Project description:One of the dysbioses often observed in CD patients is an increased abundance of Escherichia coli (10-100 fold compared to healthy individuals) [Gevers et al., 2014]. E. coli isolates collected from CD and healthy patients were cultivated on LB medium at aerobic conditions up to medium log phase and their total proteomes were analysed by shotgun proteomics by HPLC-MS/MS. Refs. Gevers D, Kugathasan S, Denson LA, Vazquez-Baeza Y, Van Treuren W, Ren B, et al. The treatment-naive microbiome in new-onset Crohn’s disease. 2014. Cell Host Microbe 15: 382–92.
Project description:Purpose: To clarify the biological processes underlying variation in disease location and antimicrobial sero-reactivity across age-of onset in pediatric Crohn disease. Methods: We characterize the ileal global pattern of gene expression using single-end, 50bp RNA-sequencing using the Illumina HiSeq2000 in 304 treatment-naïve pediatric Crohn patients and non-IBD controls. Reads were quantified using Kallisto with Gencodev23 annotations. For all analyses, data were stratified by patient age-of-onset. Results: Performing differential analysis of all reasonably-expressed transcripts (TPM>5 in ≥5 samples, with significance defined as FDR-corrected p-value<0.05 and fold change≥1.5), we identify a robust gene signature with higher expresison of an immune gene set in older patients (≥10 years at diagnosis) compared to younger patients (<10 years at diagnosis), and a decrease in expression of antimicrobial Paneth cell-derived α-defensins. Conclusion: We provide evidence for maturation of mucosal Th1 immune response and loss of epithelial antimicrobial α-defensins with increasing age-of-onset.
Project description:The Study Of Urban and Rural Crohn disease Evolution (SOURCE, n=380) characterized exposures, diet, and host and microbial factors in rural and urban Chinese controls and newly diagnosed Crohn Disease (CD), and in treatment-naïve Israeli CD and controls. We considered diet-omics domains simultaneously to detect complex interactions in the gut to prioritize potential beneficial and pathogenic factors.
Project description:Background and aims: Celiac disease is provoked by gluten exposure, but the resultant pathogenic process in the duodenum is not well understood. We aimed to define the core celiac transcriptomic signature and pathologic pathways in pre-treatment diagnostic duodenum biopsies. Methods: We use mRNAseq to define pre-treatment diagnostic duodenum gene expression in 54 pediatric celiac patients and non-celiac controls, and we validate our key findings in an independent cohort of 40 participants. We further define similar and divergent genes and pathways in 177 Crohn disease patients and controls. Results: We observe a marked suppression of mature epithelial metabolic functions in celiac patients, overlapping substantially with the Crohn signature. A marked adaptive immune response was noted for the up-regulated signature including interferon response, alpha-beta, and gamma-delta T-cells that overlapped to some extant with the Crohn signature. However, we identified a celiac specific signature linked to increased cell proliferation, nuclear division, and cell cycle activity that was localized primarily to the epithelia as noted by CCNB1 and Ki67 staining. Lastly, we demonstrate the utility of the transcriptomic date to correctly classify disease or healthy states in the discovery and validation cohorts. Conclusion: Our data provide insights into celiac pathogenesis and can stimulate new approaches to address this highly prevalent condition.
Project description:Pancreatic cancer is the 3rd most prevalent cause of cancer related deaths in United states alone, with over 55000 patients being diagnosed in 2019 alone and nearly as many succumbing to it. Late detection, lack of effective therapy and poor understanding of pancreatic cancer systemically contributes to its poor survival statistics. Obesity and high caloric intake linked co-morbidities like type 2 diabetes (T2D) have been attributed as being risk factors for a number of cancers including pancreatic cancer. Studies on gut microbiome has shown that lifestyle factors as well as diet has a huge effect on the microbial flora of the gut. Further, modulation of gut microbiome has been seen to contribute to effects of intensive insulin therapy in mice on high fat diet. In another study, abnormal gut microbiota was reported to contribute to development of diabetes in Db/Db mice. Recent studies indicate that microbiome and microbial dysbiosis plays a role in not only the onset of disease but also in its outcome. In colorectal cancer, Fusobacterium has been reported to promote therapy resistance. Certain intra-tumoral bacteria have also been shown to elicit chemo-resistance by metabolizing anti-cancerous agents. In pancreatic cancer, studies on altered gut microbiome have been relatively recent. Microbial dysbiosis has been observed to be associated with pancreatic tumor progression. Modulation of microbiome has been shown to affect response to anti-PD1 therapy in this disease as well. However, most of the studies in pancreatic cancer and microbiome have remained focused om immune modulation. In the current study, we observed that in a T2D mouse model, the microbiome changed significantly as the hyperglycemia developed in these animals. Our results further showed that, tumors implanted in the T2D mice responded poorly to Gemcitabine/Paclitaxel (Gem/Pac) standard of care compared to those in the control group. A metabolomic reconstruction of the WGS of the gut microbiota further revealed that an enrichment of bacterial population involved in drug metabolism in the T2D group.
Project description:We report the global pattern of ileal gene expression in a cohort of 310 treatment-naïve pediatric Crohn Disease patients and controls. We focus on genes with consistent altered expression in the ileum of younger (Paris age A1a) vs older (Paris age A1b) patients.