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Comparative Study
. 2012 Aug;61(8):1124-31.
doi: 10.1136/gutjnl-2011-301104. Epub 2011 Nov 23.

Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88

Erik Larsson  1 , Valentina Tremaroli, Ying Shiuan Lee, Omry Koren, Intawat Nookaew, Ashwana Fricker, Jens Nielsen, Ruth E Ley, Fredrik Bäckhed
Affiliations
Comparative Study

Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88

Erik Larsson et al. Gut. 2012 Aug.

Abstract

Background: The gut microbiota has profound effects on host physiology but local host-microbial interactions in the gut are only poorly characterised and are likely to vary from the sparsely colonised duodenum to the densely colonised colon VSports手机版. Microorganisms are recognised by pattern recognition receptors such as Toll-like receptors, which signal through the adaptor molecule MyD88. .

Methods: To identify host responses induced by gut microbiota along the length of the gut and whether these required MyD88, transcriptional profiles of duodenum, jejunum, ileum and colon were compared from germ-free and conventionally raised wild-type and Myd88-/- mice. The gut microbial ecology was assessed by 454-based pyrosequencing and viruses were analysed by PCR. V体育安卓版.

Results: The gut microbiota modulated the expression of a large set of genes in the small intestine and fewer genes in the colon but surprisingly few microbiota-regulated genes required MyD88 signalling. However, MyD88 was essential for microbiota-induced colonic expression of the antimicrobial genes Reg3β and Reg3γ in the epithelium, and Myd88 deficiency was associated with both a shift in bacterial diversity and a greater proportion of segmented filamentous bacteria in the small intestine. In addition, conventionally raised Myd88-/- mice had increased expression of antiviral genes in the colon, which correlated with norovirus infection in the colonic epithelium V体育ios版. .

Conclusion: This study provides a detailed description of tissue-specific host transcriptional responses to the normal gut microbiota along the length of the gut and demonstrates that the absence of MyD88 alters gut microbial ecology. VSports最新版本.

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Conflict of interest statement

Competing interests: None.

Figures

Figure 1
Figure 1
Transcriptional profiling of intestinal tissue samples from germ-free (GF) and conventionally raised (CONV-R) mice. (A) Hierachical clustering dendrogram of whole-transcriptome expression profiles obtained using DNA microarrays. (B) Principal component analysis of transcription profiles performed separately on each tissue. PC1, principal component 1; PC2, principal component 2. (C) All genes were evaluated by two-way analysis of variance for differential expression in germ-free versus conventionally raised mice (blue), Myd88−/− versus wild-type (green), as well as interaction between these two factors to reveal microbial responses that were modulated by Myd88 genotype (red). Quantile–quantile plots illustrate expected versus observed distributions of p values obtained in these tests. Dotted lines show the expected distribution under the null hypothesis (no genes regulated). Strong deviations from this line indicate large effects on the transcriptome. (D) Venn diagram showing the number of differentially expressed genes (at 5% false discovery rate) between germ-free and conventionally raised mice in blue, Myd88−/− and wild-type mice in green, and genes that are regulated by the microbiota in a MyD88-dependent fashion (interaction) in red. (E) Enriched gene categories among regulated genes. The heat map indicates the level of statistical enrichment (Fisher's exact test) for select gene ontology (GO) categories among the 500 most significantly regulated genes. Representative GO terms were selected from the complete list of significant (p<10−4, see Methods section) categories (see supplementary table S2, available online only). The arrows indicate, in cases in which the enrichment is p<0.01, the proportion of genes (among top 500) in each category that are up or downregulated. Arrows are not shown for the interaction test as these per definition respond differentially depending on genotype. n=4–6 mice per group, but note that due to poor RNA quality of two duodenal samples from wild-type germ-free mice we only included two samples in the analyses.
Figure 2
Figure 2
Relative expression levels of antiviral genes in the colon of germ-free (GF) and conventionally raised (CONV-R) wild-type (WT) and Myd88−/− mice. Data are from the microarray experiment and were corroborated by quantitated reverse transcription PCR in supplementary figure S2 available online only. n=4–6 per group. *p<0.05, **p<0.01, ***p<0.001; analysis of variance.
Figure 3
Figure 3
Effect of host genotype on the microbiota composition along the length of the gut from conventionally raised wild-type and Myd88−/− mice. (A) Relative abundance of segmented filamentous bacteria (SFB) in the two genotypes (Myd88+/+ or −/−) along the length of the gut. ***p<0.001; two-tailed Student's t test with Bonferroni correction for multiple comparisons. (B) Principal coordinates analysis of unweighted UniFrac distances between bacterial communities determined from 16S rRNA genes. Percentage variation explained by each principal coordinate (PC) is indicated on the axis. Symbols repesent individual intestinal segments obtained from replicate mice: duodenum, first three segments; jejunum, segments 4–5; ileum, segments 6–8; cecum, 9; large intestine, 10–12. n=4–7 mice per group. Low sequence counts were obtained for some samples, which were removed from further analysis.
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