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Post-transcriptional regulation by the gut microbiota decoded by nanopore direct RNA sequencing

ABSTRACT: It has been widely recognized that the microbiota has the capacity to shape host gene expression and physiological functions. However, there remains a paucity of comprehensive study revealing host transcriptional landscape regulated by the microbiota. Here, we comprehensively examined mRNA landscapes in mouse tissues (brain and cecum) from specific pathogen free (SPF) and germ-free mouse (GF) using Nanopore direct RNA sequencing. Our results show that the microbiome has global influence on host’s RNA modifications (m6A, m5C, Ψ), isoform generation, poly(A) tail length (PAL), and transcript abundance in both brain and cecum tissues. Moreover, the microbiome exerts tissue-specific effects on various post-transcriptional regulatory processes. In addition, the microbiome impacts the coordination of multiple RNA modifications in host brain and cecum tissues. In conclusion, we establish the relationship between microbial regulation and gene expression, our results help the understanding of the mechanisms by which the microbiome reprograms host gene expression.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE261301 | GEO | 2024/09/11

REPOSITORIES: GEO

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Project description:The preferential localization of some neoplasms, such as serrated polyps, in specific areas of the intestine suggests that non-genetic factors may be important for their development. To test this hypothesis, we took advantage of transgenic mice that expressed HB-EGF throughout the intestine, but develop serrated polyps only in the cecum. Here we show that a host-specific microbiome was associated with serrated polyps, and that alterations of the microbiota induced by antibiotic treatment or by embryo-transfer rederivation markedly inhibited the formation of serrated polyps in the cecum. Mechanistically, development of serrated polyps was associated with a local decrease in epithelial barrier-function, bacterial invasion, production of antimicrobials, and increased expression of several inflammatory factors such as IL-17, Cxcl2, Tnf-Œ±, and IL-1. Increased number of neutrophils were found within the serrated polyps, and their depletion significantly reduced polyp growth. Together these results indicate that non-genetic factors contribute to the development of serrated polyps and suggest that the development of these intestinal neoplasms in the cecum is driven by the interplay between genetic changes in the host, an inflammatory response, and a host-specific microbiota. SUMMARY: Serrated polyps (SP) are a heterogeneous group of neoplasms found in particular areas of the gut. To define the factors contributing to their specific localization, we analyzed a strain of transgenic mice that carry a genetic alteration throughout the intestinal epithelium, but only develop SP in the cecum. Transcriptome and immunostaining analyses showed increased expression of antimicrobial genes, inflammatory factors, and the presence of bacteria within SP. Alteration of the cecal microbiota by antibiotic treatment or by embryo-transfer rederivation dramatically reduced SP incidence. Microbiome analysis implicated a limited set of bacteria in the development of SP. Together, these results point to a crucial role for the microbiota in the localized development of SP in a genetically susceptible host. We obtained serrated polyp (SP) and surrounding normal (NM) tissue from the ceca of three affected mice (paired design) and assessed expression differences by RNA-Seq.

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Post-transcriptional regulation by the gut microbiota decoded by nanopore direct RNA sequencing

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