Helicobacter pylori promotes hepatocarcinogenesis by abrogating the protective effect of intestinal Bacteroides acidifaciens in females.

BACKGROUND

Hepatocellular carcinoma (HCC) exhibits sexual dimorphism, with a lower incidence observed in females. However, the mechanisms underlying the disruption of this protective effect remain inadequately understood. Helicobacter pylori (Hp) is associated with HCC and can cause gut microbiota imbalances that promote HCC progression. This study explored how Hp might influence female susceptibility to HCC via the gut-liver axis, focusing on gut bacteria and their metabolites.

METHODS

A Hp-infected DEN + CCl₄-induced HCC mouse model was established, and a cohort of 186 HCC patients was analyzed. Fecal metagenomics and serum metabolomics were employed to identify Hp-responsive gut microbes and metabolites. The therapeutic potential of Bacteroides acidifaciens (Ba) and its metabolite 4‑hydroxybenzyl alcohol (4‑HBA), alone or combined with Hp eradication, was evaluated in mouse models and in mechanistic cell-based assays.

RESULTS

Hp increased tumor burden and fibrosis especially in female mice. Hp-positive female patients exhibited larger tumors, more advanced disease stages, higher cirrhosis incidence, and poorer overall survival compared to Hp-negative females. Hp also reduced gut microbiota diversity and decreased female-enriched Ba. The Ba-specific metabolite 4-HBA, which is higher in females and reduced by Hp, suppressed TGF‑β/SMAD signaling by binding to TGFBR2, thereby inhibiting hepatic stellate cell activation and HCC cell proliferation. Ba/4-HBA alleviated Hp-induced liver pathology in both sexes, with the combination of Hp eradication and Ba/4-HBA treatment proving more effective than eradication alone in females.

CONCLUSIONS

Hp exacerbates hepatic fibrogenesis and HCC in females by depleting Ba and its metabolite 4-HBA, which inhibits TGF-β/SMAD signaling through binding to TGFBR2. Supplementation with Ba/4-HBA, particularly when combined with Hp eradication, tend to be a promising microbiota-metabolite-targeted strategy for attenuating female HCC progression.