Antibiotics treatment promotes squamocolumnar junction tumor progression via tumor immune evasion in K19-Wnt1/C2mE mice fed high-fat diet and acidic bile salts

Am J Physiol Gastrointest Liver Physiol. 2026 Jul 1;331(1):G38-G59. doi: 10.1152/ajpgi.00056.2026. Epub 2026 May 22.

ABSTRACT

Clinical studies suggested that antibiotics (ABx) administration might increase esophagogastric junction adenocarcinoma risk, but the underlying mechanisms remain unclear. We previously demonstrated that the administration of a high-fat diet (HFD) and acid bile salts (ABS) to K19-Wnt1/C2mE mice might promote the metabolic-driven tumor growth at the squamocolumnar junction (SCJ) cooperatively with gut dysbiosis. To clarify whether ABx-induced dysbiosis promotes tumorigenesis, we evaluated the effects of HFD + ABS ± ABx treatment on tumor immune evasion in mice. In HFD + ABS + ABx-treated mice, SCJ tumor growth with increased tumor cell proliferation and infiltration of inflammatory cells positive for CD8, programmed cell death protein 1, and programmed cell death-ligand 1 (PD-L1) was observed, along with apoptosis suppression. Protein expressions of interferon-gamma (IFNγ) and phosphorylated signal transducer and activator of transcription (p-STAT) 3 were upregulated in the tumors of the HFD + ABS + ABx group, whose p-STAT1 expression was equivalent to that of the control group. The mice exhibited insulin resistance and metabolic endotoxemia, and metagenomic analysis of their ileal excrement revealed dysbiosis with a decrease in butyrate-producing bacteria and bacterial butanoate metabolism activity. Moreover, IFNγ stimulation of human-derived NUGC-4 cells increased the protein expression of PD-L1, p-STAT1, and p-STAT3, all of which decreased in response to STAT inhibitors. Transfection with small interfering RNA targeting STAT1 or STAT3 did not attenuate PD-L1 induction, which was inhibited by the combined knockdown. Therefore, oral HFD + ABS + ABx administration to K19-Wnt1/C2mE mice may promote SCJ tumors through tumor immune evasion via IFNγ-STAT1/STAT3-PD-L1 signaling, along with metabolic endotoxemia.NEW & NOTEWORTHY Coadministration of antibiotics with a high-fat diet and acid bile salts exacerbated dysbiosis, insulin resistance, and systemic inflammation, thereby promoting tumor progression via tumor immune evasion at the squamocolumnar junction (SCJ) in K19-Wnt1/C2mE mice. In the tumor, interferon-gamma-induced programmed death-ligand 1 through the activation of signal transducer and activator of transcription 1 (STAT1) and STAT3. Understanding the link between dysbiosis and tumor immunity might aid in the development of new immunotherapies for SCJ tumors.

PMID:42173516 | DOI:10.1152/ajpgi.00056.2026