An Asparagus cochinchinensis neutral polysaccharide alleviates slow transit constipation by regulating the Akkermansia muciniphila kynurenic acid NLRP3 axis in a gut microbiota dependent manner

Slow transit constipation (STC) is characterized by colonic motility dysfunction, and current therapeutic options remain limited. Intestinal motility is regulated by complex interactions among the gut microbiota, host metabolism, and the enteric nervous. In this study, an Asparagus cochinchinensis neutral polysaccharide (ACNP) was used to remodel the gut microbiota and explore the mechanisms linking host metabolic and neuro-immune pathways with enteric nervous integrity, providing a foundation for developing novel intervention strategies. In present study, we found ACNP markedly ameliorated STC phenotypes, including restricted body weight gain, prolonged first black stool time, delayed intestinal transit, and histological damage. Moreover, ACNP enhanced the expression of intestinal epithelial tight junction proteins and restored the integrity of enteric neurons and nerve fibers. Multi-omics analysis revealed that ACNP promoted the proliferation of Akkermansia muciniphila (AKK) and increased the levels of kynurenic acid (KYNA). To confirm the dependence of these effects on the microbiota, antibiotic depletion and fecal microbiota transplantation experiments were performed, which confirmed that the protective effects of ACNP relied on the gut microbiota. Investigations further demonstrated that supplementation with live AKK or exogenous KYNA recapitulated the beneficial effects of ACNP, accompanied by suppression of NLRP3 activation. Molecular docking studies suggested that KYNA could stably bind to the NLRP3 receptor, providing direct evidence to support its mechanistic role. Collectively, this study identified a novel mechanism whereby ACNP alleviates STC through modulation of the AKK KYNA NLRP3 axis, linking the microbial and metabolic pathways.