Project description:Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation in gut microbial metagenome and host genome but they could not adequately represent the protein-level variants. Single amino-acid polymorphisms (SAP) derived from non-synonymous SNPs can cause functional changes of proteins and are important forces of adaption. However, SAP remain quite unexplored for human gut microbiome. Here, we present a comprehensive large-scale analysis of SAP in the gut ecosystem, introducing a rigorous computational pipeline for detecting such protein variation from 992 published human metaproteomes.
Project description:The gut-brain axis allows gut microbes to influence host social behavior, yet the specific role of microbial genetic variation in this process and its potential transgenerational effects remains poorly understood. Using C. elegans as a model, we identified 77 E. coli strains among 3,983 mutants that markedly enhanced C. elegans aggregation behavior. Our findings reveal that mutant bacteria modulate C. elegans social behavior through distinct neurobehavioral pathways, demonstrating a synergistic regulatory mechanism between microbial genetics and host heredity. Mechanistically, ycgJ mutant bacteria were found to impact C. elegans social behavior via the mitochondrial pathway. Additionally, even F2 offspring of parent C. elegans exposed to these mutant bacteria exhibited enhanced social behavior within their populations. These insights underscore the significance of investigating microbial genetic variation in relation to host behavior, particularly for the development of genetically engineered probiotics, aimed at promoting well-being across generations.
Project description:Here we use appropriate taxon-specific models along with support from independent cohorts to show association between human host genotype and gut microbiome variation. Using fecal derived 16S rRNA gene sequences and host genotype data from the Flemish Gut Flora Project (FGFP) we identify genetic associations involving multiple microbial traits. Mendelian randomization analysis was able to estimate associations between microbial traits and disease, however in the absence of clear microbiome driven effects, caution is needed in interpretation. This work marks a growing catalog of genetic associations which will provide insight into the contribution of host genotype to gut microbiome. Despite this, the uncertain origin of association signals will likely complicate future work looking to dissect function or use associations for causal inference analysis.
Project description:The gut microbiota impacts many aspects of host biology including immune function. One hypothesis is that microbial communities induce epigenetic changes with accompanying alterations in chromatin accessibility, providing a mechanism that allows a community to have sustained host effects even in the face of its structural or functional variation. We used ATAC-seq to define chromatin accessibility in predicted enhancer regions of intestinal αβ+ and γδ+ intraepithelial lymphocytes (IELs) purified from germ-free mice, their conventionally-raised (CONV-R) counterparts, and mice reared GF and then colonized with a CONV-R gut microbiota at the end of the suckling-weaning transition. Characterizing genes adjacent to traditional enhancers and super-enhancers revealed signaling networks, metabolic pathways, and enhancer-associated transcription factors affected by the microbiota. Our results support the notion that epigenetic modifications help define microbial community-affiliated functional features of host immune cell lineages.
Project description:The gut microbiome is significantly altered in inflammatory bowel diseases, but the basis of these changes is not well understood. We have combined metagenomic and metatranscriptomic profiling of the gut microbiome to assess changes to both bacterial community structure and transcriptional activity in a mouse model of colitis. Gene families involved in microbial resistance to oxidative stress, including Dps/ferritin, Fe-dependent peroxidase and glutathione S-transferase, were transcriptionally up-regulated in colitis, implicating a role for increased oxygen tension in gut microbiota modulation. Transcriptional profiling of the host gut tissue and host RNA in the gut lumen revealed a marked increase in the transcription of genes with an activated macrophage and granulocyte signature, suggesting the involvement of these cell types in influencing microbial gene expression. Down-regulation of host glycosylation genes further supports a role for inflammation-driven changes to the gut niche that may impact the microbiome. We propose that members of the bacterial community react to inflammation-associated increased oxygen tension by inducing genes involved in oxidative stress resistance. Furthermore, correlated transcriptional responses between host glycosylation and bacterial glycan utilisation support a role for altered usage of host-derived carbohydrates in colitis. Complementary transcription profiling data from the mouse hosts have also been deposited at ArrayExpress under accession number E-MTAB-3590 ( http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-3590/ ).
Project description:The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease pathogenesis has been difficult due to the apparent disconnect between animal and human studies and a lack of an integrated multi-omics view in the context of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases.
Project description:Microbial genome-wide association studies (GWAS) have uncovered numerous host genetic variants associated with gut microbiota. However, links between host genetics, the gut microbiome and specific cellular context remains unclear. Here, we use a computational framework, scBPS (single-cell Bacteria Polygenic Score), to integrate existing microbial GWAS and single-cell RNA-sequencing profiles of 24 human organs, including the liver, pancreas, lung, and intestine, to identify host tissues and cell types relevant to gut microbes. Analyzing 207 microbial taxa and 254 host cell types, scBPS-inferred cellular enrichments confirmed known biology such as dominant communications between gut microbes and the digestive tissue module and liver epithelial cell compartment. scBPS also identified a robust association between Collinsella and central-veinal hepatocyte subpopulation. We experimentally validated the causal effects of Collinsella on cholesterol metabolism in mice through single-nuclei RNA sequencing on liver tissue to identify relevant cell subpopulations. Mechanistically, oral gavage of Collinsella modulated cholesterol pathway gene expression in central-veinal hepatocytes. We further validated our approach using independent microbial GWAS data, alongside single-cell and bulk transcriptomic analyses, demonstrating its robustness and reproducibility. Together, scBPS enables a systematic mapping of the host-microbe crosstalk by linking cell populations to their interacting gut microbes.