Site-specific programming of the host epithelial transcriptome by the gut microbiota

Abstract

BackgroundThe intestinal epithelium separates us from the microbiota but also interacts with it and thus affects host immune status and physiology. Previous studies investigated microbiota-induced responses in the gut using intact tissues or unfractionated epithelial cells, thereby limiting conclusions about regional differences in the epithelium. Here, we sought to investigate microbiota-induced transcriptional responses in specific fractions of intestinal epithelial cells. To this end, we used microarray analysis of laser capture microdissection (LCM)-harvested ileal and colonic tip and crypt epithelial fractions from germ-free and conventionally raised mice and from mice during the time course of colonization.ResultsWe found that about 10% of the host’s transcriptome was microbially regulated, mainly including genes annotated with functions in immunity, cell proliferation, and metabolism. The microbial impact on host gene expression was highly site specific, as epithelial responses to the microbiota differed between cell fractions. Specific transcriptional regulators were enriched in each fraction. In general, the gut microbiota induced a more rapid response in the colon than in the ileum.ConclusionsOur study indicates that the microbiota engage different regulatory networks to alter host gene expression in a particular niche. Understanding host-microbiota interactions on a cellular level may facilitate signaling pathways that contribute to health and disease and thus provide new therapeutic strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0614-4) contains supplementary material, which is available to authorized users.

Genetic Determinants of the Gut Microbiome in UK Twins

“…Akkermansia can cleave sialic acids: Its genome encodes four neuraminidase enzymes responsible for the removal of sialic acids from glycoconjugates (Huang et al, 2015). SIGLEC15 is expressed on macrophages and DCs in humans, and is reported to be expressed in ileum tips in mice (Sommer et al, 2015). Another gene reported by Sommer et al (2015) to be expressed at the villus tips of the small intestine, PLD1 , was linked genetically with Akkermansia in the Hutterites (Davenport et al, 2015).…”

“…SIGLEC15 is expressed on macrophages and DCs in humans, and is reported to be expressed in ileum tips in mice (Sommer et al, 2015). Another gene reported by Sommer et al (2015) to be expressed at the villus tips of the small intestine, PLD1 , was linked genetically with Akkermansia in the Hutterites (Davenport et al, 2015). Given that both studies associate Akkermansia with genes expressed in its physical niche space, an investigation of host genetic interaction with this important bacterium is warranted.…”

“…SLIT3 was reported as frequently methylated in colorectal cancers (Dickinson et al, 2004) has been shown to exhibit dysregulated exons in colorectal adenomas (Pesson et al, 2014). Notably, SLIT3 expression was shown to be upregulated in colon crypts when germfree mice are conventionalized (Sommer et al, 2015). Until these gene-microbe links are validated they are essentially hypothetical, however, it is interesting that the gene products are expressed in the gut epithelium.…”

How colonization by microbiota in early life shapes the immune system

“…In parallel, microbial derived factors such as acetate from Bifidobacterium longum can enhance protective functions of IECs in response to infection (61). Current studies also suggest that conventionalization of GF adult animals leads to substantial changes in gene expression associated with IECs (62). In future studies, it will be interesting to examine the age dependency of these effects and the manner in which they alter epithelial expression of factors well known to play an important role in epithelial cell–immune interactions such as IL-25, transforming growth factor–β (TGF-β), B cell activating factor (BAFF), a proliferator-inducing ligand (APRIL), and thymic stromal lymphopoietin (TSLP).…”

Gut microbiota in hypertension

“…The gut microbiota can regulate about 10% of the host’s transcriptome, especially those genes related to immunity, cell proliferation, and metabolism (49, 50). The gut microbiota may play a role in the development of cardiovascular disease, including arteriosclerosis and hypertension.…”