Proano Vasco, A. I. | Search bioRxiv

bioRxiv2025

Colibactin-producing E. coli promote carcinogenesis of gastroesophageal adenocarcinoma and simultaneously induce autophagy and differentiation

Background & AimsGastroesophageal adenocarcinoma (GEAC) is a malignancy of the gastroesophageal junction (GEJ) and is associated with reflux of gastroduodenal contents and Barretts Esophagus (BE). A shift towards gram-negative bacteria in the microbiota of the GEJ additionally promotes inflammation and likely carcinogenesis. Enterobacteriaceae are enriched in advanced stages of GEAC development, and members of this family can produce colibactin, a genotoxin implicated in DNA damage and tumor progression. We aimed to validate these observations and investigate the effect of E. coli with or without colibactin production on GEAC-carcinogenesis. MethodsBacteria were profiled in human biopsies with imaging and 16S rRNA gene sequencing. Organoids of our L2-IL1B mouse model of GEAC were exposed to E. coli with colibactin (CoPEC) and without colibactin production (noCoPEC) via organoid microinjection. The phenotypic and transcriptomic changes in the organoids after the coculture with E. coli were evaluated via histology and single-cell RNA sequencing. ResultsIn human specimens, we observed an infiltration of bacteria in GEJ-tissue upon tumor formation and detected Enterobacteriaceae in one third of BE-patients. CoPEC-injected organoids exhibited high rates of proliferation and DNA damage, and an upregulation of cancer-associated genes and pathways. Furthermore, genes and pathways associated with immune activation, defense mechanisms, metabolic reprogramming, autophagy and differentiation were upregulated in CoPEC-injected organoids. ConclusionIn addition to the enrichment of Enterobacteriaceae in the GEJ-tissue of patients at late stages of GEAC, we show that the exposure of colibactin-producing E. coli to murine BE-organoids promotes genetic instability and proliferation, and the activation of cancer-associated pathways, while also activating autophagy and enhancing intercellular homeostasis. This indicates that colibactin-producing E. coli have a dual effect on early stages of GEAC-carcinogenesis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/687579v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1281a14org.highwire.dtl.DTLVardef@1c83c91org.highwire.dtl.DTLVardef@10088d2org.highwire.dtl.DTLVardef@1698a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Microbiota metabolized Bile Acids accelerate Gastroesophageal Adenocarcinoma via FXR inhibition

BackgroundThe incidence of Barrett esophagus (BE) and Gastroesophageal Adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BA) support fat digestion and undergo microbial metabolization in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. The capacity of inhibiting cancer-related processes when activated, make FXR an appealing therapeutic target. In this work, we assess the role of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression. ResultsHere we show that high fat diet (HFD) accelerated tumorigenesis in L2-IL1B mice (BE- and GEAC- mouse model) while increasing BA levels and enriching gut microbiota that convert primary to secondary BA. While upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine organoids and L2-IL1B mice with the FXR agonist obeticholic acid (OCA) deacelerated GEAC progression. ConclusionWe provide a novel concept of GEAC carcinogenesis being accelerated via the diet-microbiome-metabolome axis and FXR inhibition on progenitor cells. Further, FXR activation protected with OCA ameliorated the phenotype in vitro and in vivo, suggesting that FXR agonists have potential as differentiation therapy in GEAC prevention. Statement of significanceIf its inhibition is linked to disease progression and its activation to cancer prevention, exploring the potential of FXR as a therapeutic target has great clinical relevance in GEAC context.

cancer biology↗