Type 3 resistant starch attenuates concanavalin A-induced immune-mediated hepatitis by preserving intestinal barrier integrity and remodeling the gut microbiota.

BACKGROUND: Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disorder characterized by loss of immune tolerance and progressive hepatocellular injury. Although corticosteroids remain standard therapy, incomplete responses and adverse effects necessitate safer adjunctive strategies. Growing evidence indicates that intestinal barrier disruption and gut microbiota dysbiosis contribute to AIH pathogenesis. Resistant starch (RS), a dietary fiber with immunomodulatory, anti-inflammatory, and microbiota-regulating properties, benefits metabolic liver diseases; however, its effect on ConA-induced acute immune-mediated hepatitis, a widely used experimental model for AIH-related immune liver injury, remains unclear.

METHODS: We investigated the preventive effects of RS3 pretreatment (5 g/kg/day for 6 weeks) in a ConA-induced murine model of acute liver injury by evaluating serum biochemistry, cytokine profiles, liver histopathology, splenic T-cell subsets, hepatic transcriptomics, and 16S rRNA gene sequencing.

RESULTS: Compared with the ConA+Vehicle mice, RS3 pretreatment markedly reduced serum ALT and AST levels (ALT: 4538 ± 2900 vs. 15,987 ± 4749 U/L; AST: 3360 ± 2150 vs. 10,495 ± 2422 U/L; both p < 0.001), alleviated hepatic histopathological injury, decreased Th1/Th17 cell frequencies, and increased Treg frequencies. RS3 also improved colonic barrier integrity, reduced systemic LPS accumulation, attenuated hepatic TLR4/NF-κB and PI3K/AKT/mTOR signaling activation, and altered gut microbial community structure.

CONCLUSION: RS3 pretreatment alleviated ConA-induced acute immune-mediated hepatitis, potentially through coordinated regulation of intestinal barrier integrity, immune homeostasis, and gut microbial composition.