Time

TL;DR

This study shows that a synbiotic optimized using bacterial generation time improves constipation in mice by enhancing gut function and water content.

Contribution

The novel GT-guided strategy pairs prebiotics with probiotics based on strain-specific growth rates to optimize synbiotic efficacy.

Findings

GT-optimized synbiotic significantly reduced time to first black stool and increased fecal water content in mice.

The synbiotic restored colonic neurotransmitter balance and enriched butyrate-producing bacteria.

It suppressed aquaporin expression and repaired gut barrier integrity, improving intestinal motility.

Abstract

Background: Functional constipation (FC) represents a highly prevalent gastrointestinal disorder, affecting approximately 8.5% of the population in China. It is frequently associated with anxiety and depression, significantly impairing patients’ quality of life. Conventional microecological therapeutic approaches predominantly rely on empirical probiotic–prebiotic combinations. However, these pairings are seldom selected based on strain-specific metabolic characteristics, ultimately leading to suboptimal therapeutic synergy. Methods: The generation time (GT) of four constipation-relief strains was measured across eight oligosaccharides to identify optimal substrates for synbiotic formulation. The GT-optimized synbiotic was verified in a loperamide-induced mouse model vs. single probiotics/prebiotics. The related mechanisms of were assessed through 16S rDNA sequencing, targeted metabolomics, and qPCR. Results: The GT-optimized synbiotic significantly outperformed all single components. Specifically, the synbiotic significantly decreased the time to first black stool and increased fecal water content. Mechanistically, it restored colonic neurotransmitter balance, suppressed aquaporin expression, enriched butyrate-producing bacteria, and repaired barrier integrity. Overall, these effects work together, increasing the moisture content of the feces and accelerating intestinal peristalsis, ultimately alleviating constipation. Conclusions: We propose a GT-guided precision-pairing strategy that identifies optimal prebiotics based on strain-specific generation times, demonstrating synergistic enhancement of short-chain fatty acid (SCFA) production, enteric neurotransmitter signaling, and aquaporin-mediated water transport. This GT guided synbiotic approach shows promise in preclinical models and warrants validation in human trials.

Figures