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See detailMobilome-driven segregation of the resistome in biological wastewater treatment 2021.11.15.468621
de Nies, Laura UL; Busi, Susheel Bhanu UL; Kunath, Benoit Josef et al

E-print/Working paper (2021)

Biological wastewater treatment plants (BWWTP) are considered to be hotspots of evolution and subsequent spread of antimicrobial resistance (AMR). Mobile genetic elements (MGEs) promote the mobilization ... [more ▼]

Biological wastewater treatment plants (BWWTP) are considered to be hotspots of evolution and subsequent spread of antimicrobial resistance (AMR). Mobile genetic elements (MGEs) promote the mobilization and dissemination of antimicrobial resistance genes (ARGs) and are thereby critical mediators of AMR within the BWWTP microbial community. At present, it is unclear whether specific AMR categories are differentially disseminated via bacteriophages (phages) or plasmids. To understand the segregation of AMR in relation to MGEs, we analyzed meta-omic (metagenomic, metatranscriptomic and metaproteomic) data systematically collected over 1.5 years from a BWWTP. Our results showed a core group of fifteen AMR categories which were found across all timepoints. Some of these AMR categories were disseminated exclusively (bacitracin) or primarily (aminoglycoside, MLS, sulfonamide) via plasmids or phages (fosfomycin and peptide), whereas others were disseminated equally by both MGEs. Subsequent expression- and protein-level analyses further demonstrated that aminoglycoside, bacitracin and sulfonamide resistance genes were expressed more by plasmids, in contrast to fosfomycin and peptide AMR expression by phages, thereby validating our genomic findings. Longitudinal assessment further underlined these findings whereby the log2-fold changes of aminoglycoside, bacitracin and sulfonamide resistance genes were increased in plasmids, while fosfomycin and peptide resistance showed similar trends in phages. In the analyzed communities, the dominant taxon Candidatus Microthrix parvicella was a major contributor to several AMR categories whereby its plasmids primarily mediated aminoglycoside resistance. Importantly, we also found AMR associated with ESKAPEE pathogens within the BWWTP, for which MGEs also contributed differentially to the dissemination of ARGs. Collectively our findings pave the way towards understanding the segmentation of AMR within MGEs, thereby shedding new light on resistome populations and their mediators, essential elements that are of immediate relevance to human health.Competing Interest StatementThe authors have declared no competing interest. [less ▲]

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See detailGlacier-fed stream biofilms harbour diverse resistomes and biosynthetic gene clusters 2021.11.18.469141
Busi, Susheel Bhanu UL; de Nies, Laura UL; Pramateftaki, Paraskevi et al

E-print/Working paper (2021)

Background Antimicrobial resistance (AMR) is a universal phenomenon whose origins lay in natural ecological interactions such as competition within niches, within and between micro- to higher-order ... [more ▼]

Background Antimicrobial resistance (AMR) is a universal phenomenon whose origins lay in natural ecological interactions such as competition within niches, within and between micro- to higher-order organisms. However, the ecological and evolutionary processes shaping AMR need to be better understood in view of better antimicrobial stewardship. Resolving antibiotic biosynthetic pathways, including biosynthetic gene clusters (BGCs), and corresponding antimicrobial resistance genes (ARGs) may therefore help in understanding the inherent mechanisms. However, to study these phenomena, it is crucial to examine the origins of AMR in pristine environments with limited anthropogenic influences. In this context, epilithic biofilms residing in glacier-fed streams (GFSs) are an excellent model system to study diverse, intra- and inter-domain, ecological crosstalk.Results We assessed the resistomes of epilithic biofilms from GFSs across the Southern Alps (New Zealand) and the Caucasus (Russia) and observed that both bacteria and eukaryotes encoded twenty-nine distinct AMR categories. Of these, beta-lactam, aminoglycoside, and multidrug resistance were both abundant and taxonomically distributed in most of the bacterial and eukaryotic phyla. AMR-encoding phyla included Bacteroidota and Proteobacteria among the bacteria, alongside Ochrophyta (algae) among the eukaryotes. Additionally, BGCs involved in the production of antibacterial compounds were identified across all phyla in the epilithic biofilms. Furthermore, we found that several bacterial genera (Flavobacterium, Polaromonas, etc.) including representatives of the superphylum Patescibacteria encode both ARGs and BGCs within close proximity of each other, thereby demonstrating their capacity to simultaneously influence and compete within the microbial community.Conclusions Our findings highlight the presence and abundance of AMR in epilithic biofilms within GFSs. Additionally, we identify their role in the complex intra- and inter-domain competition and the underlying mechanisms influencing microbial survival in GFS epilithic biofilms. We demonstrate that eukaryotes may serve as AMR reservoirs owing to their potential for encoding ARGs. We also find that the taxonomic affiliation of the AMR and the BGCs are congruent. Importantly, our findings allow for understanding how naturally occurring BGCs and AMR contribute to the epilithic biofilms mode of life in GFSs. Importantly, these observations may be generalizable and potentially extended to other environments which may be more or less impacted by human activity.Competing Interest StatementThe authors have declared no competing interest.AMRAntimicrobial resistanceARGsAntimicrobial resistance gene(s)BGCBiosynthetic gene clustersCACaucasusCPRCandidate Phyla radiationGFSsGlacier-fed stream(s)GLGlacierIRS-RSisoleucyl-tRNA synthetase - high resistanceIMPIntegrate Meta-Omics PipelineKEGGKyoto Encyclopedia of Genes and GenomesMAGsMetagenome-assembled genome(s)NRPSNon-ribosomal peptide synthetasesPKSPolyketide synthases (type I and type II)RiPPsPost-translationally modified peptide(s)SASouthern Alps [less ▲]

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See detailGenomic and metabolic adaptations of biofilms to ecological windows of opportunities in glacier-fed streams 2021.10.07.463499
Busi, Susheel Bhanu UL; Bourquin, Massimo; Fodelianakis, Stilianos et al

E-print/Working paper (2021)

Microorganisms dominate life in cryospheric ecosystems. In glacier-fed streams (GFSs), ecological windows of opportunities allow complex microbial biofilms to develop and transiently form the basis of the ... [more ▼]

Microorganisms dominate life in cryospheric ecosystems. In glacier-fed streams (GFSs), ecological windows of opportunities allow complex microbial biofilms to develop and transiently form the basis of the food web, thereby controlling key ecosystem processes. Here, using high-resolution metagenomics, we unravel strategies that allow biofilms to seize this opportunity in an ecosystem otherwise characterized by harsh environmental conditions. We found a diverse microbiome spanning the entire tree of life and including a rich virome. Various and co-existing energy acquisition pathways point to diverse niches and the simultaneous exploitation of available resources, likely fostering the establishment of complex biofilms in GFSs during windows of opportunity. The wide occurrence of rhodopsins across metagenome-assembled genomes (MAGs), besides chlorophyll, highlights the role of solar energy capture in these biofilms. Concomitantly, internal carbon and nutrient cycling between photoautotrophs and heterotrophs may help overcome constraints imposed by the high oligotrophy in GFSs. MAGs also revealed mechanisms potentially protecting bacteria against low temperatures and high UV-radiation. The selective pressure of the GFS environment is further highlighted by the phylogenomic analysis, differentiating the representatives of the genus Polaromonas, an important component of the GFS microbiome, from those found in other ecosystems. Our findings reveal key genomic underpinnings of adaptive traits that contribute to the success of complex biofilms to exploit environmental opportunities in GFSs, now rapidly changing owing to global warming.Competing Interest StatementThe authors have declared no competing interest. [less ▲]

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See detailSARS-CoV-2 transmission risk from asymptomatic carriers: Results from a mass screening programme in Luxembourg
Wilmes, Paul UL; Zimmer, Jacques UL; Schulz, Jasmin et al

in The Lancet Regional Health. Europe (2021), 4

Background To accompany the lifting of COVID-19 lockdown measures, Luxembourg implemented a mass screening (MS) programme. The first phase coincided with an early summer epidemic wave in 2020. Methods rRT ... [more ▼]

Background To accompany the lifting of COVID-19 lockdown measures, Luxembourg implemented a mass screening (MS) programme. The first phase coincided with an early summer epidemic wave in 2020. Methods rRT-PCR-based screening for SARS-CoV-2 was performed by pooling of samples. The infrastructure allowed the testing of the entire resident and cross-border worker populations. The strategy relied on social connectivity within different activity sectors. Invitation frequencies were tactically increased in sectors and regions with higher prevalence. The results were analysed alongside contact tracing data. Findings The voluntary programme covered 49 of the resident and 22 of the cross-border worker populations. It identified 850 index cases with an additional 249 cases from contact tracing. Over-representation was observed in the services, hospitality and construction sectors alongside regional differences. Asymptomatic cases had a significant but lower secondary attack rate when compared to symptomatic individuals. Based on simulations using an agent-based SEIR model, the total number of expected cases would have been 42·9 (90 CI [-0·3, 96·7]) higher without MS. Mandatory participation would have resulted in a further difference of 39·7 [19·6, 59·2]. Interpretation Strategic and tactical MS allows the suppression of epidemic dynamics. Asymptomatic carriers represent a significant risk for transmission. Containment of future outbreaks will depend on early testing in sectors and regions. Higher participation rates must be assured through targeted incentivisation and recurrent invitation. Funding This project was funded by the Luxembourg Ministries of Higher Education and Research, and Health. [less ▲]

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See detailCritical Assessment of MetaProteome Investigation (CAMPI): a multi-laboratory comparison of established workflows
Van Den Bossche, Tim; Kunath, Benoît UL; Schallert, Kay et al

in Nature Communications (2021), 12(1), 7305

Abstract Metaproteomics has matured into a powerful tool to assess functional interactions in microbial communities. While many metaproteomic workflows are available, the impact of method choice on ... [more ▼]

Abstract Metaproteomics has matured into a powerful tool to assess functional interactions in microbial communities. While many metaproteomic workflows are available, the impact of method choice on results remains unclear. Here, we carry out a community-driven, multi-laboratory comparison in metaproteomics: the critical assessment of metaproteome investigation study (CAMPI). Based on well-established workflows, we evaluate the effect of sample preparation, mass spectrometry, and bioinformatic analysis using two samples: a simplified, laboratory-assembled human intestinal model and a human fecal sample. We observe that variability at the peptide level is predominantly due to sample processing workflows, with a smaller contribution of bioinformatic pipelines. These peptide-level differences largely disappear at the protein group level. While differences are observed for predicted community composition, similar functional profiles are obtained across workflows. CAMPI demonstrates the robustness of present-day metaproteomics research, serves as a template for multi-laboratory studies in metaproteomics, and provides publicly available data sets for benchmarking future developments. [less ▲]

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See detailDichloromethane Degradation Pathway from Unsequenced Hyphomicrobium sp. MC8b Rapidly Explored by Pan-Proteomics
Hayoun, Karim; Geersens, Emilie; Laczny, Cedric Christian UL et al

in Microorganisms (2020)

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See detailPatterns and Drivers of Extracellular Enzyme Activity in New Zealand Glacier-Fed Streams
Kohler, Tyler J.; Peter, Hannes; Fodelianakis, Stilianos et al

in Frontiers in Microbiology (2020), 11

Glacier-fed streams (GFSs) exhibit near-freezing temperatures, variable flows, and often high turbidities. Currently, the rapid shrinkage of mountain glaciers is altering the delivery of meltwater ... [more ▼]

Glacier-fed streams (GFSs) exhibit near-freezing temperatures, variable flows, and often high turbidities. Currently, the rapid shrinkage of mountain glaciers is altering the delivery of meltwater, solutes, and particulate matter to GFSs, with unknown consequences for their ecology. Benthic biofilms dominate microbial life in GFSs, and play a major role in their biogeochemical cycling. Mineralization is likely an important process for microbes to meet elemental budgets in these systems due to commonly oligotrophic conditions, and extracellular enzymes retained within the biofilm enable the degradation of organic matter and acquisition of carbon (C), nitrogen (N), and phosphorus (P). The measurement and comparison of these extracellular enzyme activities (EEA) can in turn provide insight into microbial elemental acquisition effort relative to environmental availability. To better understand how benthic biofilm communities meet resource demands, and how this might shift as glaciers vanish under climate change, we investigated biofilm EEA in 20 GFSs varying in glacier influence from New Zealand’s Southern Alps. Using turbidity and distance to the glacier snout normalized for glacier size as proxies for glacier influence, we found that bacterial abundance (BA), chlorophyll a (Chl a), extracellular polymeric substances (EPS), and total EEA per gram of sediment increased with decreasing glacier influence. Yet, when normalized by BA, EPS decreased with decreasing glacier influence, Chl a still increased, and there was no relationship with total EEA. Based on EEA ratios, we found that the majority of GFS microbial communities were N-limited, with a few streams of different underlying bedrock geology exhibiting P-limitation. Cell-specific C-acquiring EEA was positively related to the ratio of Chl a to BA, presumably reflecting the utilization of algal exudates. Meanwhile, cell-specific N-acquiring EEA were positively correlated with the concentration of dissolved inorganic nitrogen (DIN), and both N- and P-acquiring EEA increased with greater cell-specific EPS. Overall, our results reveal greater glacier influence to be negatively related to GFS biofilm biomass parameters, and generally associated with greater microbial N demand. These results help to illuminate the ecology of GFS biofilms, along with their biogeochemical response to a shifting habitat template with ongoing climate change. [less ▲]

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See detailRoles of bacteriophages, plasmids and CRISPR immunity in microbial community dynamics revealed using time-series integrated meta-omics
Martinez Arbas, Susana UL; Narayanasamy, Shaman; Herold, Malte et al

in Nature Microbiology (2020)

Viruses and plasmids (invasive mobile genetic elements (iMGEs)) have important roles in shaping microbial communities, but their dynamic interactions with CRISPR-based immunity remain unresolved. We ... [more ▼]

Viruses and plasmids (invasive mobile genetic elements (iMGEs)) have important roles in shaping microbial communities, but their dynamic interactions with CRISPR-based immunity remain unresolved. We analysed generation-resolved iMGE–host dynamics spanning one and a half years in a microbial consortium from a biological wastewater treatment plant using integrated meta-omics. We identified 31 bacterial metagenome-assembled genomes encoding complete CRISPR–Cas systems and their corresponding iMGEs. CRISPR-targeted plasmids outnumbered their bacteriophage counterparts by at least fivefold, highlighting the importance of CRISPR-mediated defence against plasmids. Linear modelling of our time-series data revealed that the variation in plasmid abundance over time explained more of the observed community dynamics than phages. Community-scale CRISPR-based plasmid–host and phage–host interaction networks revealed an increase in CRISPR-mediated interactions coinciding with a decrease in the dominant ‘Candidatus Microthrix parvicella’ population. Protospacers were enriched in sequences targeting genes involved in the transmission of iMGEs. Understanding the factors shaping the fitness of specific populations is necessary to devise control strategies for undesirable species and to predict or explain community-wide phenotypes. [less ▲]

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See detailOptimised biomolecular extraction for metagenomic analysis of microbial biofilms from high-mountain streams
Busi, Susheel Bhanu UL; Pramateftaki, Paraskevi; Brandani, Jade et al

in PeerJ (2020)

Glacier-fed streams (GFS) are harsh ecosystems dominated by microbial life organized in benthic biofilms, yet the biodiversity and ecosystem functions provided by these communities remain under ... [more ▼]

Glacier-fed streams (GFS) are harsh ecosystems dominated by microbial life organized in benthic biofilms, yet the biodiversity and ecosystem functions provided by these communities remain under-appreciated. To better understand the microbial processes and communities contributing to GFS ecosystems, it is necessary to leverage high throughput sequencing. Low biomass and high inorganic particle load in GFS sediment samples may affect nucleic acid extraction efficiency using extraction methods tailored to other extreme environments such as deep-sea sediments. Here, we benchmarked the utility and efficacy of four extraction protocols, including an up-scaled phenol-chloroform protocol. We found that established protocols for comparable sample types consistently failed to yield sufficient high-quality DNA, delineating the extreme character of GFS. The methods differed in the success of downstream applications such as library preparation and sequencing. An adapted phenol-chloroform-based extraction method resulted in higher yields and better recovered the expected taxonomic profile and abundance of reconstructed genomes when compared to commercially-available methods. Affordable and straight-forward, this method consistently recapitulated the abundance and genomes of a mock community, including eukaryotes. Moreover, by increasing the amount of input sediment, the protocol is readily adjustable to the microbial load of the processed samples without compromising protocol efficiency. Our study provides a first systematic and extensive analysis of the different options for extraction of nucleic acids from glacier-fed streams for high-throughput sequencing applications, which may be applied to other extreme environments. [less ▲]

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See detailSARS-CoV-2 Transmission in Educational Settings During an Early Summer Epidemic Wave in Luxembourg
Mossong, Joël; Mombaerts, Laurent UL; Veiber, Lisa UL et al

E-print/Working paper (2020)

Background: The role of schools and children in the transmission of SARS-CoV-2 remains to be determined. Following a first wave in spring and gradual easing of lockdown, Luxembourg experienced an early ... [more ▼]

Background: The role of schools and children in the transmission of SARS-CoV-2 remains to be determined. Following a first wave in spring and gradual easing of lockdown, Luxembourg experienced an early second epidemic wave before the start of summer school holidays on 15th July. This provided the opportunity to study the role of school-age children and school settings in SARS-CoV-2 transmission. More specifically, we compared the incidence in school-age children, teachers and the general working population, and estimated the number of secondary transmissions occurring at schools using contact tracing data. Findings: While SARS-CoV-2 incidence was much higher in adults aged 20 and above than in children aged 0 to 19 during the first wave in spring, no significant difference was found during the second wave in early summer. The incidence during the second wave was similar for pupils, teachers and the general working population. Based on a total of 424 reported confirmed COVID-19 cases in school-age children and teachers, we estimate that 179 index cases caused 49 secondary transmissions in schools. While some small clusters of mainly student-to-student transmission within the same class were identified, we did not observe any large outbreaks with multiple generations of infection. Interpretation: Transmission of SARS-CoV-2 within Luxembourg schools was limited during the early summer epidemic wave in 2020. Precautionary measures including physical distancing as well as easy access to testing, systematic contact tracing appears to have been successful in mitigating transmission within educational settings. Funding Statement: LV is supported by the Luxembourg National Research Fund grant COVID-19/2020- 1/14701707/REBORN, LM is supported by Luxembourg National Research Fund grant COVID19/14863306/PREVID, PW is supported by the European Research Council (ERC-CoG 863664). Declaration of Interests: No competing interests. Ethics Approval Statement: The Health Directorate has the legal permission to process patient confidential information for national surveillance of communicable diseases in general and contact tracing for the COVID-19 pandemic and individual patient consent is not required. [less ▲]

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See detailIntegration of time-series meta-omics data reveals how microbial ecosystems respond to disturbance
Herold, Malte; Martinez Arbas, Susana UL; Narayanasamy, Shaman et al

in Nature Communications (2020)

The development of reliable, mixed-culture biotechnological processes hinges on understanding how microbial ecosystems respond to disturbances. Here we reveal extensive phenotypic plasticity and niche ... [more ▼]

The development of reliable, mixed-culture biotechnological processes hinges on understanding how microbial ecosystems respond to disturbances. Here we reveal extensive phenotypic plasticity and niche complementarity in oleaginous microbial populations from a biological wastewater treatment plant. We perform meta-omics analyses (metagenomics, metatranscriptomics, metaproteomics and metabolomics) on in situ samples over 14 months at weekly intervals. Based on 1,364 de novo metagenome-assembled genomes, we uncover four distinct fundamental niche types. Throughout the time-series, we observe a major, transient shift in community structure, coinciding with substrate availability changes. Functional omics data reveals extensive variation in gene expression and substrate usage amongst community members. Ex situ bioreactor experiments confirm that responses occur within five hours of a pulse disturbance, demonstrating rapid adaptation by specific populations. Our results show that community resistance and resilience are a function of phenotypic plasticity and niche complementarity, and set the foundation for future ecological engineering efforts. [less ▲]

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See detailCompositional and functional characterisation of biomass-degrading microbial communities in guts of plant fibre- and soil-feeding higher termites.
Marynowska, Martyna; Goux, Xavier; Sillam-Dusses, David et al

in Microbiome (2020)

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See detailIntegrative omics analysis of the termite gut system adaptation to Miscanthus diet identifies lignocellulose degradation enzymes.
Calusinska, Magdalena; Marynowska, Martyna; Bertucci, Marie UL et al

in Communications Biology (2020)

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See detailGlutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function
Kurniawan, Henry; Franchina, Davide G.; Guerra, Luana UL et al

in Cell Metabolism (2020), 31(5), 920--9367

Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for ... [more ▼]

Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine’s functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase ( Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality. [less ▲]

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See detailUnderstanding the role of Fusobacterium nucleatum metabolism in colon cancer initiation and progression
Ternes, Dominik UL; Karta, Jessica UL; Tsenkova, Mina UL et al

Poster (2020, February 22)

Accumulating evidence suggests that dysbiosis, a state of pathological imbalance in the human gut microbiome, is present in patients suffering from colorectal cancer (CRC). 16S rRNA gene sequencing, as ... [more ▼]

Accumulating evidence suggests that dysbiosis, a state of pathological imbalance in the human gut microbiome, is present in patients suffering from colorectal cancer (CRC). 16S rRNA gene sequencing, as well as metagenomic and metatranscriptomic analyses, identified specific bacteria being associated with CRC. Among others, Fusobacterium ssp. have been found to directly interact with cancer or immune cells of their host. However, only a limited number of CRC-associated microbes have been examined for host-microbial interactions and, as such, the role of bacteria in the etiology of the disease remains largely elusive. Our aim is the development of predictive and experimental models that allow to not only study the host-microbiota interactions but are also amenable to high-throughput experimentation and large-scale omics-data integration. Ultimately, such models should help to get from meta-omics to cellular mechanism and, moreover, serve as tools for reproducible analyses of host-microbial interaction mechanisms of on a transcriptomic, proteomic, and metabolomic level. Our research proposes an integrative study approach allowing us to bridge meta-omics with functional mechanisms by focusing on the interaction taking place between F. nucleatum and patient-derived CRC cells. [less ▲]

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See detailMicrobiome in Colorectal Cancer: How to Getfrom Meta-omics to Mechanism?
Ternes, Dominik UL; Karta, Jessica UL; Tsenkova, Mina UL et al

in Trends in Microbiology (2020)

Mounting evidence from metagenomic analyses suggests that a state of pathological microbial imbalance or dysbiosis is prevalent in the gut of patients with colorectal cancer. Several bacterial taxa have ... [more ▼]

Mounting evidence from metagenomic analyses suggests that a state of pathological microbial imbalance or dysbiosis is prevalent in the gut of patients with colorectal cancer. Several bacterial taxa have been identified of which representative isolate cultures interact with human cancer cells in vitro and trigger disease path-ways in animal models. However, how the complex interrelationships in dysbiotic communities may be involved in cancer pathogenesis remains a crucial question.Here, we provide a survey of current knowledge of the gut microbiome in colorectal cancer. Moving beyond observational studies, we outline new experimental approaches for gaining ecosystem-level mechanistic understanding of the gut microbiome’s role in cancer pathogenesis [less ▲]

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See detailConnecting environmental exposure and neurodegeneration using cheminformatics and high resolution mass spectrometry: potential and challenges
Schymanski, Emma UL; Baker, Nancy C.; Williams, Antony J et al

in Environmental Science. Processes and Impacts (2019)

Connecting chemical exposures over a lifetime to complex chronic diseases with multifactorial causes such as neurodegenerative diseases is an immense challenge requiring a long-term, interdisciplinary ... [more ▼]

Connecting chemical exposures over a lifetime to complex chronic diseases with multifactorial causes such as neurodegenerative diseases is an immense challenge requiring a long-term, interdisciplinary approach. Rapid developments in analytical and data technologies, such as non-target high resolution mass spectrometry (NT-HR-MS), have opened up new possibilities to accomplish this, inconceivable 20 years ago. While NT-HR-MS is being applied to increasingly complex research questions, there are still many unidentified chemicals and uncertainties in linking exposures to human health outcomes and environmental impacts. In this perspective, we explore the possibilities and challenges involved in using cheminformatics and NT-HR-MS to answer complex questions that cross many scientific disciplines, taking the identification of potential (small molecule) neurotoxicants in environmental or biological matrices as a case study. We explore capturing literature knowledge and patient exposure information in a form amenable to high-throughput data mining, and the related cheminformatic challenges. We then briefly cover which sample matrices are available, which method(s) could potentially be used to detect these chemicals in various matrices and what remains beyond the reach of NT-HR-MS. We touch on the potential for biological validation systems to contribute to mechanistic understanding of observations and explore which sampling and data archiving strategies may be required to form an accurate, sustained picture of small molecule signatures on extensive cohorts of patients with chronic neurodegenerative disorders. Finally, we reflect on how NT-HR-MS can support unravelling the contribution of the environment to complex diseases. [less ▲]

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See detailIntegrated In Vitro and In Silico Modeling Delineates the Molecular Effects of a Synbiotic Regimen on Colorectal-Cancer-Derived Cells
Greenhalgh, Kacy UL; Ramiro Garcia, Javier UL; Heinken et al

in Cell Reports (2019), 27

By modulating the human gut microbiome, prebiotics and probiotics (combinations of which are called synbiotics) may be used to treat diseases such as colorectal cancer (CRC). Methodological limitations ... [more ▼]

By modulating the human gut microbiome, prebiotics and probiotics (combinations of which are called synbiotics) may be used to treat diseases such as colorectal cancer (CRC). Methodological limitations have prevented determining the potential combina- torial mechanisms of action of such regimens. We expanded our HuMiX gut-on-a-chip model to co-culture CRC-derived epithelial cells with a model probiotic under a simulated prebiotic regimen, and we integrated the multi-omic results with in silico metabolic modeling. In contrast to individual prebi- otic or probiotic treatments, the synbiotic regimen caused downregulation of genes involved in procarci- nogenic pathways and drug resistance, and reduced levels of the oncometabolite lactate. Distinct ratios of organic and short-chain fatty acids were produced during the simulated regimens. Treatment of primary CRC-derived cells with a molecular cocktail reflecting the synbiotic regimen attenuated self-renewal ca- pacity. Our integrated approach demonstrates the potential of modeling for rationally formulating synbi- otics-based treatments in the future. [less ▲]

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See detailDeep neural networks outperform human expert's capacity in characterizing bioleaching bacterial biofilm composition
Buetti-Dinh, Antoine; Galli, Vanni; Bellenberg, Sören et al

in Biotechnology Reports (2019)

Background Deep neural networks have been successfully applied to diverse fields of computer vision. However, they only outperform human capacities in a few cases. Methods The ability of deep neural ... [more ▼]

Background Deep neural networks have been successfully applied to diverse fields of computer vision. However, they only outperform human capacities in a few cases. Methods The ability of deep neural networks versus human experts to classify microscopy images was tested on biofilm colonization patterns formed on sulfide minerals composed of up to three different bioleaching bacterial species attached to chalcopyrite sample particles. Results A low number of microscopy images per category (<600) was sufficient for highly efficient computational analysis of the biofilm's bacterial composition. The use of deep neural networks reached an accuracy of classification of ∼90% compared to ∼50% for human experts. Conclusions Deep neural networks outperform human experts’ capacity in characterizing bacterial biofilm composition involved in the degradation of chalcopyrite. This approach provides an alternative to standard, time-consuming biochemical methods. [less ▲]

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See detailExtensive transmission of microbes along the gastrointestinal tract
Schmidt, Thomas; Hayward, Matthew; Coelho, Luis et al

in eLife (2019)

The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary ... [more ▼]

The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary and fecal microbial strain populations of 310 species in 470 individuals from five countries, we found that transmission to, and subsequent colonization of, the large intestine by oral microbes is common and extensive among healthy individuals. We found evidence for a vast majority of oral species to be transferable, with increased levels of transmission in colorectal cancer and rheumatoid arthritis patients and, more generally, for species described as opportunistic pathogens. This establishes the oral cavity as an endogenous reservoir for gut microbial strains, and oral-fecal transmission as an important process that shapes the gastrointestinal microbiome in health and disease. [less ▲]

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