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. 2016 Nov 23:7:13419.
doi: 10.1038/ncomms13419.

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

Walid Mottawea  1   2   3 , Cheng-Kang Chiang  1   2 , Marcus Mühlbauer  4 , Amanda E Starr  1   2 , James Butcher  1   2 , Turki Abujamel  1   2 , Shelley A Deeke  1   2 , Annette Brandel  1   2 , Hu Zhou  2   5 , Shadi Shokralla  6 , Mehrdad Hajibabaei  6 , Ruth Singleton  7 , Eric I Benchimol  7   8   9 , Christian Jobin  10 , David R Mack  7   8 , Daniel Figeys  1   2   11 , Alain Stintzi  1   2
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Altered intestinal microbiota-host mitochondria crosstalk in new onset Crohn's disease

Walid Mottawea et al. Nat Commun. .

"VSports" 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. 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, mitochondrial proteins implicated in H2S detoxification are downregulated, while the relative abundance of H2S microbial producers is increased. Network correlation analysis reveals that Atopobium parvulum controls the central hub of H2S producers. A. parvulum induces pancolitis in colitis-susceptible interleukin-10-deficient mice and this phenotype requires the presence of the intestinal microbiota. Administrating the H2S scavenger bismuth mitigates A. parvulum-induced colitis in vivo. This study reveals that host-microbiota interactions are disturbed in CD and thus provides mechanistic insights into CD pathogenesis VSports手机版. .

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Conflict of interest statement

A. S. , D. M. , D. F. , W. M. , T. A. and C. -K. C. have a corresponding patent application ‘Methods for the diagnosis and treatment of inflammatory bowel disease' filed in 2014 (WO/2014/138999). A. S. , D. M. and D V体育安卓版. F. have co-founded Biotagenics, a clinical microbiomics company. The remaining authors declare no competing financial interests.

"VSports app下载" Figures

Figure 1
Figure 1. Assessment of the microbiota composition at the mucosa-luminal interface of new-onset paediatric IBD.
(a) Diversity of the intestinal microbiota in control and CD paediatric patients as a function of disease severity. Shannon index was calculated using 500,000 reads per sample. Crosses indicate the mean while horizontal lines indicate the median. (b) Histogram of linear discriminant analysis (LDA) effect size score for CD differentially abundant taxa compared with controls (n=65 and 42 for CD and controls, respectively); only OTUs meeting an LDA significant threshold ≥2 with a P<0.05 (pairwise Wilcoxon test) are shown and are denoted with their lowest defined taxonomy. (c) Phylogenetic tree of the differentially abundant OTUs identified by metagenomeSeq analysis (fold change ≥2 and P<0.05); an increasing red intensity indicates OTUs whose relative abundance increased, whereas an increasing blue intensity indicates OTUs whose relative abundance decreased in CD patients with severe inflammation as compared with mild (outer circle) or severe as compared with moderate (inner circle); the maximum colour output for this figure was set at a Log2 value of ±3. (d) The qPCR quantification of butyrate producing bacteria in control and CD microbiota. Butyryl-CoA: acetyl-CoA transferase gene (BCoAT); n=20 and 34 for control and CD, respectively; statistical comparison by Mann–Whitney two-tailed test; **P<0.01). (e) Log2 sum of rarefied reads assigned to taxa known to produce H2S through amino acid fermentation were plotted for the control and as a function of CD severity (n=39, 11, 11, 43 for control subjects and mild, moderate and severe CD, respectively). (f) The qPCR quantification of sulfate reducing bacteria in control and CD patient microbiota as a function of disease severity. Dissimilatory sulfide reductase gene (DSR); n=16, 9, 9 and 8 for control, mild, moderate and severe CD, respectively). (a,e,f) Statistical comparison by Kruskal–Wallis test using Dunn's post hoc test and followed by a Bonferroni correction for the significance level; *P<0.05; **P<0.01. Crosses indicate the mean while horizontal lines indicate the median.
Figure 2
Figure 2. Enrichment of A. parvulum and altered mitochondrial proteome define the severity of Crohn's disease.
(a) Interaction network of differentially abundant OTUs; each node represents an OTU and are sized according to their number of interactions; each edge denotes a significant co-exclusion (red) or co-occurence (grey) relationship between OTUs. Nodes are coloured by their number of significant co-exclusions. (b) The qPCR quantification of A. parvulum in control and CD microbiota as a function of disease severity. ΔCt was calculated by subtracting average Ct values of universal 16S rDNA from average Ct values of A. parvulum specific primers (n=18 for controls, nine for mild CD and seven for moderate and severe CD). **P<0.01 estimated using Kruskal–Wallis followed by Dunn's post hoc test. Crosses indicate the mean while horizontal lines indicate the median. (c) Principal component analysis of the differentially expressed proteins among controls and CD patients categorized as a function of disease severity. (d) Functional annotation (cellular component) analysis of the differentially expressed proteins; the 10 most significantly enriched functional groups (GO terms) are shown (Fisher's exact test P<10−13). The illustrated P values are for classifications that were significantly enriched compared to the whole proteomic data set.
Figure 3
Figure 3. Microbiota–mitochondria correlation analysis.
Clustered heatmap of Spearman–Kendall correlation analysis between differentially abundant OTUs and mitochondrial proteins; red and blue colours indicate a positive or negative Spearman correlation respectively (P value <0.05 for both the Kendall Tau and the Spearman's rank statistics was used to define significance denoted by ‘+'). Note: only OTUs and mitochondrial proteins with at least one significant correlation are shown. Whether the OTU was increased or decreased in mild versus severe CD patients is denoted on the bar to the left of the OTU name (blue decreased, red increased).
Figure 4
Figure 4. Atopobium parvulum induces rapid and severe pan-colitis in Il10−/− mice.
(a) Representative histological sections of the cecum and colon of Il10−/− mice under specific pathogen free (SPF) conditions that were either associated with (+) or without (−) A. parvulum. (b) Blinded histological score of inflammation (n=6 to 7 per group; crosses indicate the mean while horizontal lines indicate the median; comparison by Mann–Whitney two-tailed test; *P<0.05). (c) Macroscopic monitoring of inflammation with a murine endoscope (data is representative of two animals). (d) Representative histological sections of the distal colon of germ-free (GF) Il10−/− mice mono-associated with or without A. parvulum.
Figure 5
Figure 5. Induction of A. parvulum-associated colitis requires the gut microbiota and hydrogen sulfide.
(a) Representative histological Swiss-rolled sections of the colon of Il10−/− mice associated (+) or not associated (−) with A. parvulum, treated (+) or not treated (−) with bismuth and kept under specific pathogen free (SPF) conditions for 14 weeks. (b) Representative murine endoscopies of SPF Il10−/− mice associated (+) or not-associated (−) with A. parvulum, treated (+) or not-treated (−) with bismuth. (c) Blinded inflammation scores (n=7 to 8 per group) for Il10−/− mice under SPF conditions; crosses indicate the mean while horizontal lines indicate the median; two-tailed Mann–Whitney test was used for statistical comparison; *P<0.05, ***P<0.001.
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