Intestinal microRNAs and bacterial taxa in juvenile mice are associated, modifiable by allochthonous lactobacilli, and affect postnatal maturation

ABSTRACT The interplay between the intestinal microbiota and host is critical to intestinal ontogeny and homeostasis. MicroRNAs (miRNAs) may be an underlying link. Intestinal miRNAs are microbiota-dependent and, when shed in the lumen, affect resident microorganisms. Yet, longitudinal relationships between intestinal tissue miRNAs, luminal miRNAs, and luminal microorganisms have not been elucidated, especially in early life. Here, we investigated the postnatal cecal miRNA and microbiota populations, their relationship, and their impact on intestinal maturation in specific pathogen-free mice; we also assessed if they can be modified by intervention with allochthonous probiotic lactobacilli. We report that cecal and cecal content miRNA and microbiota signatures are temporally regulated, correlated, and modifiable by probiotics with implications for intestinal maturation. These findings help understand causal relationships within the gut ecosystem and provide a basis for preventing and managing their alterations in diseases throughout life. IMPORTANCE The gut microbiota affects intestinal microRNA (miRNA) signatures and is modified by host-derived luminal miRNA. This suggests the existence of close miRNA-microbiota relationships that are critical to intestinal homeostasis. However, an integrative analysis of these relationships and their evolution during intestinal postnatal maturation is lacking. We provide a system-level longitudinal analysis of miRNA-microbiota networks in the intestine of mice at the weaning transition, including tissue and luminal miRNA and luminal microbiota. To address causality and move toward translational applications, we used allochthonous probiotic lactobacilli to modify these longitudinal relationships and showed that they are critical for intestinal maturation in early life. These findings contribute to understand mechanisms that underlie the maturation of the intestinal ecosystem and suggest that interventions aiming at maintaining, or restoring, homeostasis cannot prescind from considering relationships among its components. The gut microbiota affects intestinal microRNA (miRNA) signatures and is modified by host-derived luminal miRNA. This suggests the existence of close miRNA-microbiota relationships that are critical to intestinal homeostasis. However, an integrative analysis of these relationships and their evolution during intestinal postnatal maturation is lacking. We provide a system-level longitudinal analysis of miRNA-microbiota networks in the intestine of mice at the weaning transition, including tissue and luminal miRNA and luminal microbiota. To address causality and move toward translational applications, we used allochthonous probiotic lactobacilli to modify these longitudinal relationships and showed that they are critical for intestinal maturation in early life. These findings contribute to understand mechanisms that underlie the maturation of the intestinal ecosystem and suggest that interventions aiming at maintaining, or restoring, homeostasis cannot prescind from considering relationships among its components.

[1]  Bo Li,et al.  Human milk oligosaccharides protect against necrotizing enterocolitis by activating intestinal cell differentiation. , 2020, Molecular nutrition & food research.

[2]  H. Weiner,et al.  Oral Administration of miR-30d from Feces of MS Patients Suppresses MS-like Symptoms in Mice by Expanding Akkermansia muciniphila. , 2019, Cell host & microbe.

[3]  T. Yau,et al.  Faecal microRNAs as a non-invasive tool in the diagnosis of colonic adenomas and colorectal cancer: A meta-analysis , 2019, Scientific Reports.

[4]  R. Goldberg,et al.  Disrupted Maturation of the Microbiota and Metabolome among Extremely Preterm Infants with Postnatal Growth Failure , 2019, Scientific Reports.

[5]  M. Bellini,et al.  Fecal Clostridiales distribution and short‐chain fatty acids reflect bowel habits in irritable bowel syndrome , 2018, Environmental microbiology.

[6]  M. Nickerson,et al.  Pea-protein alginate encapsulation adversely affects development of clinical signs of Citrobacter rodentium-induced colitis in mice treated with probiotics. , 2018, Canadian journal of microbiology.

[7]  Thomas Lengauer,et al.  Exposure to the gut microbiota drives distinct methylome and transcriptome changes in intestinal epithelial cells during postnatal development , 2018, Genome Medicine.

[8]  K. Barrett,et al.  Modulation of the microbiota-gut-brain axis by probiotics in a murine model of inflammatory bowel disease. , 2016, American journal of physiology. Gastrointestinal and liver physiology.

[9]  A. Mercenier,et al.  Live and heat-treated probiotics differently modulate IL10 mRNA stabilization and microRNA expression. , 2016, The Journal of allergy and clinical immunology.

[10]  H. Weiner,et al.  The Host Shapes the Gut Microbiota via Fecal MicroRNA. , 2016, Cell host & microbe.

[11]  É. Yergeau,et al.  Transplanting Soil Microbiomes Leads to Lasting Effects on Willow Growth, but not on the Rhizosphere Microbiome , 2015, Front. Microbiol..

[12]  S. Tringe,et al.  Primer and platform effects on 16S rRNA tag sequencing , 2015, Front. Microbiol..

[13]  H. Dweep,et al.  miRWalk2.0: a comprehensive atlas of microRNA-target interactions , 2015, Nature Methods.

[14]  J. Gerber,et al.  Antibiotics, pediatric dysbiosis, and disease. , 2015, Cell host & microbe.

[15]  Jaak Vilo,et al.  ClustVis: a web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap , 2015, Nucleic Acids Res..

[16]  C. McClain,et al.  Inhibition of miR122a by Lactobacillus rhamnosus GG Culture Supernatant Increases Intestinal Occludin Expression and Protects Mice from Alcoholic Liver Disease , 2015, Toxicology letters.

[17]  I. Nookaew,et al.  Site-specific programming of the host epithelial transcriptome by the gut microbiota , 2015, Genome Biology.

[18]  H. Ibelings …Toronto , 2014, Architectural Research Quarterly.

[19]  Glenn R. Gibson,et al.  The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic , 2014 .

[20]  Qunyuan Zhang,et al.  Persistent Gut Microbiota Immaturity in Malnourished Bangladeshi Children , 2014, Nature.

[21]  P. Stothard,et al.  Potential Regulatory Role of MicroRNAs in the Development of Bovine Gastrointestinal Tract during Early Life , 2014, PloS one.

[22]  E. Comelli,et al.  Impact of Bifidobacterium bifidum MIMBb75 on mouse intestinal microorganisms. , 2013, FEMS microbiology ecology.

[23]  J. Doré,et al.  The gut microbiota elicits a profound metabolic reorientation in the mouse jejunal mucosa during conventionalisation , 2012, Gut.

[24]  I. Elmadfa,et al.  Regulation of TLR4, p38 MAPkinase, IκB and miRNAs by inactivated strains of lactobacilli in human dendritic cells. , 2012, Beneficial microbes.

[25]  J. Doré,et al.  Temporal and spatial interplay of microbiota and intestinal mucosa drive establishment of immune homeostasis in conventionalized mice , 2012, Mucosal Immunology.

[26]  Guangchuang Yu,et al.  clusterProfiler: an R package for comparing biological themes among gene clusters. , 2012, Omics : a journal of integrative biology.

[27]  Paul C. Boutros,et al.  NanoStringNorm: an extensible R package for the pre-processing of NanoString mRNA and miRNA data , 2012, Bioinform..

[28]  L. Waldron,et al.  The Murine Caecal MicroRNA Signature Depends on the Presence of the Endogenous Microbiota , 2011, International journal of biological sciences.

[29]  T. Tompkins,et al.  A comprehensive post-market review of studies on a probiotic product containing Lactobacillus helveticus R0052 and Lactobacillus rhamnosus R0011. , 2011, Beneficial microbes.

[30]  Norbert Gretz,et al.  miRWalk - Database: Prediction of possible miRNA binding sites by "walking" the genes of three genomes , 2011, J. Biomed. Informatics.

[31]  C. Huttenhower,et al.  Metagenomic biomarker discovery and explanation , 2011, Genome Biology.

[32]  G. Dalmasso,et al.  Microbiota Modulate Host Gene Expression via MicroRNAs , 2011, PloS one.

[33]  Anders F. Andersson,et al.  Transitions in bacterial communities along the 2000 km salinity gradient of the Baltic Sea , 2011, The ISME Journal.

[34]  H. Baba,et al.  MicroRNA Expression Profiling of Exfoliated Colonocytes Isolated from Feces for Colorectal Cancer Screening , 2010, Cancer Prevention Research.

[35]  I. Cuthill,et al.  Animal Research: Reporting In Vivo Experiments: The ARRIVE Guidelines , 2010, British journal of pharmacology.

[36]  C. Kilkenny,et al.  Guidelines for reporting experiments involving animals: the ARRIVE guidelines , 2010, British journal of pharmacology.

[37]  B. Lönnerdal,et al.  miR-584 mediates post-transcriptional expression of lactoferrin receptor in Caco-2 cells and in mouse small intestine during the perinatal period. , 2010, International Journal of Biochemistry and Cell Biology.

[38]  William A. Walters,et al.  QIIME allows analysis of high-throughput community sequencing data , 2010, Nature Methods.

[39]  Igor Jurisica,et al.  NAViGaTOR: Network Analysis, Visualization and Graphing Toronto , 2009, Bioinform..

[40]  J. Doré,et al.  Comparative assessment of human and farm animal faecal microbiota using real-time quantitative PCR. , 2009, FEMS microbiology ecology.

[41]  Jennifer L. Osborn,et al.  Direct multiplexed measurement of gene expression with color-coded probe pairs , 2008, Nature Biotechnology.

[42]  J. Tiedje,et al.  Naïve Bayesian Classifier for Rapid Assignment of rRNA Sequences into the New Bacterial Taxonomy , 2007, Applied and Environmental Microbiology.

[43]  L. Hooper,et al.  Bacterial contributions to mammalian gut development. , 2004, Trends in microbiology.

[44]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[45]  J. Gilbert,et al.  Introducing the Microbiome into Precision Medicine. , 2017, Trends in pharmacological sciences.

[46]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .