The gut microbiota plays a pivotal role in modulating the immune system, fostering immune tolerance, and defending against pathogens. Among its bioactive products, microbiota-derived peptides hold therapeutic promise for inflammatory diseases. In this study, we present EB1010, a 28-residue peptide derived from an unknown protein of a Christensenellaceae bacterium, as potential treatment of ulcerative colitis (UC). EB1010 exhibit strong anti-inflammatory effects in vitro by reducing proinflammatory mediator secretion and inhibiting NF-κB signaling in immune cells. Ex vivo human intestinal model confirmed its ability to promote mucosal healing, while in vivo studies demonstrated that oral administration effectively reversed inflammation in both trinitrobenzene sulfonic acid- (TNBS)-induced rat and DSS-induced mouse models of colitis. Caco-2 transport assays revealed minimal peptide permeability, consistent with pharmacokinetic (PK) data showing no plasma detection in orally treated rats, supporting a local intestinal mode of action. EB1010 was well tolerated in a 4-week rat toxicology study, with no adverse effect observed at doses up to 1.5 mg/kg/d by intravenous administration. These findings position EB1010 as a safe, locally acting, microbiota-derived peptide with potential therapeutic applications.

Background:Advancing research in oncology highlights the inverse correlation between antibiotic treatment and the positive outcomes of immune checkpoint inhibitor (ICI) administration, confirming once more the importance of microbiota and microbiota-derived compounds as complementary tools for treating cancer. Among the immune checkpoints, the CD200 cell surface glycoprotein has gained attention for its role in promoting self-tolerance and potentially facilitating tumor growth through interaction with the CD200R1 receptor. Methods:We developed a robust AlphaLISA-based screening to identify human gut microbiota-derived proteins that may interact with CD200R1 and screened a library of 10,966 gut bacterial proteins. The antitumor activity of BOC1 was investigated in vitro by cytokine analysis, mixed lymphocyte reactions, and myeloid-derived suppressor cell (MDSC)-T-cell suppression assay. AlphaFold modeling was used to predict potential interaction points between BOC1 and CD200R1. Results:We successfully identified BOC1, a protein from the Bacteroides genus, showing better affinity than the natural ligand, CD200, toward the CD200R1 receptor. BOC1 induces cytokine secretion by monocyte-derived dendritic cells (MoDCs) and enhances CD8+/CD4+ T-cell populations and IFNγ production, highlighting its potent immunostimulatory properties. BOC1 also negatively impacts the differentiation of MDSCs, maintaining an immature monocytic profile (high CD14 and HLA-DR expression) and restoring T-cell proliferation even at low (10 nM) concentration. Mutation of amino acids within the N-terminal region of BOC1 reduces binding to CD200R1, supporting the importance of this region for a possible interaction with CD200R1. Conclusion:The immunostimulatory properties of BOC1 observed in vitro are compatible with an ICI-like behavior of this bacterial protein. Given that neither the CD200 protein nor the anti-CD200 antibody is able to compete with BOC1 for binding to CD200R1, and as supported by AlphaFold modeling predictions, CD200 and BOC1 might target different regions of CD200R1.

Background Molecular mimicry between commensal bacterial antigens and tumor-associated antigens (TAAs) has shown potential in enhancing antitumor immune responses. This study leveraged this concept using commensal bacterial antigens, termed OncoMimics, to induce TAA-derived peptide (TAAp)-specific cross-reactive cytotoxic T cells and improve the efficacy of peptide-based immunotherapies.Methods The discovery of OncoMimics primarily relied on a bioinformatics approach to identify commensal bacteria-derived peptide sequences mimicking TAAps. Several OncoMimics peptide (OMP) candidates were selected in silico based on multiple key parameters to assess their potential to elicit and ameliorate immune responses against TAAs. Selected OMPs were synthesized and tested for their affinity and stability on the major histocompatibility complex (MHC) in vitro and for their capacity to elicit cross-reactive OMP-specific/TAAp-specific CD8+T cell responses in human leukocyte antigen (HLA)-A2-humanized mice, human peripheral blood mononuclear cells (PBMC) and patients with cancer.Results Selected OMPs demonstrated superior HLA-A2 binding affinities and stabilities compared with homologous TAAps. Vaccination of HLA-A2-humanized mice with OMPs led to the expansion of OMP-specific CD8+T cells that recognize both OMPs and homologous TAAps, exhibiting cytotoxic capacities towards tumor antigens and resulting in tumor protection in a prophylactic setting. Using PBMCs from HLA-A2+healthy donors, we confirmed the ability of OMPs to elicit potent cross-reactive OMP-specific/TAAp-specific CD8+ T-cell responses. Interestingly, we observed a high prevalence of OMP-specific T cells across donors. Cytotoxicity assays revealed that OMP-stimulated human T cells specifically targeted and killed tumor cells loaded with OMPs or TAAps. Preliminary data from an ongoing clinical trial (NCT04116658) support these findings, indicating that OMPs elicit robust OMP-specific/TAAp-specific CD8+T cell responses in patients. Initial immunomonitoring data revealed sustained T-cell responses over time, with T cells maintaining a polyfunctional, cytotoxic and memory phenotype, which is critical for effective antitumor activity and long-term immune surveillance.Conclusions These findings suggest that leveraging naturally occurring commensal-derived antigens through OMPs could significantly remodel the tumor immune landscape, offering guidance for a promising strategy for cancer peptide-based immunotherapies.

Gut microbiota-derived compounds are pivotal in modulating host immunity by regulating the functions of various key innate and adaptive immune cells. Epstein-Barr virus-induced gene 3 (EBI3) serves as the beta subunit shared by the heterodimeric cytokines interleukin (IL)-27 and IL-35. Both these cytokines have been documented to inhibit the development of T helper 2 (Th2) and T helper 17 (Th17) cells, while enhancing the function of regulatory T cells (Tregs). EBI3, itself, has also been shown to regulate cell-mediated immune responses. Despite their critical roles in maintaining immune homeostasis, there is a significant lack of robust, high-throughput-compatible assays to evaluate the secretion of IL-27, IL-35, or EBI3. In this study, we detail the development of a novel amplified luminescent proximity homogeneous assay (AlphaLISA™) to quantify EBI3 secretion by tolerogenic dendritic cells. We utilized this assay to screen a library of 9739 small proteins derived from the human gut microbiota to identify compounds that could stimulate EBI3 secretion. Our findings revealed the immunoregulatory potential of VAC18, an unknown protein from Fusicatenibacter saccharivorans (Clostridiumcluster XIVa) which significantly induces the secretion of both EBI3 and IL-27. This is the first study to demonstrate the effect of gut microbiota derived peptides on the balanced secretion of EBI3 and IL-27.

Abstract The crosstalk between gut microbiome and anti-tumor immunity has recently gained attention in clinical settings. The administration of antibiotics during immune checkpoint blockade (ICB) therapies has been correlated with poorer outcomes in cancer patients, suggesting that microbiome alterations affect overall responses to ICB. The establishment of microbiota-specific T cell clones with tumor cross-reactivity potential was proposed as one of the mechanisms linking the microbiome to anti-tumor responses. Vaccine-based strategies aimed at reactivating these dormant pools of T cells to help eliminate tumors have been proposed as an alternate approach, but the parameters required for successful responses remain poorly understood. Here, we performed in silico selection of bacterial peptides derived from healthy mice based on their mimicry of either tumor-associated antigens (TAAs) or neoantigens expressed by murine melanoma cells and not healthy tissue. We show that in silico predicted peptide binding affinity to MHC I correlates with experimental MHC I binding, a key factor associated with strong immune responses. Moreover, we confirmed that a significant proportion of selected peptide candidates can provoke an immune reaction in a vaccination setting. From this group of peptides, we selected candidates which triggered cross-reactive immune responses against TAAs or neoantigens. Data from preliminary tumor challenge experiments with prophylactic peptide vaccination and ICB allowed us to define key parameters such as target gene expression levels which can predict the cross-reactive potential of bacterial peptides that mimic tumor antigens. These findings provide novel insights into the design of gut microbiome peptide-based tumor vaccines and pave the way for establishing combinatorial therapies with immunomodulatory drugs. Citation Format: Vincent Panneton, Mathieu Gigoux, Abderezak Zebboudj, Norah Sadek, Hyejin Choi, Levi M. Mangarin, Mariam M. George, Guillaume Kulakowski, Joao G. Magalhaes, Jean-Marie Carpier, Thibaud Dugat, Camille Gaal, Francesco Strozzi, Lorenzo Tibaldi, Laurent Chene, Jedd D. Wolchok, Vinod P. Balachandran, Taha Merghoub. Gut microbiota mimics as a source of cross-reactive tumor rejection antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4090.

Peptide vaccines have emerged as a promising strategy for cancer immunotherapy, yet often lack of strong, specific and sustained immune responses against tumor antigens. To achieve a robust immune response, the effective selection of tumour antigens is crucial. While neoantigens trigger potent immune responses, their use suffers from patient specificity and their rarity in low-mutational tumors. Alternatively, the immunogenic potential of tumor-associated antigens (TAAs) is limited by central immune tolerance. Molecular mimicry and T cell cross-reactivity is a proposed mechanism to trigger a robust T cell-mediated antitumor response. Although molecular mimicry between pathogens and tumor antigens has been described, the potential benefits of exploiting this molecular mimicry with commensal bacterial antigens in antitumor immunity have not been thoroughly investigated despite strong evidence that the composition of the human microbiota significantly influences immune competency. Our new approach called OncoMimics™, which uses molecular mimicry between commensal bacterial and tumoral antigens to induce cross-reactive cytotoxic T cells against tumor cells. In preclinical studies, vaccination with OncoMimic™ peptides (OMPs) led to the expansion of CD8+ T cells reacting against homologous tumor-associated antigen peptides and elicits cytotoxic activity against tumor cells. OMPs are efficiently recognized by a prevalent T cell population within the peripheral blood mononuclear cells of healthy individuals. An ongoing clinical trial ([NCT04116658][1]) using OncoMimics™ in patients with glioblastoma demonstrates early, durable, and cross-reactive tumor antigen CD8+ T cell responses with pronounced memory persistence. By overcoming the current vaccine limitations, OncoMimics™ constitutes a promising strategy for enhancing cancer immunity and improving patient outcomes. Statement of Significance This study introduces OncoMimics™, a peptide-based immunotherapy leveraging molecular mimicry to induce robust, cross-reactive T cell responses against tumor antigens, showing promising early results in an ongoing glioblastoma clinical trial ([NCT04116658][1]) ### Competing Interest Statement Conflict of Interest FS, CB1 and LC are co-inventors of the international patent application PCT/EP2019/059329 entitled : Antigenic peptides for the prevention and treatment of cancer. GK, FS, LC, and JGM are co-inventors of the international patent application PCT/EP2020/082101 entitled: Antigenic peptides for prevention and treatment of B-cell malignancy. GK, CG, AT, FS, LC, and JGM are co-inventors of the international patent application PCT/EP2023/058415, entitled: Antigenic peptides for prevention and treatment of cancer. These patent applications claim the OncoMimic peptides described in this manuscript. Enterome employed AT, JMC, GK, TM, AG, CPO, CC, DB, CV, JM, LA1, LA2, JK, MB, CB1, CG1, FS, CG2, CB2, LC, and JGM at the time of this study. All other authors declare no competing interests. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04116658&atom=%2Fbiorxiv%2Fearly%2F2024%2F06%2F01%2F2024.05.27.596102.atom

The gut microbiota is a considerable source of biologically active compounds that can promote intestinal homeostasis and improve immune responses. Here, we used large expression libraries of cloned metagenomic DNA to identify compounds able to sustain an anti-inflammatory reaction on host cells. Starting with a screen for NF-κB activation, we have identified overlapping clones harbouring a heterodimeric ATP-binding cassette (ABC)-transporter from a Firmicutes. Extensive purification of the clone’s supernatant demonstrates that the ABC-transporter allows for the efficient extracellular accumulation of three muropeptide precursor, with anti-inflammatory properties. They induce IL-10 secretion from human monocyte-derived dendritic cells and proved effective in reducing AIEC LF82 epithelial damage and IL-8 secretion in human intestinal resections. In addition, treatment with supernatants containing the muropeptide precursor reduces body weight loss and improves histological parameters in Dextran Sulfate Sodium (DSS)-treated mice. Until now, the source of peptidoglycan fragments was shown to come from the natural turnover of the peptidoglycan layer by endogenous peptidoglycan hydrolases. This is a report showing an ABC-transporter as a natural source of secreted muropeptide precursor and as an indirect player in epithelial barrier strengthening. The mechanism described here might represent an important component of the host immune homeostasis.

Gut microbiota dysbiosis is associated with inflammatory bowel diseases and with cardiometabolic, neurological, and autoimmune diseases. Gut microbiota composition has a direct effect on the immune system, and vice versa, and it has a particular effect on Treg homeostasis. Low-dose IL-2 (IL-2LD) stimulates Tregs and is a promising treatment for autoimmune and inflammatory diseases. We aimed to evaluate the impact of IL-2LD on gut microbiota and correlatively on the immune system. We used 16S ribosomal RNA profiling and metagenomics to characterize gut microbiota of mice and humans treated or not with IL-2LD. We performed fecal microbiota transplantation (FMT) from IL-2LD–treated to naive recipient mice and evaluated its effects in models of gut inflammation and diabetes. IL-2LD markedly affected gut microbiota composition in mice and humans. Transfer of an IL-2–tuned microbiota by FMT protected C57BL/6J mice from dextran sulfate sodium–induced colitis and prevented diabetes in NOD mice. Metagenomic analyses highlighted a role for several species affected by IL-2LD and for microbial pathways involved in the biosynthesis of amino acids, short-chain fatty acids, and L-arginine. Our results demonstrate that IL-2LD induced changes in gut microbiota that are involved in the immunoregulatory effects of IL-2LD and suggest a crosstalk between Tregs and gut microbiota. These results provide potentially novel insight for understanding the mode of action of Treg-directed therapies.

The gut microbiome has the singular property of shaping the immune system through a multitude of antigens that educate the T cell repertoire. Since microbial peptides can share similarities with tumor antigens, cross-reactive memory T cells that recognize both bacterial and tumor-derived peptides can thus emerge from the imprinting of the T cell repertoire by gut commensals. Harnessing the full potential of cross-reactive CD8+ T cells against tumor cells could therefore be achieved through the rational design of a microbiota-derived peptide vaccine. Enterome developed a novel peptide-based immunotherapy built on the principle of T cell cross-reactivity and molecular mimicry between bacterial-derived peptides called OncoMimicsTM peptides (OMP) and Tumor-Associated Antigens (TAA). HLA-A2-restricted OMP candidates targeting human TAA were first selected in silico from our proprietary metagenomic bank of human gut microbiota and then confirmed through in vitro binding assays, and in vivo evaluations of their immunogenicity and capacity to induce cross-reactive T cell responses against TAA in HLA-A2/DR1 humanized mice. Finally, the prevalence and functionality of OMP-specific T cells were assessed in human blood from healthy donors using tetramers, in vitro stimulation, and cytotoxicity assays. Selected OMPs could elicit cross-reactive cytotoxic T cell (CTL) responses against human TAA. This was demonstrated by the propensity of these CTL to secrete IFN-γ upon recognition of OMP or TAA peptides, reject TAA peptide-pulsed splenocytes as well as tumors ectopically expressing the selected TAA targets. We finally demonstrated that OMP-specific memory CD8+ T cells pre-exist in human blood, with high prevalence (>80% in the population), and harbor strong CTL functions against TAA when activated ex vivo with OMPs. We show that gut microbiota-derived peptides mimicking TAAs can elicit strong immune responses against tumors. The pre-existence of these cross-reactive CD8+ T cells in healthy donors exemplifies the strong promises of this innovative approach to develop efficient therapeutic cancer immunotherapies. To date, two OMP-based immunotherapies are evaluated in 3 clinical trials (Glioblastoma, Adrenal cancers, B lymphomas).

Non-alcoholic fatty liver diseases (NAFLD) are associated with changes in the composition and metabolic activities of the gut microbiota. However, the causal role played by the gut microbiota in individual susceptibility to NAFLD and particularly at its early stage is still unclear. In this context, we transplanted the microbiota from a patient with fatty liver (NAFL) and from a healthy individual to two groups of mice. We first showed that the microbiota composition in recipient mice resembled the microbiota composition of their respective human donor. Following administration of a high-fructose, high-fat diet, mice that received the human NAFL microbiota (NAFLR) gained more weight and had a higher liver triglycerides level and higher plasma LDL cholesterol than mice that received the human healthy microbiota (HR). Metabolomic analyses revealed that it was associated with lower and higher plasma levels of glycine and 3-Indolepropionic acid in NAFLR mice, respectively. Moreover, several bacterial genera and OTUs were identified as differently represented in the NAFLR and HR microbiota and therefore potentially responsible for the different phenotypes observed. Altogether, our results confirm that the gut bacteria play a role in obesity and steatosis development and that targeting the gut microbiota may be a preventive or therapeutic strategy in NAFLD management.

An Escherichia coli (E. coli) pathotype with invasive properties, first reported by Darfeuille-Michaud and termed adherent-invasive E. coli (AIEC), was shown to be prevalent in up to half the individuals with Crohn’s Disease (CD), suggesting that these bacteria could be involved in the pathophysiology of CD. Among the genes related to AIEC pathogenicity, fim has the potential to generate an inflammatory reaction from the intestinal epithelial cells and macrophages, as it interacts with TLR4, inducing the production of inflammatory cytokines independently of LPS. Therefore, targeting the bacterial adhesion of FimH-expressing bacteria seems a promising therapeutic approach, consisting of disarming bacteria without killing them, representing a selective strategy to suppress a potentially critical trigger of intestinal inflammation, without disturbing the intestinal microbiota. We analyzed the metagenomic composition of the gut microbiome of 358 patients with CD from two different cohorts and characterized the presence of FimH-expressing bacteria. To assess the pathogenic role of FimH, we used human intestinal explants and tested a specific FimH blocker to prevent bacterial adhesion and associated inflammation. We observed a significant and disease activity-dependent enrichment of Enterobacteriaceae in the gut microbiome of patients with CD. Bacterial FimH expression was functionally confirmed in ileal biopsies from 65% of the patients with CD. Using human intestinal explants, we further show that FimH is essential for adhesion and to trigger inflammation. Finally, a specific FimH-blocker, TAK-018, inhibits bacterial adhesion to the intestinal epithelium and prevents inflammation, thus preserving mucosal integrity. We propose that TAK-018, which is safe and well tolerated in humans, is a promising candidate for the treatment of CD and in particular in preventing its recurrence.

Computational reconstruction of nearly complete genomes from metagenomic reads may identify thousands of new uncultured candidate bacterial species. We have shown that reconstructed prokaryotic genomes along with genomes of sequenced microbial isolates can be used to support more accurate gene prediction in novel metagenomic sequences. We have proposed an approach that used three types of gene prediction algorithms and found for all contigs in a metagenome nearly optimal models of protein-coding regions either in libraries of pre-computed models or constructed de novo. The model selection process and gene annotation were done by the new GeneMark-HM pipeline. We have created a database of the species level pan-genomes for the human microbiome. To create a library of models representing each pan-genome we used a self-training algorithm GeneMarkS-2. Genes initially predicted in each contig served as queries for a fast similarity search through the pan-genome database. The best matches led to selection of the model for gene prediction. Contigs not assigned to pan-genomes were analyzed by crude, but still accurate models designed for sequences with particular GC compositions. Tests of GeneMark-HM on simulated metagenomes demonstrated improvement in gene annotation of human metagenomic sequences in comparison with the current state-of-the-art gene prediction tools.

The adherent invasive Escherichia coli (AIEC) pathotype has been associated with the aetiology of Crohn's disease (CD). Scarce reports have shown the antimicrobial resistance (AMR) profiles of AIEC. Despite antibiotics not being recommended to treat CD, antimicrobial therapy could be useful in stratified patients, such as AIEC carriers. We examined the antimicrobial resistance profiles of AIEC strains to identify which therapies could be effective or confer a risk for such patients. Phenotypic resistance to 30 antimicrobials was tested according to CLSI standards. AIEC (n = 22) and non-pathogenic E. coli (non-AIEC) strains (n = 37) isolated from the gut mucosa of 31 CD patients and 18 controls were studied. De novo genome sequencing was carried out for 39 of the 59 strains, and AMR genes were searched using the DeepARG database in these genomes and 33 additional AIEC publicly available genomes. The strains isolated from CD and controls showed similar phenotypic AMR profiles. The genomic analysis did not reveal an increased prevalence of AMR genes. However, AIEC strains were more frequently resistant to β-lactams than non-AIEC strains (11 AIEC (50%) and 5 non-AIEC (22%) strains were resistant to at least one β-lactam; p < 0.042). Two AIEC strains were resistant to expanded-spectrum cephalosporins. One strain carried a plasmid-mediated AmpC β-lactamase (CMY-69), and the other presented mutations in the promotor of the intrinsic chromosomal AmpC related to the hyperproduction of this enzyme. The rest of the strains were resistant to β-lactams not including expanded-spectrum cephalosporins. The majority carried TEM-related β-lactamases. Genomic analysis including external AIEC revealed that the gene sul1 encoding for sulphonamide resistance was more frequent in AIEC strains than non-AIEC strains (34.6% vs. 9.5%, p = 0.030). AMR in AIEC is a matter of concern regarding the putative implication of the pathotype in CD. The high proportion of AIEC resistant to β-lactams warrants caution about the risk there may be in the use of these antimicrobials in AIEC-colonized CD patients.

Comprehensive, high-quality reference genomes are required for functional characterization and taxonomic assignment of the human gut microbiota. We present the Unified Human Gastrointestinal Genome (UHGG) collection, comprising 204,938 nonredundant genomes from 4,644 gut prokaryotes. These genomes encode >170 million protein sequences, which we collated in the Unified Human Gastrointestinal Protein (UHGP) catalog. The UHGP more than doubles the number of gut proteins in comparison to those present in the Integrated Gene Catalog. More than 70% of the UHGG species lack cultured representatives, and 40% of the UHGP lack functional annotations. Intraspecies genomic variation analyses revealed a large reservoir of accessory genes and single-nucleotide variants, many of which are specific to individual human populations. The UHGG and UHGP collections will enable studies linking genotypes to phenotypes in the human gut microbiome.

Comprehensive reference data is essential for accurate taxonomic and functional characterization of the human gut microbiome. Here we present the Unified Human Gastrointestinal Genome (UHGG) collection, a resource combining 286,997 genomes representing 4,644 prokaryotic species from the human gut. These genomes contain over 625 million protein sequences used to generate the Unified Human Gastrointestinal Protein (UHGP) catalogue, a collection that more than doubles the number of gut protein clusters over the Integrated Gene Catalogue. We find that a large portion of the human gut microbiome remains to be fully explored, with over 70% of the UHGG species lacking cultured representatives, and 40% of the UHGP missing meaningful functional annotations. Intra-species genomic variation analyses revealed a large reservoir of accessory genes and single-nucleotide variants, many of which were specific to individual human populations. These freely available genomic resources should greatly facilitate investigations into the human gut microbiome.

Peptide-based vaccination is an immunotherapeutic approach for the treatment of cancer that aims to deliver immunogenic peptides corresponding to specific tumor associated antigens to patients. Despite promising pre-clinical results in animal models, most cancer vaccination approach has not demonstrated unequivocal efficacy in patients. The ability of a peptide cancer vaccine to generate a strong immune response depends on several factors including the avidity of the peptide for the MHC complexes, the capacity of the antigen to be recognized by the immune system as self or non-self and the existence of T cell clones (naïve or memory) that are able to recognize those peptides. Gut colonization is one of the factor that drive the development of T cells and the presence of commensal specific memory T-cell is well reported in the literature and is now currently admitted. Several evidences support that these T cells can be re-activated and can migrate to inflammatory sites where the antigen is expressed. We have developed an innovative, microbiome-based approach for the development of therapeutic peptide cancer vaccines base. Our approach is based on the notion of molecular mimicry, by which a microbial derived peptide vaccine holding molecular similarity with a tumor-associated epitope would trigger a tumor-specific cytotoxic T cell immune response. By developing a dedicated in silico pipeline, we were able to identify bacterial antigens that could elicit strong immune response in WT mice. Furthermore, these bacterial antigens could be selected to generate T cell reactivity against self-peptides that are by themselves not immunogenic. The same pipeline was used to identify bacterial antigens able to bind human HLA-A2 and displaying molecular mimicry with selected tumor associated antigens. While HLA-A2 transgenic mice vaccination with tumor associated antigens doesn’t lead to immunization, vaccination with bacterial antigens results in a strong immune response against both bacterial peptides and selected tumor associated antigens. Furthermore, adoptive transfer of T cell from mice immunized with bacterial peptides into tumor engrafted nude mice leads to tumor control in the presence of Check Point Inhibitors. A first vaccine candidate targeting three different tumor drivers overexpressed in Glioblastoma and other solid tumors will enter the clinic this year. Citation Format: Laurent Chene, Caroline Diveu Sader, Joao Magalhaes, Francesco Strozzi, Lorenzo Tibaldi, Celia Mendez, Simon Baeriswyl, Arnaud Laveissiere, Christophe Bonny. Microbiome derived peptides stimulate strong immune response against tumor associated antigens and trigger in vivo tumor regression after vaccination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1475.

Biological, clinical, and pharmacological research now often involves analyses of genomes, transcriptomes, proteomes, and interactomes, within and between individuals and across species. Due to large volumes, the analysis and integration of data generated by such high-throughput technologies have become computationally intensive, and analysis can no longer happen on a typical desktop computer. In this chapter we show how to describe and execute the same analysis using a number of workflow systems and how these follow different approaches to tackle execution and reproducibility issues. We show how any researcher can create a reusable and reproducible bioinformatics pipeline that can be deployed and run anywhere. We show how to create a scalable, reusable, and shareable workflow using four different workflow engines: the Common Workflow Language (CWL), Guix Workflow Language (GWL), Snake-make, and Nextflow. Each of which can be run in parallel. We show how to bundle a number of tools used in evolutionary biology by using Debian, GNU Guix, and Bioconda software distributions, along with the use of container systems, such as Docker, GNU Guix, and Singularity. Together these distributions represent the overall majority of software packages relevant for biology, including PAML, Muscle, MAFFT, MrBayes, and BLAST. By bundling software in lightweight containers, they can be deployed on a desktop, in the cloud, and, increasingly, on compute clusters. By bundling software through these public software distributions, and by creating reproducible and shareable pipelines using these workflow engines, not only do bioinformaticians have to spend less time reinventing the wheel but also do we get closer to the ideal of making science reproducible. The examples in this chapter allow a quick comparison of different solutions.

Publishing databases in the Resource Description Framework (RDF) model is becoming widely accepted to maximize the syntactic and semantic interoperability of open data in life sciences. Here we report advancements made in the 6th and 7th annual BioHackathons which were held in Tokyo and Miyagi respectively. This review consists of two major sections covering: 1) improvement and utilization of RDF data in various domains of the life sciences and 2) meta-data about these RDF data, the resources that store them, and the service quality of SPARQL Protocol and RDF Query Language (SPARQL) endpoints. The first section describes how we developed RDF data, ontologies and tools in genomics, proteomics, metabolomics, glycomics and by literature text mining. The second section describes how we defined descriptions of datasets, the provenance of data, and quality assessment of services and service discovery. By enhancing the harmonization of these two layers of machine-readable data and knowledge, we improve the way community wide resources are developed and published. Moreover, we outline best practices for the future, and prepare ourselves for an exciting and unanticipatable variety of real world applications in coming years.

SummaryBroadening the genetic base of crops is crucial for developing varieties to respond to global agricultural challenges such as climate change. Here, we analysed a diverse panel of 371 domesticated lines of the model crop barley to explore the genetics of crop adaptation. We first collected exome sequence data and phenotypes of key life history traits from contrasting multi‐environment common garden trials. Then we applied refined statistical methods, including some based on exomic haplotype states, for genotype‐by‐environment (G×E) modelling. Sub‐populations defined from exomic profiles were coincident with barley's biology, geography and history, and explained a high proportion of trial phenotypic variance. Clear G×E interactions indicated adaptation profiles that varied for landraces and cultivars. Exploration of circadian clock‐related genes, associated with the environmentally adaptive days to heading trait (crucial for the crop's spread from the Fertile Crescent), illustrated complexities in G×E effect directions, and the importance of latitudinally based genic context in the expression of large‐effect alleles. Our analysis supports a gene‐level scientific understanding of crop adaption and leads to practical opportunities for crop improvement, allowing the prioritisation of genomic regions and particular sets of lines for breeding efforts seeking to cope with climate change and other stresses.

A 1000-cow study across four European countries was undertaken to understand to what extent ruminant microbiomes can be controlled by the host animal and to identify characteristics of the host rumen microbiome axis that determine productivity and methane emissions. A core rumen microbiome, phylogenetically linked and with a preserved hierarchical structure, was identified. A 39-member subset of the core formed hubs in co-occurrence networks linking microbiome structure to host genetics and phenotype (methane emissions, rumen and blood metabolites, and milk production efficiency). These phenotypes can be predicted from the core microbiome using machine learning algorithms. The heritable core microbes, therefore, present primary targets for rumen manipulation toward sustainable and environmentally friendly agriculture.