BACKGROUND:Although Helicobacter pylori plays a central role in gastric cancer (GC), other microorganisms involved in gastric dysbiosis may also impact carcinogenesis. We aimed to characterize gastric dysbiosis and its role in the transition from non-atrophic gastritis (NAG) to gastric premalignant lesions (GPLs) in two populations from Nariño, Colombia, with distinct GC risks: low-risk Afro-Colombians from Barbacoas and high-risk Amerindian-Mestizos from Cumbal. METHODS:Gastric biopsies from 200 individuals were analyzed using 16S rRNA gene sequencing. Microbial diversity and composition were assessed based on relevant clinical and sociodemographic characteristics. RESULTS:H. pylori infection was more prevalent in Barbacoas (83.8%) than Cumbal (70.5%), alongside higher rates of obesity (p < 0.001), alcohol intake (p : 0.07), and smoking (p : 0.02), but less severe OLGIM stages (p : 0.04). In Barbacoas, alpha diversity remained stable, whereas in Cumbal, richness significantly increased in GPL (p < 0.001). Beta diversity showed significant microbial composition differences between municipalities (p < 0.001). In Barbacoas, taxa such as Prevotella, Haemophilus, and Veillonella were dominant, whereas lactic acid bacteria such as Streptococcus were predominant in Cumbal. Barbacoas showed stable gastric microbiota composition across histological stages, whereas Cumbal exhibited enrichment of Gemella, Leptotrichia, and Prevotella in GPL. CONCLUSION:The Streptococcus-driven dysbiosis in Cumbal may help identify microbial biomarkers for GC progression, particularly other oral pathobionts.

BackgroundATG16L1 plays a fundamental role in the degradative intracellular pathway known as autophagy, being a mediator of inflammation and microbial homeostasis. The variant rs2241880 can diminish these capabilities, potentially contributing to inflammatory bowel disease (IBD) pathogenesis.ObjectivesTo perform an updated meta-analysis on the association between ATG16L1 rs2241880 and IBD susceptibility by exploring the impact of age, ethnicity, and geography. Moreover, to investigate the association between rs2241880 and clinical features.MethodsLiterature searches up until September 2022 across 7 electronic public databases were performed for all case-control studies on ATG16L1 rs2241880 and IBD. Pooled odds ratios (ORP) and 95% CI were calculated under the random effects model.ResultsOur analyses included a total of 30,606 IBD patients, comprising 21,270 Crohn's disease (CD) and 9336 ulcerative colitis (UC) patients, and 33,329 controls. ATG16L1 rs2241880 was significantly associated with CD susceptibility, where the A allele was protective (ORP: 0.74, 95% CI: 0.72-0.77, p-value: <0.001), while the G allele was a risk factor (ORP: 1.23, 95% CI: 1.09-1.39, p-value: 0.001), depending on the minor allele frequencies observed in this multi-ancestry study sample. rs2241880 was predominantly relevant in Caucasians from North America and Europe, and in Latin American populations. Importantly, CD patients harbouring the G allele were significantly more predisposed to perianal disease (ORP: 1.21, 95% CI: 1.07-1.38, p-value: 0.003).ConclusionsATG16L1 rs2241880 (G allele) is a consistent risk factor for IBD in Caucasian cohorts and influences clinical outcomes. As its role in non-Caucasian populations remains ambiguous, further studies in under-reported populations are necessary. image

Autophagy is a cellular degradation mechanism, which is triggered by the bacterium Helicobacter pylori. A single nucleotide polymorphism (SNP) in the autophagy gene ATG16L1 (rs2241880, G-allele) has been shown to dysregulate autophagy and increase intestinal endoplasmic reticulum (ER) stress. Here, we investigate the role of this SNP in H. pylori-mediated gastric carcinogenesis and its molecular pathways. ATG16L1 rs2241880 was genotyped in subjects from different ethnic cohorts (Dutch and Australian) presenting with gastric (pre)malignant lesions of various severity. Expression of GRP78 (a marker for ER stress) was assessed in gastric tissues. The effect of ATG16L1 rs2241880 on H. pylori-mediated ER stress and pro-inflammatory cytokine induction was investigated in organoids and CRISPR/Cas9 modified cell lines. Development of gastric cancer was associated with the ATG16L1 rs2241880 G-allele. Intestinal metaplastic cells in gastric tissue of patients showed increased levels of ER-stress. In vitro models showed that H. pylori increases autophagy while reducing ER stress, which appeared partly mediated by the ATG16L1 rs2241880 genotype. H. pylori-induced IL-8 production was increased while TNF-α production was decreased, in cells homozygous for the G-allele. The ATG16L1 rs2241880 G-allele is associated with progression of gastric premalignant lesions and cancer. Modulation of H. pylori-induced ER stress pathways and pro-inflammatory mediators by ATG16L1 rs2441880 may underlie this increased risk.

Opioid-binding protein/cell adhesion molecule (OPCML) is expressed in many tissues and localizes to the plasma membrane. It is a putative tumor suppressor that acts on receptor tyrosine kinases (RTKs), influencing cell cycle arrest, apoptosis, and migration. Its expression is silenced epigenetically in cancer, inferring potential diagnostic, prognostic, and therapeutic roles.