A water-soluble Dendrobium officinale polysaccharide (DOPW) attenuates hepatic fibrosis via gut microbiota-mediated autophagy activation.

BACKGROUND

Hepatic fibrosis currently lacks effective therapies. DOPW, a water-soluble polysaccharide isolated from Dendrobium officinale, exerts anti-fibrotic effects, but its underlying mechanisms remain unclear.

PURPOSE: This study investigates whether DOPW attenuates fibrosis through a gut microbiota-dependent mechanism involving key microbial metabolites and the hepatic ERK1/2-autophagy signaling pathway.

METHODS

DOPW was structurally characterized. Its anti-fibrotic efficacy was evaluated in a mouse model of CCl₄-induced hepatic fibrosis and in TGF-β1-induced LX-2 cells. Mechanistic investigations integrated transcriptomic analysis (RNA‑seq) with pharmacological targeting of ERK1/2 signaling and autophagy, combined with 16S rRNA sequencing and fecal microbiota transplantation (FMT) to assess the role of the gut microbiota. The key microbial metabolite butyrate was quantified in both colonic and hepatic tissues.

RESULTS

DOPW is a polysaccharide (256 kDa) composed of glucose and mannose in a 5:1 molar ratio. DOPW dose-dependently alleviated hepatic fibrosis, reducing liver injury, inflammation, and collagen deposition (all p < 0.001). Mechanistically, DOPW activated hepatic stellate cell autophagy by inhibiting ERK1/2 signaling, as confirmed by rescue experiments with ERK1/2 modulators (all p < 0.05). Notably, DOPW enriched short-chain fatty acid-producing gut microbiota (Parabacteroides, Bifidobacterium, and Prevotella), elevated fecal butyrate by 2.11-fold (p = 0.0443), and reinforced intestinal barrier integrity (all p < 0.05). These microbiota and metabolite changes were associated with suppression of hepatic ERK1/2 phosphorylation. Antibiotic depletion abolished these effects, while FMT with DOPW-modified microbiota reproduced the anti-fibrotic benefits (all p < 0.05).

CONCLUSION

DOPW attenuates hepatic fibrosis by remodeling gut microbiota to enhance short-chain fatty acid production and intestinal barrier integrity, with butyrate and ERK1/2-dependent autophagy emerging as key mediators of this gut-liver crosstalk. These findings position DOPW as a promising microbiota-targeted anti-fibrotic candidate.