Summary of Study ST000338

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000270. The data can be accessed directly via it's Project DOI: 10.21228/M8W894 This work is supported by NIH grant, U2C- DK119886.

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Study IDST000338
Study TitleGut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease
Study SummaryTaxonomic alterations in the intestinal microbiota are being progressively associated with many diseases, including graft-versus host disease (GVHD). However, the impact of these alterations on microbial metabolites and by-products and their subsequent impact on disease processes, such as GVHD, are not known. Here we utilized a targetedn unbiased and blinded approach in a blinded fashion to identify novel alterations in the levels of microbial metabolites, specifically levels including the short chain fatty acid (SCFA) and endogenous histone deacetylase inhibitor (HDACi), butyrate, after allo-BMT. Surprisingly, alterations were observed only in intestinal epithelial cells (IECs) but not in the luminal contents. The reduced butyrate in IECs (CD326+) after allo-BMT resulted in decreased histone acetylation, which was restored upon local administration of exogenous butyrate. This resulted in improved IEC junctional integrity, increased anti-apoptotic proteins, decreased GVHD, and improved survival. Furthermore, alteration of endogenous microflora with 17 rationally selected strains of high butyrate producing Clostridia, also decreased GVHD and increased survival following allo-BMT in experiments performed at two different institutions. These data demonstrate an heretofore unrecognized role of microbial metabolites and suggests that local and specific alteration of microbial metabolites has direct salutary effects on GVHD target tissues and mitigates its severity.
Institute
University of Michigan
Last NameMathew
First NameAnna
Address6112 Brehm 1000 Wall Street
Emailamat@umich.edu
Phone7342328228
Submit Date2016-01-21
Raw Data File Type(s)d
Analysis Type DetailGC-MS
Release Date2016-06-18
Release Version1
Anna Mathew Anna Mathew
https://dx.doi.org/10.21228/M8W894
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000270
Project DOI:doi: 10.21228/M8W894
Project Title:Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease
Project Summary:Taxonomic alterations in the intestinal microbiota are being progressively associated with many diseases, including graft-versus host disease (GVHD). However, the impact of these alterations on microbial metabolites and by-products and their subsequent impact on disease processes, such as GVHD, are not known. Here we utilized a targetedn unbiased and blinded approach in a blinded fashion to identify novel alterations in the levels of microbial metabolites, specifically levels including the short chain fatty acid (SCFA) and endogenous histone deacetylase inhibitor (HDACi), butyrate, after allo-BMT. Surprisingly, alterations were observed only in intestinal epithelial cells (IECs) but not in the luminal contents. The reduced butyrate in IECs (CD326+) after allo-BMT resulted in decreased histone acetylation, which was restored upon local administration of exogenous butyrate. This resulted in improved IEC junctional integrity, increased anti-apoptotic proteins, decreased GVHD, and improved survival. Furthermore, alteration of endogenous microflora with 17 rationally selected strains of high butyrate producing Clostridia, also decreased GVHD and increased survival following allo-BMT in experiments performed at two different institutions. These data demonstrate an heretofore unrecognized role of microbial metabolites and suggests that local and specific alteration of microbial metabolites has direct salutary effects on GVHD target tissues and mitigates its severity.
Institute:University of Michigan
Last Name:Mathew
First Name:Anna
Address:6112 Brehm 1000 Wall Center
Email:amat@umich.edu
Phone:7342328228

Subject:

Subject ID:SU000358
Subject Type:Animal
Subject Species:Mus musculus
Taxonomy ID:10090
Species Group:Mammal

Factors:

Subject type: Animal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Site
SA015071Syngeneic 4IntestineIntestine
SA015072Syngeneic 5IntestineIntestine
SA015073Allogeneic 1IntestineIntestine
SA015074Allogeneic 4IntestineIntestine
SA015075Allogeneic 3IntestineIntestine
SA015076Syngeneic 3IntestineIntestine
SA015077Syngeneic 1IntestineIntestine
SA015078Naïve 2IntestineIntestine
SA015079Naïve 1IntestineIntestine
SA015080Naïve 3IntestineIntestine
SA015081Naïve 4IntestineIntestine
SA015082Naïve 5IntestineIntestine
SA015083Syngeneic 2IntestineIntestine
SA015084Allogeneic 2IntestineIntestine
SA015085Naïve 5LiverLiver
SA015086Allogeneic 4LiverLiver
SA015087Naïve 4LiverLiver
SA015088Naïve 3LiverLiver
SA015089Naïve 1LiverLiver
SA015090Naïve 2LiverLiver
SA015091Syngeneic 2LiverLiver
SA015092Syngeneic 1LiverLiver
SA015093Syngeneic 3LiverLiver
SA015094Allogeneic 3LiverLiver
SA015095Allogeneic 2LiverLiver
SA015096Allogeneic 1LiverLiver
SA015097Syngeneic 4LiverLiver
SA015098Syngeneic 5LiverLiver
SA015099Syngeneic 5SerumSerum
SA015100Allogeneic 1SerumSerum
SA015101Syngeneic 4SerumSerum
SA015102Allogeneic 4SerumSerum
SA015103Allogeneic 3SerumSerum
SA015104Allogeneic 2SerumSerum
SA015105Syngeneic 3SerumSerum
SA015106Naïve 2SerumSerum
SA015107Syngeneic 2SerumSerum
SA015108Naïve 3SerumSerum
SA015109Naïve 1SerumSerum
SA015110Syngeneic 1SerumSerum
SA015111Naïve 4SerumSerum
SA015112Syngeneic 1SpleenSpleen
SA015113Naïve 5SpleenSpleen
SA015114Naïve 2SpleenSpleen
SA015115Syngeneic 2SpleenSpleen
SA015116Naïve 1SpleenSpleen
SA015117Naïve 3SpleenSpleen
SA015118Naïve 4SpleenSpleen
SA015119Allogeneic 3SpleenSpleen
SA015120Syngeneic 3SpleenSpleen
SA015121Allogeneic 2SpleenSpleen
SA015122Allogeneic 4SpleenSpleen
SA015123Syngeneic 4SpleenSpleen
SA015124Syngeneic 5SpleenSpleen
SA015125Allogeneic 1SpleenSpleen
SA015126Syngeneic 5StoolStool
SA015127Allogeneic 2StoolStool
SA015128Allogeneic 1StoolStool
SA015129Allogeneic 3StoolStool
SA015130Syngeneic 4StoolStool
SA015131Allogeneic 4StoolStool
SA015132Naïve 4StoolStool
SA015133Naïve 2StoolStool
SA015134Naïve 1StoolStool
SA015135Naïve 3StoolStool
SA015136Syngeneic 1StoolStool
SA015137Syngeneic 2StoolStool
SA015138Syngeneic 3StoolStool
Showing results 1 to 68 of 68

Collection:

Collection ID:CO000352
Collection Summary:Female C57BL/6 (I-Ab; CD45.2+), BALB/c (H2d), and C3H.sw (H2b) mice were purchased from National Cancer Institute. The age of mice used for experiments ranged between 7 and 12 weeks.
Sample Type:Blood

Treatment:

Treatment ID:TR000372
Treatment Summary:BMTs were performed as previously described {Reddy:2005dc}{Reddy:2008kl}. Briefly, syngeneic (BALB/c ? BALC/b or C57BL/6 ? C57BL/6) and allogeneic (C57BL/6 ? BALB/c or C3H.sw ? C57BL/6) recipients received lethal irradiation. On day -1, BALB/c recipients received a total of 800 cGy of irradiation (split dose separated by 3 hours) and B6 animals received a single dose of 1000 cGy. Donor splenic CD90.2+ T cells were magnetically separated using an autoMACs (Miltenyi Biotec; Bergisch Gladbach, Germany) and 0.5 x 106 – 1 x 106 T cells were transferred to BALB/c recipients and 2 x 106 T cells were transferred to C57BL/6 recipients. 5 x 106 donor whole bone marrow was transferred to all recipients.

Sample Preparation:

Sampleprep ID:SP000365
Sampleprep Summary:To determine targeted fatty acid quantitation, samples (plasma, spleen, liver, intestine, and intestinal fecal content) from mice 7d and 21d post-transplant were harvested, homogenized, and snap-frozen in liquid N2. Homogenized tissues were normalized to their protein content, while 50µL of plasma was used per sample and Equal volumes of plasma and homogenized tissue were utilized, while50 mg fecal content was weighed at necropsy before extraction. Samples were dispersed in acidified water spiked with stable isotope-labeled SCFA standards and extracted with diethyl ether.

Combined analysis:

Analysis ID AN000549
Analysis type MS
Chromatography type GC
Chromatography system Agilent 6890N
Column Phenomenex ZB-WAX
MS Type EI
MS instrument type Single quadrupole
MS instrument name Agilent 5973
Ion Mode POSITIVE
Units mmol/mg

Chromatography:

Chromatography ID:CH000386
Instrument Name:Agilent 6890N
Column Name:Phenomenex ZB-WAX
Chromatography Type:GC

MS:

MS ID:MS000485
Analysis ID:AN000549
Instrument Name:Agilent 5973
Instrument Type:Single quadrupole
MS Type:EI
Ion Mode:POSITIVE
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