Klaus-Peter Janssen

Barrett's esophagus is the established precursor of gastroesophageal adenocarcinoma, yet most cases are diagnosed outside surveillance. The study investigated demographic, life-style, and genetic contributions to disease stage and progression Barrett's esophagus. Data from 870 participants in the prospective, multicenter BarrettNET registry (10-year follow-up period) were analyzed. Epidemiological data (smoking, alcohol, physical activity, diet, BMI, reflux symptoms) were collected via standardized questionnaires; dietary quality was assessed with a validated nutrition score. Multivariable logistic regression identified factors associated with advanced disease at diagnosis (non-dysplastic disease versus dysplasia or cancer); progression was evaluated using Firth penalized logistic regression. In a genotyped subgroup (739 participants), weighted polygenic risk scores from 41 variants were included as a sensitivity analysis. Among 598 patients with non-dysplastic disease, 116 with dysplasia, and 156 with cancer, older age (OR 1.03, 95% CI 1.01–1.04), male sex (OR 1.92, 95% CI 1.28–2.90), and smoking (OR 1.64, 95% CI 1.15–2.35) were associated with advanced disease. Of 21 participants who progressed during follow-up, older age (OR 1.06, 95% CI 1.02–1.11) and smoking (OR 4.31, 95% CI 1.62–11.47) were associated with progression, whereas reflux symptoms were associated with lower odds (OR 0.36, 95% CI 0.15–0.84; apparent AUC 0.825). Dietary factors and polygenic risk scores showed no independent association with either outcome and did not improve prediction. Age, male sex, and smoking predicted advanced disease and progression in Barrett's esophagus, while currently available polygenic risk scores added little predictive value, supporting lifestyle-based approaches to risk stratification.

The gut microbiota influences host metabolism, but the mechanisms of lipid uptake from food remain mysterious. Here we used stable isotope-labelled tracers in gnotobiotic mouse models, which revealed that host uptake of dietary lipids depends on microbial colonization. Systemic lipid metabolism modelling predicted that the gut microbiota restricts intestinal lipid absorption, and labelled lipid administration verified that the gut contents of microbiota-colonized mice contained up to 12-fold more lipids than those of germ-free animals. A combination of lipidomics and proteomics showed that gut microbes trigger Myd88 signalling, leading to a downregulation of hepatic Cyp7b1 activity and increased taurocholate production. Taurocholate stimulates phospholipase A1 activity in bile, causing the degradation of phosphatidylcholine that is essential for luminal micelle formation and lipid uptake. A diverse microbiome was associated with lower phosphatidylcholine content. This previously unrecognized host–gut microbiota interplay via enzymes in bile could provide future targets to modulate dietary lipid absorption.

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Background: Colorectal cancer (CRC) exhibits increased levels of arachidonic acid-derived pro-inflammatory derivatives indicating an uptake of dietary polyunsaturated fatty acids (PUFAs). Objective: We aimed to investigate uptake of extrinsic fatty acids (FAs) in tumours and their relevance for CRC lipid metabolism and progression. Design: Total FAs were quantified using gas chromatography-mass spectrometry in non-diseased mucosa and tumour tissue from patients with CRC of a discovery cohort (n=152), validated in an independent cohort (n=28) and associated with clinical, genomic and microbiome data. The genetic mouse tumour model Apc ^1638N was used to track the flux of stable isotope-labelled FAs in tumours from the intestinal lumen. The relationship between FA uptake and tumour progression was investigated in 2D and 3D cell models. Results: Extrinsic long chain PUFAs, including arachidonic acid, accumulate in CRC, particularly in right-sided tumours, and in tumours of Apc ^1638N mice. The CRC-specific FA profiles were independent of sex, molecular subtypes, early-disease or late-disease onset. The absorption of FAs from the intestinal lumen in tumours was confirmed in specific pathogen-free Apc ^1638N mice. In the absence of the microbiome, in germ-free Apc ^1638N mice, fewer tumours were developed, and survival was increased. Inhibition of FA import or β-oxidation reduces cancer cell proliferation. Conclusion: Extrinsic FAs accumulate in CRC, verifying a central role of arachidonic acid-derived inflammatory mediators, but also suggesting a relevance of dietary FAs for cancer cell proliferation. It will be intriguing to explore to what extent targeting this flux pathway together with the interrelated microbiome opens new therapeutic avenues for CRC in humans.

Background: Tumor lipid metabolism has emerged as a critical, yet underexplored, determinant of cancer progression with clinical and prognostic importance. A membrane lipid species of particular interest is globotriaosylceramide (Gb ₃ /CD77), a glycosphingolipid that serves as cellular receptor for the bacterial Shiga toxins, and is upregulated in various malignancies. While preclinical studies have suggested a pro-tumorigenic role for Gb ₃ , the regulatory drivers of its biosynthesis in human tumors have remained elusive. Methods: The glycosyltransferase A4GALT, responsible for Gb ₃ biosynthesis, and the degrading enzyme α-galactosidase A (α-GLA) are two essential molecular determinants of Gb ₃ cell surface expression. Expression of these enzymes was analyzed on mRNA level in tissues from colorectal cancer, published datasets from gastric, pancreatic, esophageal and colorectal cancer (1213 patients) and in human cell lines. Pharmacological manipulation in vitro using the hypomethylating agent 5-Aza-2-deoxycytidine and histone deacetylase (HDAC) inhibitors induced A4GALT expression in DLD1 colon cancer cells and Gb ₃ biosynthesis. A4GALT deficiency was induced by CRISPR-Cas9 mutagenesis in human HCT116 colon cancer cells, and its putative effects tested for proliferation, cell migration and invasion. Results: A4GALT deficiency in HCT116 cells confirmed its essential role for Gb ₃ biosynthesis, leading to resistance against Shiga toxin 1a, and to reduced cancer cell migration and invasion. Gene enrichment analyses revealed that high A4GALT and low α-GLA expression is associated with a distinct gene expression program in gastric, pancreatic and colorectal cancer, including increased signatures of epithelial–mesenchymal transition. A4GALT expression is regulated by chromatin accessibility and DNA methylation at a defined intronic enhancer. In accordance, pan‑cancer analysis of TCGA datasets validated the A4GALT‑high/α‑GLA‑low signature as a negative prognostic indicator across gastrointestinal tumor entities. Conclusions: Our study uncovers an epigenetically regulated lipid metabolic axis involving A4GALT and Gb ₃ that contributes to aggressive tumor behavior. Of note, this pathway may be therapeutically targetable using natural or synthetic Shiga toxin B-subunit derivatives.

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in patients receiving allo-HSCT. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DAT´s beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DAT’s dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

Endoplasmic reticulum unfolded protein responses contribute to cancer development, with activating transcription factor 6 (ATF6) involved in microbiota-dependent tumorigenesis. Here we show the clinical relevance of ATF6 in individuals with early-onset and late colorectal cancer, and link ATF6 signalling to changes in lipid metabolism and intestinal microbiota. Transcriptional analysis in intestinal epithelial cells of ATF6 transgenic mice (nATF6^IEC) identifies bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics and isotype labelling confirm ATF6-related enrichment of long-chain fatty acids in colonic tissue of humans, mice and organoids. FASN inhibition and microbiota transfer in germ-free nATF6^IEC mice confirm the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumour-relevant microbial taxa, including Desulfovibrio fairfieldensis, is mechanistically linked to long-chain fatty acid exposure using bioorthogonal non-canonical amino acid tagging, and growth analysis of Desulfovibrio isolates. We postulate chronic ATF6 signalling to select for tumour-promoting microbiota by altering lipid metabolism.