A Disease-Associated Microbial and Metabolomics State in Relatives of Pediatric Inflammatory Bowel Disease Patients.

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Abstract

Microbes may increase susceptibility to inflammatory bowel disease (IBD) by producing bioactive metabolites that affect immune activity and epithelial function. We undertook a family based study to identify microbial and metabolic features of IBD that may represent a predisease risk state when found in healthy first-degree relatives.

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Most cited references 20

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METLIN: a metabolite mass spectral database.

Colin A Smith, Grace O'Maille, Elizabeth J. Want … (2005)

Endogenous metabolites have gained increasing interest over the past 5 years largely for their implications in diagnostic and pharmaceutical biomarker discovery. METLIN (http://metlin.scripps.edu), a freely accessible web-based data repository, has been developed to assist in a broad array of metabolite research and to facilitate metabolite identification through mass analysis. METLINincludes an annotated list of known metabolite structural information that is easily cross-correlated with its catalogue of high-resolution Fourier transform mass spectrometry (FTMS) spectra, tandem mass spectrometry (MS/MS) spectra, and LC/MS data.

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Dirichlet Multinomial Mixtures: Generative Models for Microbial Metagenomics

Ian Holmes, Keith Harris, Christopher Quince (2012)

We introduce Dirichlet multinomial mixtures (DMM) for the probabilistic modelling of microbial metagenomics data. This data can be represented as a frequency matrix giving the number of times each taxa is observed in each sample. The samples have different size, and the matrix is sparse, as communities are diverse and skewed to rare taxa. Most methods used previously to classify or cluster samples have ignored these features. We describe each community by a vector of taxa probabilities. These vectors are generated from one of a finite number of Dirichlet mixture components each with different hyperparameters. Observed samples are generated through multinomial sampling. The mixture components cluster communities into distinct ‘metacommunities’, and, hence, determine envirotypes or enterotypes, groups of communities with a similar composition. The model can also deduce the impact of a treatment and be used for classification. We wrote software for the fitting of DMM models using the ‘evidence framework’ (http://code.google.com/p/microbedmm/). This includes the Laplace approximation of the model evidence. We applied the DMM model to human gut microbe genera frequencies from Obese and Lean twins. From the model evidence four clusters fit this data best. Two clusters were dominated by Bacteroides and were homogenous; two had a more variable community composition. We could not find a significant impact of body mass on community structure. However, Obese twins were more likely to derive from the high variance clusters. We propose that obesity is not associated with a distinct microbiota but increases the chance that an individual derives from a disturbed enterotype. This is an example of the ‘Anna Karenina principle (AKP)’ applied to microbial communities: disturbed states having many more configurations than undisturbed. We verify this by showing that in a study of inflammatory bowel disease (IBD) phenotypes, ileal Crohn's disease (ICD) is associated with a more variable community.

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Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases.

Henri Duboc, Sylvie Rajca, Dominique Rainteau … (2013)

Gut microbiota metabolises bile acids (BA). As dysbiosis has been reported in inflammatory bowel diseases (IBD), we aim to investigate the impact of IBD-associated dysbiosis on BA metabolism and its influence on the epithelial cell inflammation response. Faecal and serum BA rates, expressed as a proportion of total BA, were assessed by high-performance liquid chromatography tandem mass spectrometry in colonic IBD patients (42) and healthy subjects (29). The faecal microbiota composition was assessed by quantitative real-time PCR. Using BA profiles and microbiota composition, cluster formation between groups was generated by ranking models. The faecal BA profiles in germ-free and conventional mice were compared. Direct enzymatic activities of BA biotransformation were measured in faeces. The impact of BA on the inflammatory response was investigated in vitro using Caco-2 cells stimulated by IL-1β. IBD-associated dysbiosis was characterised by a decrease in the ratio between Faecalibacterium prausntizii and Escherichia coli. Faecal-conjugated BA rates were significantly higher in active IBD, whereas, secondary BA rates were significantly lower. Interestingly, active IBD patients exhibited higher levels of faecal 3-OH-sulphated BA. The deconjugation, transformation and desulphation activities of the microbiota were impaired in IBD patients. In vitro, secondary BA exerted anti-inflammatory effects, but sulphation of secondary BAs abolished their anti-inflammatory properties. Impaired microbiota enzymatic activity observed in IBD-associated dysbiosis leads to modifications in the luminal BA pool composition. Altered BA transformation in the gut lumen can erase the anti-inflammatory effects of some BA species on gut epithelial cells and could participate in the chronic inflammation loop of IBD.

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Author and article information

Journal

Journal ID (iso-abbrev): Cell Mol Gastroenterol Hepatol

Title: Cellular and molecular gastroenterology and hepatology

Publisher: Elsevier BV

ISSN: 2352-345X

ISSN (Print): 2352-345X

Publication date (Electronic): Nov 2016

Volume: 2

Issue: 6

Affiliations

[1 ] Division of Digestive Diseases, Department of Medicine, University of California Los Angeles, Los Angeles, California.

[2 ] Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, District of Columbia.

[3 ] Pediatric Gastroenterology and Inflammatory Bowel Disease, Cedars-Sinai Medical Center, Los Angeles, California.

[4 ] Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California.

[5 ] Department of Plant Pathology and Microbiology, University of California Riverside, Riverside, California.

[6 ] F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.

[7 ] Susan and Leonard Feinstein Inflammatory Bowel Disease Center, Department of Pediatrics, Icahn School of Medicine, Mount Sinai, New York.

Article

Publisher Item ID: S2352-345X(16)30074-1

DOI: 10.1016/j.jcmgh.2016.06.004

PMC ID: 5247316

PubMed ID: 28174747

SO-VID: 1454c424-54d6-418f-94a3-69aedcc27775

History

Keywords: rRNA, ribosomal RNA,Microbiome,UPLC, ultra-performance liquid chromatography,UC, ulcerative colitis,Metabolomics,AUC, area under the curve,LC/MS, liquid chromatography/mass spectrometry,ToFMS, time-of-flight mass spectrometry,OTU, operational taxonomic unit,PCoA, principal coordinates analysis,CD, Crohn’s disease,Family Cohort,PCR, polymerase chain reaction,IBD, inflammatory bowel disease,Inflammatory Bowel Disease

Data availability:

Keywords: rRNA, ribosomal RNA, Microbiome, UPLC, ultra-performance liquid chromatography, UC, ulcerative colitis, Metabolomics, AUC, area under the curve, LC/MS, liquid chromatography/mass spectrometry, ToFMS, time-of-flight mass spectrometry, OTU, operational taxonomic unit, PCoA, principal coordinates analysis, CD, Crohn’s disease, Family Cohort, PCR, polymerase chain reaction, IBD, inflammatory bowel disease, Inflammatory Bowel Disease

A Disease-Associated Microbial and Metabolomics State in Relatives of Pediatric Inflammatory Bowel Disease Patients.

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Abstract

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Most cited references 20

METLIN: a metabolite mass spectral database.

Dirichlet Multinomial Mixtures: Generative Models for Microbial Metagenomics

Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases.

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