High molecular weight polysaccharides from Ganoderma lucidum attenuates inflammatory responses, gut microbiota, and liver metabolomic in lipopolysaccharide-induced liver injury mice.

High molecular weight polysaccharides (GLPH, ≥300 kDa) are the major compounds of Ganoderma lucidum with improving liver function. However, the effect of GLPH on improving acute liver injury (ALI) wasn't revealed. Herein, the ameliorating effects and mechanisms of GLPH were revealed in lipopolysaccharide (LPS)-ALI mice. The results indicated that GLPH intervention (100 mg/kg day) reduced the serum ALT (22.67 ± 6.48 U/L), AST (21.19 ± 7.08 U/L), ALP (56.98 ± 12.71 U/L), GGT (1.48 ± 0.22 U/L) levels in ALI mice (p < 0.01). GLPH activated the hepatic antioxidant enzymes activity [SOD (3.75 ± 1.17 U/mg prot.) and CAT (3.01 ± 0.85 U/mg prot.)] and suppressed the hepatic inflammatory cytokines production [TNF-α (40.14 ± 8.15 pg/mg prot.), IL-1β (35.47 ± 10.90 pg/mg prot.), and IL-6 (8.44 ± 1.71 pg/mg prot.)] by regulating the Nrf2/OH-1 and Tlr4/NF-κB pathway (p < 0.05). Furthermore, GLPH regulated the abundance of Bifidobacterium, Akkermansia, Anaerovorax, and Tyzzerella, which associated with cecal SCFAs, hepatic inflammatory cytokines and antioxidant enzymes. GLPH significantly changed 85 liver metabolites (p < 0.01), which is beneficial for prevent the development of ALI. These results suggested GLPH displayed promising prebiotic properties in relieving ALI, regulating gut microbiota and liver metabolism.