G protein-coupled receptors: A target for microbial metabolites and a mechanistic link to microbiome-immune-brain interactions

Human-microorganism interactions play a key role in human health. However, the underlying molecular mechanisms remain poorly understood. Small-molecules that offer a functional readout of microbe-microbe-human relationship are of great interest for deeper understanding of the inter-kingdom crosstalk at the molecular level. Recent studies have demonstrated that small-molecules from gut microbiota act as ligands for specific human G protein-coupled receptors (GPCRs) and modulate a range of human physiological functions, offering a mechanistic insight into the microbe-human interaction. To this end, we focused on analysis of bacterial metabolites that are currently recognized to bind to GPCRs and are found to activate the known downstream signaling pathways. We further mapped the distribution of these molecules across the public mass spectrometry-based metabolomics data, to identify the presence of these molecules across body sites and their association with health status. By combining this with RNA-Seq expression and spatial localization of GPCRs from a public human protein atlas database, we inferred the most predominant GPCR-mediated microbial metabolite-human cell interactions regulating gut-immune-brain axis. Furthermore, by evaluating the intestinal absorption properties and blood-brain barrier permeability of the small-molecules we elucidated their molecular interactions with specific human cell receptors, particularly expressed on human intestinal epithelial cells, immune cells and the nervous system that are shown to hold much promise for clinical translational potential. Furthermore, we provide an overview of an open-source resource for simultaneous interrogation of bioactive molecules across the druggable human GPCRome, a useful framework for integration of microbiome and metabolite cataloging with mechanistic studies for an improved understanding of gut microbiota-immune-brain molecular interactions and their potential therapeutic use

A community resource for paired genomic and metabolomic data mining

Genomics and metabolomics are widely used to explore specialized metabolite diversity. The Paired Omics Data Platform is a community initiative to systematically document links between metabolome and (meta)genome data, aiding identification of natural product biosynthetic origins and metabolite structures.Peer reviewe

MIBiG 3.0 : a community-driven effort to annotate experimentally validated biosynthetic gene clusters

With an ever-increasing amount of (meta)genomic data being deposited in sequence databases, (meta)genome mining for natural product biosynthetic pathways occupies a critical role in the discovery of novel pharmaceutical drugs, crop protection agents and biomaterials. The genes that encode these pathways are often organised into biosynthetic gene clusters (BGCs). In 2015, we defined the Minimum Information about a Biosynthetic Gene cluster (MIBiG): a standardised data format that describes the minimally required information to uniquely characterise a BGC. We simultaneously constructed an accompanying online database of BGCs, which has since been widely used by the community as a reference dataset for BGCs and was expanded to 2021 entries in 2019 (MIBiG 2.0). Here, we describe MIBiG 3.0, a database update comprising large-scale validation and re-annotation of existing entries and 661 new entries. Particular attention was paid to the annotation of compound structures and biological activities, as well as protein domain selectivities. Together, these new features keep the database up-to-date, and will provide new opportunities for the scientific community to use its freely available data, e.g. for the training of new machine learning models to predict sequence-structure-function relationships for diverse natural products. MIBiG 3.0 is accessible online at https://mibig.secondarymetabolites.org/

Secondary metabolite biosynthetic gene diversity Bacillales non-ribosomal peptides and polyketides in plant-microbe interactions

Diese Studie untersucht die biosynthetische Vielfalt von nicht-ribosomalen Peptiden und Polyketiden in Bacillales auf Grund ihrer weit verbreiteten Kapazität Sekundärmetabolite zu produzieren und ihrem Einsatz in der biologischen Schädlingsbekämpfung. Genome-Mining in Bacillales weist darauf hin, dass ein wesentlicher Teil der vorhergesagten nicht-ribosomalen Peptide und Polyketide in Pflanzen-assoziierten Bacillus Stämmen uncharakterisiert ist. Überraschenderweise produzieren viele Bacillales Gattungen aus anderen Habitaten nur wenige solcher Verbindungen, was auf die Wichtigkeit dieser Metabolite in Pflanzen-assoziierten Nischen hinweist. Das Genom von Paenibacillus polymyxa CC1-25 enthält Gene, die für Fusaricidin C, Iturin-ähnliche, Tridecaptin und Polymyxin Varianten mit veränderter Monomerzusammensetzung kodieren. Ebenso sind Gene für die Produktion eines Paenicidin A - ähnlichem Lantibiotikum und eine Polysynthetase 1 enthalten. Angesichts der Tatsache, dass 6,6 % des gesamten Genoms der Synthese von Sekundärmethaboliten gewidmet ist, bietet CCI-25 ein hohes Potenzial für medizinische und landwirtschaftliche Anwendungen. Bacillus atrophaeus 176s schützt Pflanzen von R. solani Infektionen. Dieser Stamm produziert drei Lipopeptidfamilien, die in der Biokontrolle von pflanzlichen Pathogenen eine Rolle spielen könnten. Wir isolierten Surfactin C von B. atrophaeus welches subtile strukturelle Unterschiede in der Adenylierungsdomäne der Surfactinsynthetase (srfC) im Vergleich zu Surfactin A von B. subtilis und B. amyloliquefaciens aufweist. Abweichungen in der Surfactinsynthetase sind über alle Bacillus Arten verteilt. Ferner waren die Surfactin Varianten mit Art-spezifischer Biofilmbildung und Wurzelbesiedelung assoziiert. Die Ergebnisse dieser Doktorarbeit zeigen das große, dennoch ungenutzte Potenzial von Sekundärmetaboliten und deren genetischer Vielfalt in den Gattungen Bacillus und Paenibacillus, die eine Schlüsselfunktion in Pflanzen-Mikroben-Interaktion darstellen könnten.This study aimed to investigate the biosynthetic diversity of non-ribosomal peptides and polyketides in Bacillales due to the high secondary metabolite capacity and their use in the biological control of plant diseases. Genome-mining the Bacillales suggested that a substantial fraction of the predicted non-ribosomal peptides and polyketides are uncharacterized in plant-associated Bacillus strains. Surprisingly, many genera of Bacillales from other environments produce few of such compounds indicating the importance of these metabolites in plant-associated niches. The genome of Paenibacillus polymyxa strain CCI-25 encompasses genes encoding fusaricidin C, iturin-like, tridecaptin and polymyxin variants with altered monomer composition, and a lantibiotic similar to paenicidin A, as well as a polyketide synthase type 1. Given the fact that 6.6% of the total genome is devoted to secondary metabolite biosynthesis, CCI-25 has high potential to be exploited for medical or agricultural applications. Bacillus atrophaeus strain 176s protected plants from R. solani infection and co-produced three lipopeptide families, which may play a role in biocontrol of plant pathogens. We isolated surfactin C from B. atrophaeus that has subtle structural differences when compared to surfactin A produced by B. subtilis and B. amyloliquefaciens. The dissimilarity is encoded in the adenylation domain of the surfactin synthetase (srfC) and most importantly variations in the surfactin synthetase are distributed in a species-specific manner in all Bacillus. Further, the surfactin variants were associated with species-specific biofilm induction and root colonization. The results of this thesis show that there is a huge yet untapped potential of secondary metabolites and their genetic diversity in the genera Bacillus and Paenibacillus, which may play a key role in plant-microbe interactions.submitted by Gajender AletiZusammenfassung in deutscher SpracheUniversität für Bodenkultur Wien, Dissertation, 2016OeBB(VLID)193064

G protein-coupled receptors: A target for microbial metabolites and a mechanistic link to microbiome-immune-brain interactions.

Human-microorganism interactions play a key role in human health. However, the underlying molecular mechanisms remain poorly understood. Small-molecules that offer a functional readout of microbe-microbe-human relationship are of great interest for deeper understanding of the inter-kingdom crosstalk at the molecular level. Recent studies have demonstrated that small-molecules from gut microbiota act as ligands for specific human G protein-coupled receptors (GPCRs) and modulate a range of human physiological functions, offering a mechanistic insight into the microbe-human interaction. To this end, we focused on analysis of bacterial metabolites that are currently recognized to bind to GPCRs and are found to activate the known downstream signaling pathways. We further mapped the distribution of these molecules across the public mass spectrometry-based metabolomics data, to identify the presence of these molecules across body sites and their association with health status. By combining this with RNA-Seq expression and spatial localization of GPCRs from a public human protein atlas database, we inferred the most predominant GPCR-mediated microbial metabolite-human cell interactions regulating gut-immune-brain axis. Furthermore, by evaluating the intestinal absorption properties and blood-brain barrier permeability of the small-molecules we elucidated their molecular interactions with specific human cell receptors, particularly expressed on human intestinal epithelial cells, immune cells and the nervous system that are shown to hold much promise for clinical translational potential. Furthermore, we provide an overview of an open-source resource for simultaneous interrogation of bioactive molecules across the druggable human GPCRome, a useful framework for integration of microbiome and metabolite cataloging with mechanistic studies for an improved understanding of gut microbiota-immune-brain molecular interactions and their potential therapeutic use

G protein-coupled receptors: A target for microbial metabolites and a mechanistic link to microbiome-immune-brain interactions

Human-microorganism interactions play a key role in human health. However, the underlying molecular mechanisms remain poorly understood. Small-molecules that offer a functional readout of microbe-microbe-human relationship are of great interest for deeper understanding of the inter-kingdom crosstalk at the molecular level. Recent studies have demonstrated that small-molecules from gut microbiota act as ligands for specific human G protein-coupled receptors (GPCRs) and modulate a range of human physiological functions, offering a mechanistic insight into the microbe-human interaction. To this end, we focused on analysis of bacterial metabolites that are currently recognized to bind to GPCRs and are found to activate the known downstream signaling pathways. We further mapped the distribution of these molecules across the public mass spectrometry-based metabolomics data, to identify the presence of these molecules across body sites and their association with health status. By combining this with RNA-Seq expression and spatial localization of GPCRs from a public human protein atlas database, we inferred the most predominant GPCR-mediated microbial metabolite-human cell interactions regulating gut-immune-brain axis. Furthermore, by evaluating the intestinal absorption properties and blood-brain barrier permeability of the small-molecules we elucidated their molecular interactions with specific human cell receptors, particularly expressed on human intestinal epithelial cells, immune cells and the nervous system that are shown to hold much promise for clinical translational potential. Furthermore, we provide an overview of an open-source resource for simultaneous interrogation of bioactive molecules across the druggable human GPCRome, a useful framework for integration of microbiome and metabolite cataloging with mechanistic studies for an improved understanding of gut microbiota-immune-brain molecular interactions and their potential therapeutic use

Correction: Qualitative analysis of biosurfactants from Bacillus species exhibiting antifungal activity.

[This corrects the article DOI: 10.1371/journal.pone.0198107.]

Salivary bacterial signatures in depression-obesity comorbidity are associated with neurotransmitters and neuroactive dipeptides.

BackgroundDepression and obesity are highly prevalent, often co-occurring conditions marked by inflammation. Microbiome perturbations are implicated in obesity-inflammation-depression interrelationships, but how the microbiome mechanistically contributes to pathology remains unclear. Metabolomic investigations into microbial neuroactive metabolites may offer mechanistic insights into host-microbe interactions. Using 16S sequencing and untargeted mass spectrometry of saliva, and blood monocyte inflammation regulation assays, we identified key microbes, metabolites and host inflammation in association with depressive symptomatology, obesity, and depressive symptomatology-obesity comorbidity.ResultsGram-negative bacteria with inflammation potential were enriched relative to Gram-positive bacteria in comorbid obesity-depression, supporting the inflammation-oral microbiome link in obesity-depression interrelationships. Oral microbiome was more highly predictive of depressive symptomatology-obesity co-occurrences than of obesity or depressive symptomatology independently, suggesting specific microbial signatures associated with obesity-depression co-occurrences. Mass spectrometry analysis revealed significant changes in levels of signaling molecules of microbiota, microbial or dietary derived signaling peptides and aromatic amino acids among depressive symptomatology, obesity and comorbid obesity-depression. Furthermore, integration of the microbiome and metabolomics data revealed that key oral microbes, many previously shown to have neuroactive potential, co-occurred with potential neuropeptides and biosynthetic precursors of the neurotransmitters dopamine, epinephrine and serotonin.ConclusionsTogether, our findings offer novel insights into oral microbial-brain connection and potential neuroactive metabolites involved

Identification of the Bacterial Biosynthetic Gene Clusters of the Oral Microbiome Illuminates the Unexplored Social Language of Bacteria during Health and Disease

The healthy oral microbiome is symbiotic with the human host, importantly providing colonization resistance against potential pathogens. Dental caries and periodontitis are two of the world’s most common and costly chronic infectious diseases and are caused by a localized dysbiosis of the oral microbiome. Bacterially produced small molecules, often encoded by BGCs, are the primary communication media of bacterial communities and play a crucial, yet largely unknown, role in the transition from health to dysbiosis. This study provides a comprehensive mapping of the BGC repertoire of the human oral microbiome and identifies major differences in health compared to disease. Furthermore, BGC representation and expression is linked to the abundance of particular oral bacterial taxa in health versus dental caries and periodontitis. Overall, this study provides a significant insight into the chemical communication network of the healthy oral microbiome and how it devolves in the case of two prominent diseases.Small molecules are the primary communication media of the microbial world. Recent bioinformatic studies, exploring the biosynthetic gene clusters (BGCs) which produce many small molecules, have highlighted the incredible biochemical potential of the signaling molecules encoded by the human microbiome. Thus far, most research efforts have focused on understanding the social language of the gut microbiome, leaving crucial signaling molecules produced by oral bacteria and their connection to health versus disease in need of investigation. In this study, a total of 4,915 BGCs were identified across 461 genomes representing a broad taxonomic diversity of oral bacteria. Sequence similarity networking provided a putative product class for more than 100 unclassified novel BGCs. The newly identified BGCs were cross-referenced against 254 metagenomes and metatranscriptomes derived from individuals either with good oral health or with dental caries or periodontitis. This analysis revealed 2,473 BGCs, which were differentially represented across the oral microbiomes associated with health versus disease. Coabundance network analysis identified numerous inverse correlations between BGCs and specific oral taxa. These correlations were present in healthy individuals but greatly reduced in individuals with dental caries, which may suggest a defect in colonization resistance. Finally, corroborating mass spectrometry identified several compounds with homology to products of the predicted BGC classes. Together, these findings greatly expand the number of known biosynthetic pathways present in the oral microbiome and provide an atlas for experimental characterization of these abundant, yet poorly understood, molecules and socio-chemical relationships, which impact the development of caries and periodontitis, two of the world’s most common chronic diseases