A natural pectic polysaccharide from rhubarb reprograms dysbiotic gut microbiota and resolves mucosal inflammation in...

Ulcerative colitis (UC) remains a major therapeutic challenge. Although natural polysaccharides exhibit therapeutic potential, their structure-activity relationships are still unclear, which limits their clinical application.

This study aimed to investigate the protective effect of a rhubarb-derived pectic polysaccharide (RP-2) against UC and elucidate its underlying mechanisms.

The structural characteristics of RP-2 were determined by monosaccharide composition analysis, methylation analysis, and the thiobarbituric acid assay. Its distribution within the colon was observed through in vivo fluorescence imaging, and the therapeutic activity was assessed using a DSS-induced UC model. Changes in the gut microbiota caused by RP-2 were investigated through 16S rRNA sequencing together with an antibiotic depletion experiment. The possible immunomodulatory actions were also explored by ELISA, flow cytometry, western blotting, and qRT-PCR, focusing on the TLR4/MyD88/NF-κB pathway, Th17/Treg balance, and maintenance of intestinal barrier integrity.

Structural characterization indicated that RP-2 is a complex pectic polysaccharide containing homogalacturonan, rhamnogalacturonan-I, and rhamnogalacturonan-II domains, and it exhibited prolonged retention in the inflamed colon. In RAW264.7 macrophages, RP-2 reduced the release of pro-inflammatory cytokines and the generation of reactive oxygen species following LPS stimulation. In DSS-induced UC mice, RP-2 markedly alleviated disease severity, reducing colon shortening and improving histological scores. Furthermore, RP-2 modulated gut microbial composition by enriching beneficial SCFA-producing bacteria, restored intestinal immune homeostasis, and attenuated DSS-induced intestinal barrier disruption. Notably, antibiotic-mediated microbiota depletion largely abrogated the protective effects of RP-2, highlighting the critical role of gut microbiota in its therapeutic efficacy. Mechanistically, RP-2 suppressed activation of the TLR4/MyD88/p65 pathway and restored the Th17/Treg balance.

These findings demonstrated that RP-2 alleviates UC through the microbiota-dependent "microbiota-metabolite-immune-barrier" axis, providing a scientifically grounded, natural product-based strategy for UC treatment.