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Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jff.2020.103969., This work supports the massive presence of potential immunomodulatory peptides in the human gut metaproteome. These peptides were identified through the MAHMI database as potentially anti-inflammatory, and sixteen of them synthesized for characterize their mechanism of action. From them, peptide HM14 was encrypted in an extracellular protein produced by Bifidobacterium longum, a common member of the human microbiota, and displayed the highest anti-inflammatory capability. Molecular mechanism of action of HM14 pointed to a specific interaction between this immunomodulatory peptide and antigen presenting cells, which resulted in a higher formation of iTreg cells. Moreover, HM14 was effective in decreasing pro-inflammatory parameters in PBMCs isolated from a cohort of Crohns patients. Finally, non-targeted metabolomics confirmed the ability of HM14 to modulate the metabolic activity of PBMCs to fulfil its energy and biosynthetic requirements. Overall, our combined in silico/multiomics approach supports the human gut metaproteome as a source for immunomodulatory peptides., Our work is supported by the Spanish “Programa Estatal de Investigación. Desarrollo e Innovación Orientada a los Retos de la Sociedad” (grants AGL2013-44761-P and AGL2016-78311-R); the Asociación Española Contra el Cancer (“Obtención de péptidos bioactivos contra el Cáncer Colo-Rectal a partir de secuencias genéticas de microbiomas intestinales”, Grant PS-2016), by the Asturias Regional Plan I + D + i for research groups (FYCYT-IDI/2018/000236) and by the Autonomic “Investigadores Emerxentes do Sistema Universitario de Galicia” (Grant EM2014/046). This work was partially supported by the Consellería de Educación. Universidades e Formación Profesional (Xunta de Galicia) under the scope of the strategic funding of ED431C2018/55-GRC Competitive Reference Group. Finally, the authors wish to thank Jaume Morales and Rubén García form Agilent Technologies for technical support., info:eu-repo/semantics/publishedVersion

This work presents a novel in silico approach to the prediction and characterisation of the glycolytic capacities of the beneficial intestinal bacterium Faecalibacterium prausnitzii. Available F. prausnitzii genomes were explored taking the glycolytic capacities of F. prausnitzii SL3/3 and F. prausnitzii L2-6 as reference. The comparison of the generated glycolytic profiles offered insights into the particular capabilities of F. prausnitzii SL3/3 and F. prausnitzii L2-6 as well as the potential of the rest of strains. Glycoside hydrolases were mostly detected in the pathways responsible for the starch and sucrose metabolism and the biosynthesis of secondary metabolites, but this analysis also identified some other potentially interesting, but still uncharacterised activities, such as several hexosyltransferases and some hydrolases. Gene neighbourhood maps offered additional understanding of the genes coding for relevant glycoside hydrolases. Although information about the carbohydrate preferences of F. prausnitzii is scarce, the in silico metabolic predictions were consistent with previous knowledge about the impact of fermentable sugars on the growth promotion and metabolism of F. prausnitzii. So, while the predictions still need to be validated using culturing methods, the approach holds the potential to be reproduced and scaled to accommodate the analysis of other strains (or even families and genus) as well as other metabolic activities. This will allow the exploration of novel methodologies to design or obtain targeted probiotics for F. prausnitzii and other strains of interest., This work was supported by the Spanish "Programa Estatal de Investigacion, Desarrollo e Innovacion Orientada a los Retos de la Sociedad" (Grant AGL2016-78311-R); and, the Asociacion Espanola Contra el Cancer (" Obtencion de peptidos bioactivos contra el Cancer Colo-Rectal a partir de secuencias geneticas de microbiomas intestinales," Grant PS-2016). This work was also supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER006684). This work was partially supported by the Conselleria de Educacion, Universidades e Formacion Profesional (Xunta de Galicia) under the scope of the strategic funding of ED431C2018/55-GRC Competitive Reference Group., info:eu-repo/semantics/publishedVersion

Advances in the field of genome sequencing have enabled a comprehensive analysis and annotation of the dynamics of the protein inventory of cells. This has been proven particularly rewarding for microbial cells, for which the majority of proteins are already accessible to analysis through automatic metagenome annotation. The large-scale in silico screening of proteomes and metaproteomes is key to uncover bioactivities of translational, clinical and biotechnological interest, and to help assign functions to certain proteins, such as those predicted as hypothetical. This work introduces a new method for the prediction of the bioactivity potential of proteomes/metaproteomes, supporting the discovery of functionally relevant proteins based on prior knowledge. This methodology complements functional annotation enrichment methods by allowing the assignment of functions to proteins annotated as hypothetical/putative/uncharacterised, as well as and enabling the detection of specific bioactivities and the recovery of proteins from defined taxa. This work shows how the new method can be applied to screen proteome and metaproteome sets to obtain predictions of clinical or biotechnological interest based on reference datasets. Notably, with this methodology, the large information files obtained after DNA sequencing or protein identification experiments can be associated for translational purposes that, in cases such as antibiotic-resistance pathogens or foodborne diseases, may represent changes in how these important and global health burdens are approached in the clinical practice. Finally, the Sequence-based Expert-driven pRoteome bioactivity Prediction EnvironmENT, a public Web service implemented in Scala functional programming style, is introduced as means to ensure broad access to the method as well as to discuss main implementation issues, such as modularity, extensibility and interoperability., This work was supported by the Spanish “Programa Estatal de Investigación, Desarrollo e Inovación Orientada a los Retos de la Sociedad” (grant AGL2013-44039R); the Asociación Española Contra el Cancer (“Obtención de péptidos bioactivos contra el Cáncer Colo-Rectal a partir de secuencias genéticas de microbiomas intestinales”, grant PS-2016). This study was also supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER006684). SING group thanks CITI (Centro de Investigación, Transferencia e Innovación) from University of Vigo for hosting its IT infrastructure.

The Mechanism of Action of the Human Microbiome (MAHMI) database is a unique resource that provides comprehensive information about the sequence of potential immunomodulatory and antiproliferative peptides encrypted in the proteins produced by the human gut microbiota. Currently, MAHMI database contains over 300 hundred million peptide entries, with detailed information about peptide sequence, sources and potential bioactivity. The reference peptide data section is curated manually by domain experts. The in silico peptide data section is populated automatically through the systematic processing of publicly available exoproteomes of the human microbiome. Bioactivity prediction is based on the global alignment of the automatically processed peptides with experimentally validated immunomodulatory and antiproliferative peptides, in the reference section. MAHMI provides researchers with a comparative tool for inspecting the potential immunomodulatory or antiproliferative bioactivity of new amino acidic sequences and identifying promising peptides to be further investigated. Moreover, researchers are welcome to submit new experimental evidence on peptide bioactivity, namely, empiric and structural data, as a proactive, expert means to keep the database updated and improve the implemented bioactivity prediction method. Bioactive peptides identified by MAHMI have a huge biotechnological potential, including the manipulation of aberrant immune responses and the design of new functional ingredients/foods based on the genetic sequences of the human microbiome. Hopefully, the resources provided by MAHMI will be useful to those researching gastrointestinal disorders of autoimmune and inflammatory nature, such as Inflammatory Bowel Diseases. MAHMI database is routinely updated and is available free of charge., This work was funded by the Grant AGL2013-44039-R from the Spanish “Plan Estatal de I + D+I”, and the Grant EM2014/046 from the “Plan Galego de investigación, innovación e crecemento 2011-2015”. Borja Sánchez was recipient of a Ramón y Cajal postdoctoral contract from the Spanish Ministry of Economy and Competitiveness. This work was also partially funded by the [14VI05] Contract-Programme from the University of Vigo and the Agrupamento INBIOMED from DXPCTSUG-FEDER unha maneira de facer Europa (2012/273) and the European Union’s Seventh Framework Programme FP7/REGPOT-2012-2013.1 under grant agreement n° 316265, BIOCAPS.