Sialidase inhibitor modulates gut microbiota and enhances mucosal protection in the treatment of ulcerative colitis

Ulcerative colitis (UC) is characterized by mucosal barrier erosion, a process exacerbated by bacterial sialidases. We investigated the therapeutic efficacy of the sialidase inhibitor (SI) in UC. In a pilot randomized clinical trial, SI intervention significantly improved clinical symptoms and endoscopic outcomes in mild-to-moderate UC patients. This improvement correlated with an enrichment of butyrate-producing taxa and beneficial metabolic pathways. In a dextran sulfate sodium-induced colitis mouse model, SI attenuated inflammation and restored mucus layer integrity, accompanied by increased expression of Muc2 and Tff3 . Crucially, unlike broad-spectrum antibiotics, SI preserved microbial community resilience while specifically enriching beneficial mucolytic commensals, Akkermansia muciniphila and Bacteroides acidifaciens . These findings identify SI as a promising therapeutic strategy that targets sialidase activity to reinforce the mucosal barrier and restore gut homeostasis. IMPORTANCE The gut microbiota plays a pivotal role in maintaining mucosal integrity and intestinal homeostasis; however, dysbiosis-driven mucus layer degradation remains a hallmark of ulcerative colitis (UC). Current interventions like antibiotics often disrupt microbial diversity, exacerbating dysbiosis and failing to address mucosal thinning, which is a critical factor in UC progression. Developing strategies to reinforce the mucus barrier without compromising microbial balance is urgently needed, but such approaches remain underexplored. Our study demonstrates that sialidase inhibitors (SIs) uniquely preserve mucosal thickness by curbing microbial mucin degradation while selectively enriching beneficial taxa and butyrate-producing bacteria. Unlike antibiotics, SIs enhance mucosal protection without destabilizing microbial communities, offering a dual-action therapeutic strategy. This work bridges a critical knowledge gap, providing evidence for microbiota-targeted therapies that synergistically restore mucosal health and microbial ecology in UC. CLINICAL TRIALS This study was registered with the Chinese Clinial Trial Registry as ChiCTR2000028767 .