Human metagenome
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA46307 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR944970_1.fastq.gz | Fastqsanger.gz | |||
| SRR944970_2.fastq.gz | Fastqsanger.gz | |||
| SRR944986_1.fastq.gz | Fastqsanger.gz | |||
| SRR944986_2.fastq.gz | Fastqsanger.gz |
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Project description:Esophageal adenocarcinoma (EA) is increasingly common. EA is thought to arise from a precursor lesion, Barrett’s esophagus (BE), in which chronic bile and acid reflux from the stomach injures the esophagus and induces the esophageal squamous epithelium to transition to a mixed gastric and intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We established a biobank of human patient-derived BE organoids that recapitulated the molecular heterogeneity of BE. Bulk and single-cell transcriptomics, corroborated with analysis of patient tissues, pointed to BE differentiation depending on a balance between two transcription factors that govern foregut versus hindgut embryonic gastrointestinal development: SOX2 (driving esophageal and stomach differentiation) and CDX2 (driving intestinal differentiation). Using squamous-specific inducible Sox2 knockout (Krt5CreER/+; Sox2Δ/Δ;ROSA26LSLTdTomato/+) mice, we found increased basal proliferation and decreased differentiation in the foregut squamous epithelium. Remarkably, Sox2Δ/Δ mice also harbored expanded glands at the squamocolumnar junction, some of which lineage traced to Krt5-expressing cells, indicating metaplasia from squamous epithelium. CUT&RUN analysis showed SOX2 bound and promoted differentiation-associated (e.g.,Krt13) and repressed proliferation-associated (e.g., Mki67) targets. Thus, SOX2 is critical for foregut squamous epithelial differentiation and its decreased expression likely an initiating step in progression to BE and thence to EA.
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Project description:Rates of esophageal adenocarcinoma are rising globally, with risk factors including a range of genetic and environmental factors, including obesity, tobacco smoking, TP53 mutations, and Barrett’s esophagus, a proinflammatory condition which often occurs prior to developing adenocarcinoma. Interestingly, these factors also modulate the gastrointestinal microbiome. To better understand the linkage between the microbiome, inflammation, and development of esophageal adenocarcinoma, we integrated 16S and RNA sequencing data. We found several microbial taxa enriched in tumor samples which were correlated with predicted immune cell infiltration from RNA-seq data, including a decrease in megakaryocyte-erythroid progenitor cells with a concomitant increase in platelets. These data suggest dysbiosis of the intratumoral microbiome promotes development and production of platelets, which reveal alterations in the immune microenvironment of esophageal adenocarcinoma and suggest novel therapeutic targets.
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Project description:<p>The distal esophagus is an important anatomical area where gastric acid reflux can cause reflux esophagitis (RE), Barrett's esophagus (BE) (intestinal metaplasia), and esophageal adenocarcinoma (EA). The incidence of EA has increased 6-fold in the U.S. since the 1970s, parallel to a significant increase in the prevalence of gastroesophageal reflux diseases (GERD). Although specific host factors might predispose one to disease risk, such a rapid increase in incidence must be predominantly environmental. The cause remains unknown. Our hypothesis is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in the GERD sequence.</p> <p>We will conduct a case control study to characterize the microbiome in every stage of the GERD sequence as well as analyze the trend in changes in the microbiome along disease progression toward EA.</p> <p>Specific Aim 1. To conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence, by a 16S rRNA gene survey. We will analyze samples of the foregut microbiome at three anatomic loci: mouth, distal esophagus, and gastric corpus. Changes of the microbiota in the distal esophagus will be correlated with the phenotypes. Spatial relationship between the esophageal microbiota and upstream (mouth) and downstream (stomach) foregut microbiotas as well as temporal stability of the microbiome-disease association will also be examined.</p> <p>Specific Aim 2. To define distal esophageal metagenome and demonstrate its association with GERD sequence, by shotgun metagenomic analysis. We will first classify samples of the metagenome into metagenotypes by between-sample k-mer distance and correlate the metagenotypes with the four phenotypes. Subsequent detailed analyses will include pathway-disease and gene-disease associations. DNA viruses and fungi, if identified, also will be correlated with the phenotypes.</p> <p>A significant association between the foregut microbiome composition and GERD sequence, if demonstrated, will be the first step for eventually testing the causal hypothesis that an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microbial ecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiome through use of antibiotics, probiotics, or prebiotics. Causative therapy for GERD could prevent its progression and reverse the current trend of increasing incidence of EA.</p>
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Project description:Tracheoesophageal disorders and diseases are prevalent in humans such that an organoid model of human esophagus could be greatly beneficial. We therefore established a three-dimensional esophageal organoid culture system through the directed differentiation of human pluripotent stem cells (hPSCs). We identified that sequential manipulation of several signaling pathways resulted in patterning of definitive endoderm to dorsal anterior foregut spheroids (dAFGs). Outgrowth of dAFGs for 1-2 months resulted in human esophageal organoids (HEOs) with a stratified squamous epithelium comparable to a late gestation mouse embryonic esophagus. These 1 and 2 month old HEOs were harvested for RNA to transcriptionally profile and compare them to profiles of esophageal tissue biopsies and keratinocytes. We then used HEOs and mouse embryos to identify how SOX2 mediates separation of the esophageal and respiratory lineages and found that loss of endodermal Sox2 results in complete esophageal agenesis. Using a SOX2 CRISPR interference iPS line, we generated dorsal and ventral anterior foregut progenitors (by manipulating BMP signaling) with or without SOX2-knockdown. At the transcriptional level, SOX2 acts to promote esophageal specification in both mice and humans in part by inhibiting Wnt signaling in the dorsal AFG and promoting survival of esophageal epithelium. In addition to this use of hPSC-derived esophageal organoids to study development, HEOs can be used for future studies of esophageal pathologies, such as Barrett’s metaplasia and carcinoma.
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