Dataset Information

Altered Intestinal Microbiota-Host Mitochondria Crosstalk in New Onset Crohn’s Disease

ABSTRACT: Intestinal microbial dysbiosis is associated with Crohn’s disease (CD). However, the mechanisms leading to the chronic mucosal inflammation that characterizes this disease remain unclear. To evaluate causality and mechanisms of disease, we conducted a systems level study of the interactions between the gut microbiota and host in new-onset pediatric patients. We report an altered host proteome in CD patients indicative of impaired mitochondrial functions. A downregulation of mitochondrial proteins implicated in H2S detoxification was observed, while the relative abundance of H2S microbial producers was increased. Network correlation analysis identified Atopobium parvulum as the central hub of H2S producers. Gnotobiotic and conventionalized colitis-susceptible interleukin-10-deficient (Il10-/-) mice demonstrated that A. parvulum induced colitis, a phenotype requiring the presence of the intestinal microbiota. Administration of bismuth, a H2S scavenger, prevented A. parvulum-induced colitis in Il10-/- mice. This study identified host-microbiota interactions that are disturbed in CD patients providing mechanistic insights on CD pathogenesis.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colon

DISEASE(S): Inflammatory Bowel Disease

SUBMITTER: Amanda Starr

LAB HEAD: Alain Stintzi

PROVIDER: PXD002882 | Pride | 2016-09-29

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	IBD_BIopsy_20130814_Control_315_F1.raw	Raw
	IBD_BIopsy_20131016_Control_243_Ulcer_CoN_Moderate_F1.raw	Raw
	IBD_BIopsy_20131115_CD_CoA_Severe_201_F1.raw	Raw
	IBD_BIopsy_20131115_CD_CoA_Severe_201_F2.raw	Raw
	IBD_BIopsy_20131115_CD_CoA_Severe_201_F3.raw	Raw

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Publications

Altered intestinal microbiota-host mitochondria crosstalk in new onset Crohn's disease.

Mottawea Walid W Chiang Cheng-Kang CK Mühlbauer Marcus M Starr Amanda E AE Butcher James J Abujamel Turki T Deeke Shelley A SA Brandel Annette A Zhou Hu H Shokralla Shadi S Hajibabaei Mehrdad M Singleton Ruth R Benchimol Eric I EI Jobin Christian C Mack David R DR Figeys Daniel D Stintzi Alain A

Nature communications 20161123

Intestinal microbial dysbiosis is associated with Crohn's disease (CD). However, the mechanisms leading to the chronic mucosal inflammation that characterizes this disease remain unclear. In this report, we use systems-level approaches to study the interactions between the gut microbiota and host in new-onset paediatric patients to evaluate causality and mechanisms of disease. We report an altered host proteome in CD patients indicative of impaired mitochondrial functions. In particular, mitocho ...[more]

PMID: 27876802

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Project description:This UH2/UH3 demonstration project entitled "Effects of Crohn's disease risk alleles on enteric microbiota" is focused on characterizing intestinal associated microbiota in patients with ileal Crohn's disease (ileal CD), ulcerative colitis (UC) and control patients without inflammatory bowel diseases (non-IBD). We hypothesize that genetic factors that affect Paneth cell function, contribute to compositional changes in intestinal microbiota. These changes in microbiota may lead to reduction of protective commensal organisms and increased numbers of aggressive organisms that incite intestinal inflammation. This hypothesis is being tested by high throughput 16S rRNA sequence analysis of de-identified ileal and colonic tissues that have been archived at Washington University St. Louis, University of North Carolina, Mount Sinai Hospital and the Cleveland Clinic. Multivariate analysis of the metagenomic data will be conducted with genotyping metadata (highly reproducible CD risk alleles, including NOD2 and ATG16L1) and phenotyping metadata (e.g. age, gender, race, body mass index, medications and smoking.) Shotgun sequencing will be performed on selected fecal specimens linked to ileal tissues to identify additional, or auxiliary, or synergistic pathogenic factors or other functional changes in the microbiome. Because members of this research team have observed that a chronic viral infection is required for the Paneth cell defect in Atg16l1 hypomorphic mice, a major focus of these studies will be towards identifying potential viral triggers for the defective Paneth cell phenotype in individuals harboring the ATG16L1 risk allele. Novel genetic probes for protective and aggressive organisms will be developed by mining bacterial genome and shotgun sequencing data. Genomic sequences will be produced for candidate protective and aggressive strains (e.g. adherent-invasive strains of E. coli) isolated from human intestinal tissues where there is limited existing genome information. Quantitative qPCR assays using the novel as well as established genetic probes will be conducted to test the hypothesis that an imbalance between protective and aggressive organisms is associated with genetic factors that affect Paneth cell function. Our combined expertise in multiple disciplines across multiple institutions, our demonstrated ability to collect a large number of well-phenotyped samples with longitudinal clinical information that will be linked to host response and morphologic studies, and our consortium's capacity for high-throughput sequencing will be used to investigate how alterations in human microbiome relate to CD risk alleles and CD pathogenesis.