Project description:Social behaviour is regulated by activity of host-associated microbiota across multiple species. However, the molecular mechanisms mediating this relationship remain elusive. We therefore determined the dynamic, stimulus-dependent transcriptional regulation of germ-free (GF) and GF mice colonised post weaning (exGF) in the amygdala, a brain region critically involved in regulating social interaction. In GF mice the dynamic response seen in controls was attenuated and replaced by a marked increase in expression of splicing factors and alternative exon usage in GF mice upon stimulation, which was even more pronounced in exGF mice. In conclusion, we demonstrate a molecular basis for how the host microbiome is crucial for a normal behavioural response during social interaction. Our data further suggest that social behaviour is correlated with the gene-expression response in the amygdala, established during neurodevelopment as a result of host-microbe interactions. Our findings may help toward understanding neurodevelopmental events leading to social behaviour dysregulation.
2018-05-23 | GSE114702 | GEO
Project description:Comparison of the skin microbiome of three non-cleaning gobies Coryphopterus and the cleaning goby Elacatinus evelynae
Project description:Microbes are fascinating molecular machines which can be equipped with synthetic genetic programs that allow them to produce therapeutic molecules targeted on demand upon disease sensing. Cutibacterium acnes engraftment capacity and its living habitat close to important pharmacological targets makes it an attractive chassis to create skin-delivered therapeutics. Here, we report the engineering of this bacterium, the most abundant commensal of the human skin, to produce and secrete the therapeutic molecule neutrophil gelatinase-associated lipocalin in vivo, known to modulate cutaneous sebum production.
Project description:The clinical importance of microbiomes to the chronicity of wounds is widely appreciated, yet little is understood about patient-specific processes shaping wound microbiome composition. Here, a two-cohort microbiome-genome wide association study is presented through which patient genomic loci associated with chronic wound microbiome diversity were identified. Further investigation revealed that alternative TLN2 and ZNF521 genotypes explained significant inter-patient variation in relative abundance of two key pathogens, Pseudomonas aeruginosa and Staphylococcus epidermidis. Wound diversity was lowest in Pseudomonas aeruginosa infected wounds, and decreasing wound diversity had a significant negative linear relationship with healing rate. In addition to microbiome characteristics, age, diabetic status, and genetic ancestry all significantly influenced healing. Using structural equation modeling to identify common variance among SNPs, six loci were sufficient to explain 53% of variation in wound microbiome diversity, which was a 10% increase over traditional multiple regression. Focusing on TLN2, genotype at rs8031916 explained expression differences of alternative transcripts that differ in inclusion of important focal adhesion binding domains. Such differences are hypothesized to relate to wound microbiomes and healing through effects on bacterial exploitation of focal adhesions and/or cellular migration. Related, other associated loci were functionally enriched, often with roles in cytoskeletal dynamics. This study, being the first to identify patient genetic determinants for wound microbiomes and healing, implicates genetic variation determining cellular adhesion phenotypes as important drivers of infection type. The identification of predictive biomarkers for chronic wound microbiomes may serve as risk factors and guide treatment by informing patient-specific tendencies of infection.
Project description:We developed an approach named Rapid Assay of Individual Microbiome (RapidAIM) to screen xenobiotics against individual microbiomes, and conducted a proof-of-concept (POC) study on the use of RapidAIM. We tested 43 compounds against five individual microbiomes. The individual microbiomes are cultured in 96-well plates for 24 hours and the samples are then analyzed using a metaproteomics-based analytical approach to gain functional insight into the individual microbiomes responses following drug treatments.The tested compounds significantly affected overall microbiome abundance, microbiome composition and functional pathways at multiple taxonomic levels. The microbiome responses to berberine, metformin, diclofenac, fructooligosaccharide and most antibiotics were consistent among most individual microbiomes. Interestingly, most of our tested NSAIDs, statins, and histamine-2 blockers induced individually distinct responses. Our workflow offers an effective solution to systematically study the effects of many different compounds on individual microbiomes.
Project description:Copy number variations (CNVs) of the human 16p11.2 locus are associated with several developmental/neurocognitive syndromes. Particularly, deletion and duplication of this genetic interval are found in patients with autism spectrum disorders, intellectual disability and other psychiatric traits. The high gene density associated with the region and the strong phenotypic variability of incomplete penetrance, make the study of the 16p11.2 syndromes extremely complex. To systematically study the effect of 16p11.2 CNVs and identify candidate genes and molecular mechanisms involved in the pathophysiology, mouse models were generated previously and showed learning and memory, and to some extent social deficits. To go further in understanding the social deficits caused by 16p11.2 syndromes, we engineered deletion and duplication of the homologous region to the human 16p11.2 genetic interval in two rat outbred strains, Sprague Dawley (SD) and Long Evans (LE). The 16p11.2 rat models displayed convergent defects in social behaviour and only a few cognitive defects. Interestingly major pathways affecting MAPK3 and CUL3 were found altered in the rat 16p11.2 models with additional changes in males compared to females. Altogether, the consequences of the 16p11.2 genetic region dosage on social behaviour are now found in three different species: humans, mice and rats. In addition, the rat models pointed to sexual dimorphism, with lower severity of phenotypes in rat females compared to male mutants. This phenomenon is also observed in humans. We are convinced that the two rat models will be key to further investigating social behaviour and understanding the brain mechanisms and specific brain regions that are key to controlling social behaviour.
Project description:Copy number variations (CNVs) of the human 16p11.2 locus are associated with several developmental/neurocognitive syndromes. Particularly, deletion and duplication of this genetic interval are found in patients with autism spectrum disorders, intellectual disability and other psychiatric traits. The high gene density associated with the region and the strong phenotypic variability of incomplete penetrance, make the study of the 16p11.2 syndromes extremely complex. To systematically study the effect of 16p11.2 CNVs and identify candidate genes and molecular mechanisms involved in the pathophysiology, mouse models were generated previously and showed learning and memory, and to some extent social deficits. To go further in understanding the social deficits caused by 16p11.2 syndromes, we engineered deletion and duplication of the homologous region to the human 16p11.2 genetic interval in two rat outbred strains, Sprague Dawley (SD) and Long Evans (LE). The 16p11.2 rat models displayed convergent defects in social behaviour and only a few cognitive defects. Interestingly major pathways affecting MAPK3 and CUL3 were found altered in the rat 16p11.2 models with additional changes in males compared to females. Altogether, the consequences of the 16p11.2 genetic region dosage on social behaviour are now found in three different species: humans, mice and rats. In addition, the rat models pointed to sexual dimorphism, with lower severity of phenotypes in rat females compared to male mutants. This phenomenon is also observed in humans. We are convinced that the two rat models will be key to further investigating social behaviour and understanding the brain mechanisms and specific brain regions that are key to controlling social behaviour.