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The Gut Microbiota Metabolite Succinate promotes Adipose Tissue Browning in Crohn’s Disease

ABSTRACT: In Crohn’s disease (CD), microbe-host interactions are altered, with changes in microbial’s communities and barrier defects leading to translocation of microbes to surrounding adipose tissue (AT). We evaluated the presence of beige AT depots in CD and questioned whether succinate and/or bacterial translocation promotes white-to-beige transition in adipocytes.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Crohn's Disease

SUBMITTER: Eva Borràs

LAB HEAD: Eduard Sabido

PROVIDER: PXD030520 | Pride | 2022-09-14

REPOSITORIES: Pride

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			Action	DRS
	2020MS005_MEIJ_001_02.raw	Raw
	2020MS005_MEIJ_004_02.raw	Raw
	2020MS005_MEIJ_005_02.raw	Raw
	2020MS005_MEIJ_006_02.raw	Raw
	2020MS005_MEIJ_PD2-0.pdResult	Other

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Publications

The Gut Microbiota Metabolite Succinate Promotes Adipose Tissue Browning in Crohn's Disease.

Monfort-Ferré Diandra D Caro Aleidis A Menacho Margarita M Martí Marc M Espina Beatriz B Boronat-Toscano Albert A Nuñez-Roa Cati C Seco Jesús J Bautista Michelle M Espín Eloy E Megía Ana A Vendrell Joan J Fernández-Veledo Sonia S Serena Carolina C

Journal of Crohn's & colitis 20221101 10

<h4>Background and aims</h4>Crohn's disease [CD] is associated with complex microbe-host interactions, involving changes in microbial communities, and gut barrier defects, leading to the translocation of microorganisms to surrounding adipose tissue [AT]. We evaluated the presence of beige AT depots in CD and questioned whether succinate and/or bacterial translocation promotes white-to-beige transition in adipocytes.<h4>Methods</h4>Visceral [VAT] and subcutaneous [SAT] AT biopsies, serum and plas ...[more]

PMID: 35554517

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RNA-seq of nonstenotic and stenotic areas of patients with Crohn’s disease

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Altered MHC class 1 DNA methylation of intestinal epithelial stem cells contributes to chronic inflammation in Crohn’s Disease

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

Project description: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.

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Microarray gene expression analysis of pinch biopsies from terminal ileum of patients with active and inactive Crohn’s disease and healthy controls

Project description:Biopsies from six individuals of each of the categories active CD (CDA), inactive CD (CD) and healthy controls (N) were analyzed for gene expression using microarray. The biopsies were obtained by ileo-colonoscopy and snap-frozen in nitrogen before RNA-isolation. A gastrointestinal pathologist classified the biopsies into normal, chronic active or chronic inactive inflammation based on Hematoxylin-Eosin stain of tissue sections from adjacent biopsies. Samples with discrepancy between endoscopic and histologic diagnoses were excluded from the final analysis, and uploaded with "NaN". The patients with chronic inactive inflammation all previously had verified CD of the terminal ileum. Patients coming to endoscopy for other reasons than IBD and with normal endoscopic and histological findings served as controls.

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UCP1-dependent depletion of liver extracellular succinate antagonizes inflammatory pathogenesis

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2022-02-17 | PXD024717 | Pride

DNA methylation and gene expression analyses in adipose tissue to identify new loci associated with T2D development in obesity

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Project description:An inverse correlation between countries endemic for helminth infestation and Crohn's disease (CD) incidences has been reinforced by anecdotal but successful cases of helminth therapy for CD. Recent studies have revealed that tuft cells in the small intestine are critical for sensing helminths and directing a type 2 immune response to counteract colonization. Here, we establish an inverse relationship between chemosensory tuft cells and local tissue inflammation in CD patients as well as an established mouse model of TNF-á-induced Crohn's-like ileitis (TNFÄARE). Using a combination of mouse and organoid models, single-cell RNA-sequencing, multiplex immunofluorescence, computational analysis, metabolite mass spectrometry, and microbiome sequencing and manipulation, we identified Atonal Homolog 1 (ATOH1)-independent tuft cells, as opposed to ATOH1-dependent tuft cells, to be responsive to the commensal microbiome through the tricarboxylic acid (TCA) cycle metabolite succinate. To evaluate the ability of the malleable, ATOH1-independent tuft cell population to suppress intestinal inflammation, we administered succinate to TNFÄARE animals post onset of ileal inflammatory disease. We observed significantly reduced pathology that is exquisitely dependent on succinate-induced tuft cell specification in the disease model, leading to an anti-helminth response previously shown to suppress inflammation. Inflammation suppression was triggered by cytokines critical to anti-helminthic response, such as IL-22, IL-25, and IL-13. We provide evidence implicating the modulatory role of intestinal tuft cells in chronic intestinal inflammation, which could enable the development of CD therapies around leveraging this rare and elusive cell type.

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