Cellular and molecular gastroenterology and hepatology · 2026
Gut Microbiota-Derived Propionate Governs Hepatic N2 Neutrophils in Wilson's Disease.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Mi Xiaoxiao, Liu Rongqiang, Jiang Zhenyao, Tang Mengjuan, Yan Jian, Liu Jing, Li Yingniang, Zheng Jun, Yang Wenjun, Gong Ling, Shi Junping
Аннотация
BACKGROUND & AIMS: Neutrophil functions play a pivotal role in hepatic pathogenesis. Our previous work has established that N2-polarized neutrophils promote hepatic fibrogenesis in Wilson's disease depends on hepatic transforming growth factor-β1 (TGF-β1) production. However, the regulators governing TGF-β1 production in orchestrating disease-associated N2 neutrophils remain elusive. In this study, we investigated the immunomodulatory effects of gut microbiota-derived short-chain fatty acids (SCFAs) on neutrophil polarization.
METHODS: Fecal metagenomic sequencing and short-chain fatty acid (SCFA) profiling were performed on ATP7B-knockout (ATP7B-KO) mice and their wild-type (WT) littermate controls. Fecal microbiota transplantation (FMT) experiments were conducted by transferring feces from WT mice or Akkermansia muciniphila into recipient mice. Additionally, propionate or trichostatin A (TSA) was administered to both ATP7B-KO and WT groups. Mice were assessed using histological analyses, Sirius Red staining, flow cytometry, biochemical assays, immunohistochemistry, measurement of TGF-β1 levels, immunofluorescence, and quantitative real-time polymerase chain reaction (qRT-PCR) for gene expression profiling. To elucidate the underlying molecular mechanisms, 4D label-free quantitative acetylated proteomics, site-directed mutagenesis, plasmid transfection, co-immunoprecipitation (IP), and luciferase reporter assays were employed.
RESULTS: We report that Akkermansia muciniphila was markedly reduced in the gut microbiota of mice with Wilson's disease, accompanied by decreased SCFA levels, especially propionate. Additionally, transplantation of fecal bacteria from wild-type mice or A muciniphila could promote an antifibrotic effect, elevate propionate levels, reduce TGF-β1 secretion, and decrease hepatic N2 neutrophils in mice with Wilson's disease. Moreover, administration of propionate also significantly enhanced antifibrotic immunity. Mechanistically, propionate reduced the production of TGF-β1 in hepatocytes by inhibiting histone deacetylase activity, increasing the acetylation of DNAJA3 at sites K134 and K385, thus decreasing expression of DNAJA3. Consistently, gut-derived propionate inversely correlated with hepatic injury severity in patients with Wilson's disease, which could be functionally mediated by TGF-β1.
CONCLUSIONS: Gut microbiota are pivotal for hepatic neutrophil polarization and liver fibrosis in Wilson's disease. Our findings suggest that therapeutic modulation of gut microbiota, SCFA profiles, and TGF-β1 production, particularly when combined with histone deacetylase inhibitors, may represent promising therapeutic approaches for Wilson's disease.
METHODS: Fecal metagenomic sequencing and short-chain fatty acid (SCFA) profiling were performed on ATP7B-knockout (ATP7B-KO) mice and their wild-type (WT) littermate controls. Fecal microbiota transplantation (FMT) experiments were conducted by transferring feces from WT mice or Akkermansia muciniphila into recipient mice. Additionally, propionate or trichostatin A (TSA) was administered to both ATP7B-KO and WT groups. Mice were assessed using histological analyses, Sirius Red staining, flow cytometry, biochemical assays, immunohistochemistry, measurement of TGF-β1 levels, immunofluorescence, and quantitative real-time polymerase chain reaction (qRT-PCR) for gene expression profiling. To elucidate the underlying molecular mechanisms, 4D label-free quantitative acetylated proteomics, site-directed mutagenesis, plasmid transfection, co-immunoprecipitation (IP), and luciferase reporter assays were employed.
RESULTS: We report that Akkermansia muciniphila was markedly reduced in the gut microbiota of mice with Wilson's disease, accompanied by decreased SCFA levels, especially propionate. Additionally, transplantation of fecal bacteria from wild-type mice or A muciniphila could promote an antifibrotic effect, elevate propionate levels, reduce TGF-β1 secretion, and decrease hepatic N2 neutrophils in mice with Wilson's disease. Moreover, administration of propionate also significantly enhanced antifibrotic immunity. Mechanistically, propionate reduced the production of TGF-β1 in hepatocytes by inhibiting histone deacetylase activity, increasing the acetylation of DNAJA3 at sites K134 and K385, thus decreasing expression of DNAJA3. Consistently, gut-derived propionate inversely correlated with hepatic injury severity in patients with Wilson's disease, which could be functionally mediated by TGF-β1.
CONCLUSIONS: Gut microbiota are pivotal for hepatic neutrophil polarization and liver fibrosis in Wilson's disease. Our findings suggest that therapeutic modulation of gut microbiota, SCFA profiles, and TGF-β1 production, particularly when combined with histone deacetylase inhibitors, may represent promising therapeutic approaches for Wilson's disease.