Colorectal cancer microbiome programs DNA methylation of host cells by affecting methyl donor metabolism.

BACKGROUND: Colorectal cancer (CRC) arises from complex interactions between host and environment, which include the gut and tissue microbiome. It is hypothesized that epigenetic regulation by gut microbiota is a fundamental interface by which commensal microbes dynamically influence intestinal biology. The aim of this study is to explore the interplay between gut and tissue microbiota and host DNA methylation in CRC. METHODS: Metagenomic sequencing of fecal samples was performed on matched CRC patients (n = 18) and healthy controls (n = 18). Additionally, tissue microbiome was profiled with 16S rRNA gene sequencing on tumor (n = 24) and tumor-adjacent normal (n = 24) tissues of CRC patients, while host DNA methylation was assessed through whole-genome bisulfite sequencing (WGBS) in a subset of 13 individuals. RESULTS: Our analysis revealed substantial alterations in the DNA methylome of CRC tissues compared to adjacent normal tissues. An extensive meta-analysis, incorporating publicly available and in-house data, identified significant shifts in microbial-derived methyl donor-related pathways between tumor and adjacent normal tissues. Of note, we observed a pronounced enrichment of microbial-associated CpGs within the promoter regions of genes in adjacent normal tissues, a phenomenon notably absent in tumor tissues. Furthermore, we established consistent and recurring associations between methylation patterns of tumor-related genes and specific bacterial taxa. CONCLUSIONS: This study emphasizes the pivotal role of the gut microbiota and pathogenic bacteria in dynamically shaping DNA methylation patterns, impacting physiological homeostasis, and contributing to CRC tumorigenesis. These findings provide valuable insights into the intricate host-environment interactions in CRC development and offer potential avenues for therapeutic interventions in this disease.

Multi-Omics Analysis Reveals Intratumor Microbes as Immunomodulators in Colorectal Cancer.

Recent studies indicated that intratumor microbes are an essential part of the tumor microenvironment. Here, we performed an integrated analysis of genetic, epigenetic, and intratumor microbial factors to unravel the potential remodeling mechanisms of immune-cell infiltration (ICI) and tumorigenesis of colorectal cancer (CRC). We identified the components and structure of the intratumor microbiome as primary contributors to the difference in survival between ICI subtypes. Multiple tumor-infiltrating immune cells (TIICs) and immune-related genes were associated with intratumor microbial abundance. Additionally, we found that Clostridium was enriched in CRC patients who were nonsensitive to immune checkpoint blockade (ICB) therapy. We further provided clues that the intratumor microbes might influence the response to ICB therapy by mediating TIICs, especially MAIT (mucosa-associated invariant T) cells. Finally, three ICB-related TIICs and 22 of their associated microbes showed the potential to predict the response to ICB therapy (area under the receiver operating characteristic curve [AUC] = 89%). Our findings highlight the crucial role of intratumor microbes in affecting immune-cell infiltration patterns, prognosis, and therapy response of CRC and provide insights for improving current immunotherapeutic treatment strategies and prognosis for CRC patients. IMPORTANCE Using the multi-omics data from The Cancer Genome Atlas (TCGA) colorectal cancer (CRC) cohort, we estimated the tumor microenvironment (TME) infiltration patterns of patients and unraveled the interplay of gene expression, epigenetic modification, and the intratumor microbiome. This study suggests the impact of intratumor microbes on maintaining the tumor immune microenvironment in the pathogenesis of CRC and modulating the response to immune checkpoint blockade (ICB) therapy. We identified a set of combined features, including 3 ICB-related tumor-infiltrating immune cells (TIICs) and 22 of their associated microbes, that are predictive of ICB responses.

Lead exposure results in defective behavior as well as alteration of gut microbiota composition in flies and their offsprings.

BACKGROUND: Lead (Pb) has become one of the most dangerous metals to human health, especially to the nervous system as its persistent accumulation and high toxicity. However, how the gut microbiota influence the Pb-related neurotoxicity remains unclear. The aim of our study was to explore the link among Pb exposure, behavior changes, and gut microbiota. METHODS: Using Drosophila melanogaster as model, climbing assay, social avoidance, social space, and short-term memory analysis were preformed to study the behavioral changes in flies exposed to Pb and their offspring. 16S rRNA sequencing was used to explore the changes in the gut microbiota of the flies with/without Pb-exposure. RESULTS: The crawling ability, memory, and social interactions of Pb-exposed parent flies decreased significantly. For the offspring, behaviors were more significantly affected in male offspring whose male parent was exposed to Pb. The alpha diversity and the beta diversity of gut microbiota were significantly different between the Pb-exposed flies and the controls, as well as between the male offspring and the controls. Two genera, Lactobacillus and Bifidobacterium were found significantly decreased in the Pb-exposed flies when compared to the controls and significantly correlated with the learning and memory. Four genera, Bilophila, Coprococcus, Desulfovibrio, and Ruminococcus were found depleted in the female offspring of the Pb-exposed flies. CONCLUSIONS: Lead exposure resulted in defective behavior and alteration of gut microbiota composition in flies and their offspring, alteration in gut microbiota might be the link between behavioral changes induced by Pb-exposure.