Co-stimulation with high-fat diet and acidic bile salts may promote Warburg effect in gastric carcinogenesis around the squamo-columnar junction in Gan mice

Am J Physiol Gastrointest Liver Physiol. 2025 Apr 17. doi: 10.1152/ajpgi.00305.2024. Online ahead of print.

ABSTRACT

Epidemiological studies demonstrated relationships between gastric cardia adenocarcinoma (GCA) and metabolic syndrome (MetS). We aimed to clarify mechanism underlying their relationship. To investigate whether systemic inflammation against high-fat diet (HFD)-related dysbiosis promotes Warburg effect in tumors at the squamo-columnar junction (SCJ), we applied K19-Wnt1/C2mE (Gan) mice, fed either HFD or control diet ± acidic bile salts (ABS) with/without clodronate liposomes (CLs), and in vitro studies using MKN7 cells with/without THP1-derived macrophages. Then, we assessed involvement of oxidative stress (OS) in Warburg effect by comparing between nuclear factor-erythroid 2-related factor 2 (Nrf2) knockout-Gan mice and Gan mice. Tumors with macrophage infiltration in HFD+ABS group were larger than in Control group. Gene Set Enrichment Analysis revealed enhancement of the OS signaling in tumor of HFD+ABS group. HFD+ABS group mice demonstrated induction of OS, Nqo1, TNFα, and Warburg effect in tumors and mucosal barrier dysfunction of dysbiotic gut. All of them were abolished with diminishing macrophage infiltration by additional CLs treatment. Stimulation with TNFα, but not ABS nor lipopolysaccharide, on MKN7 cells activated Warburg effect. In MKN7 cells co-cultured with the macrophages whose TNFa expression was induced by the lipopolysaccharide pretreatment, Warburg effect was enhanced in the TNFα concentration-dependent manners. In Nrf2 knockout-Gan mice, tumors shrank with reducing OS, TNFα, and Warburg effect, along with decreasing macrophage infiltration. Accordingly, MetS may develop GCA through the Nrf2-related Warburg effect under the TNFα stimulation from the macrophages activated by both local ABS exposure and systemic lipopolysaccharide exposure from leaky gut with HFD-related dysbiosis.

PMID:40246521 | DOI:10.1152/ajpgi.00305.2024