Reprograming of gut microbiome energy metabolism by the<i>FUT2</i>Crohn’s disease risk polymorphism

Tong, Man‐Li; Mchardy, Ian Howard; Ruegger, Paul; Goudarzi, Maryam; Kashyap, Purna C.; Haritunians, Talin; Li, Xiaoxiao; Graeber, Thomas G.; Schwager, Emma; Huttenhower, Curtis; Fornace, Albert J.; Sonnenburg, Justin L.; McGovern, Dermot P.; Borneman, James; Braun, Jonathan

doi:10.1038/ismej.2014.64

Cited by 178 publications

(188 citation statements)

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“…18,19 In humans, deficiency of FUT2 -which occurs in around 20% of individuals, termed "nonsecretors" -is associated with shifts in microbial composition in the colonic mucosa, feces, and bile. [20][21][22][23] Tsyn deficiency could similarly affect microbial composition by altering nutrient sources and disrupting attachment sites for the intestinal microbiota.…”

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confidence: 99%

Microbial, metabolomic, and immunologic dynamics in a relapsing genetic mouse model of colitis induced by T-synthase deficiency

et al. 2016

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(2017) Microbial, metabolomic, and immunologic dynamics in a relapsing genetic mouse model of colitis induced by T-synthase deficiency, Gut Microbes, 8:1, 1-16, DOI: 10.1080/19490976.2016 To link to this article: https://doi.org/10. 1080/19490976.2016 ABSTRACTIntestinal dysbiosis is thought to confer susceptibility to inflammatory bowel disease (IBD), but it is unknown whether dynamic changes in the microbiome contribute to fluctuations in disease activity. We explored this question using mice with intestine-specific deletion of C1galt1 (also known as T-synthase) (Tsyn mice). These mice develop spontaneous microbiota-dependent colitis with a remitting/relapsing course due to loss of mucin core-1 derived O-glycans. 16S rRNA sequencing and untargeted metabolomics demonstrated age-specific perturbations in the intestinal microbiome and metabolome of Tsyn mice compare with littermate controls at weeks 3 (disease onset), 5 (during remission), and 9 (after relapse). Colitis remission corresponded to increased levels of FoxP3CRORgtCCD4C T cells in the colonic lamina propria that were positively correlated with operational taxonomic units (OTUs) in the S24-7 family and negatively correlated with OTUs in the Clostridiales order. Relapse was characterized by marked expansion of FoxP3-RORgtCCD4C T cells expressing IFNg and IL17A, which were associated with Clostridiales OTUs distinct from those negatively correlated with FoxP3CRORgtCCD4C T cells. Our findings suggest that colitis remission and relapse in the Tsyn model may reflect alterations in the microbiome due to reduced core-1 O-glycosylation that shift the balance of regulatory and pro-inflammatory T cell subsets. We investigated whether genetic variation in C1galt1 correlated with the microbiome in a cohort of 78 Crohn's disease patients and 101 healthy controls. Polymorphisms near C1galt1 (rs10486157) and its molecular chaperone, Cosmc (rs4825729), were associated with altered composition of the colonic mucosal microbiota, supporting the relevance of core-1 O-glycosylation to host regulation of the microbiome.

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Microbial, metabolomic, and immunologic dynamics in a relapsing genetic mouse model of colitis induced by T-synthase deficiency

et al. 2016

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“…In accordance with them, we discovered that high mRNA level of PTPN2 was significantly correlated with deep ulcer in CD patients ( Figure 5). As a signaling molecule, PTPN2 has a number of target genes including Janus kinases (JAKs), signal transducer and activator of transcription (STAT) 1 and 3, mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) [39][40][41]. As mentioned above, IL17─JAK2─STAT3 and IL23R─JAK2 ─STAT3 pathway were essential for the function of Th17 in inflammation.…”

Section: Discussionmentioning

confidence: 99%

A Novel Strategy to Identify mRNA 3′ UTR and mRNA Level Difference in Crohn’s Disease

Hu¹,

Liu²,

Zhou³

et al. 2017

Chemotherapy (Los Angel)

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Background and Aims: Crohn's disease (CD) is a chronic and refractory intestinal inflammatory disease. The 3′ untranslated region (3′ UTR) of mRNA transcript can regulate its own translational process post-transciptionally, and its role in CD remains unclear. The aim of this study was to identify the critical genes influencing CD phenotype via the regulation of mRNA 3′ UTR. Methods:Isoform Structural Change Model (IsoSCM) was used to evaluate the length of 3′ UTR of the whole transciptome from a RNA-seq based online CD database. Correlations between 3′ UTR length status and mRNA level were analyzed by Spearman coefficients. Correlated genes list was overlapped with published critical CD related gene list. Univariate and multivariate analysis were performed to identify the genes associated with CD phenotype. Results:Compared with normal control, 3′ UTR of 34192 genes were shortened and 57389 were lengthened among 432784 genes in CD patients. The 3′ UTR changes of 255 genes were found significantly correlated with their mRNA level. Furthermore, 8 overlapped genes were shared by above 255 correlated genes and known CD related gene list (ABCB1, FAF1, TUT2, IL27, JAK2, LTB, NAGLU and PTPN2). The mRNA level of ABCB1 and JAK2, and shortened 3′ UTR length of JAK2 transcript were found to be correlated with deep ulcer in CD patients by univariate and multivariate analysis. Conclusions:The 3′ UTR changes of CD related genes were confirmed to be related to the phenotype of CD. Our findings may provide further insight into the epigenetic mechanisms and therapeutic strategies for CD.

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“…The first such studies in humans focused on specific genes and pathways, and have identified several significant microbiome-associated variants [41][42][43][44][45]. However, a potential shortcoming of the above studies is that they require previous knowledge of associated genes, and thus cannot discover new associations.…”

Section: Limited Power Of Microbiome Genome Wide Association Studiesmentioning

confidence: 99%

Host genetics and microbiome associations from the lens of genome wide association studies

Weissbrod

Rothschild

Barkan

et al. 2018

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Recent studies indicate that the gut microbiome is partially heritable, motivating the need to investigate microbiome-host genome associations via microbial genome-wide association studies (mGWAS). Existing mGWAS demonstrate that microbiome-host genotypes associations are typically weak and are spread across multiple variants, similar to associations often observed in genome-wide association studies (GWAS) of complex traits. Here we reconsider mGWAS by viewing them through the lens of GWAS, and demonstrate that there are striking similarities between the challenges and pitfalls faced by the two study designs. We further advocate the mGWAS community to adopt three key lessons learned over the history of GWAS: (a) Adopting uniform data and reporting formats to facilitate replication and meta-analysis efforts; (b) enforcing stringent statistical criteria to reduce the number of false positive findings; and (c) considering the microbiome and the host genome as distinct entities, rather than studying different taxa and single nucleotide polymorphism (SNPs) separately. Finally, we anticipate that mGWAS sample sizes will have to increase by orders of magnitude to reproducibly associate the host genome with the gut microbiome.PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.26615v1 | CC BY 4.0 Open Access | rec: 5

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Reprograming of gut microbiome energy metabolism by theFUT2Crohn’s disease risk polymorphism

Cited by 178 publications

References 74 publications

Microbial, metabolomic, and immunologic dynamics in a relapsing genetic mouse model of colitis induced by T-synthase deficiency

Microbial, metabolomic, and immunologic dynamics in a relapsing genetic mouse model of colitis induced by T-synthase deficiency

A Novel Strategy to Identify mRNA 3′ UTR and mRNA Level Difference in Crohn’s Disease

Host genetics and microbiome associations from the lens of genome wide association studies

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