Advances in constraint-based modelling of microbial communities

Abstract Microbial communities are near universally present in nature. A wealth of meta-omics data has been gathered from numerous ecosystems, such as the human gut, ocean or soil. Constraint-based reconstruction and analysis is a valuable tool for the contextualisation of meta-omics data and allows for the mechanistic prediction of metabolic fluxes. Advances in genome-scale reconstruction and multispecies modelling tools have enabled the construction and interrogation of constraint-based multispecies models on the microbiome scale spanning hundreds of organisms. Here, we give a comprehensive overview of the areas of application for these multiscale, strain- and molecule-resolved multispecies models, and discuss key works, in which computational modelling yielded novel biological knowledge. We show that constraint-based microbiome modelling can complement experimental approaches and has valuable applications spanning from ecology, human health, industry to environmental conservation

From coppice to high forest – vegetation change and mesophication in acidic mixed oak forests in the southeastern lowlands of Lower Saxony during 25 years

Die Wiederholung älterer Vegetationsaufnahmen auf gut relokalisierbaren Probeflächen zeigte in mitteleuropäischen Waldökosystemen oft starke Veränderungen der Vegetation als Ergebnis verschiedener Umwelteinwirkungen. Gegenstand dieser Untersuchung sind bodensaure, histo-risch vorwiegend als bäuerliche Niederwälder bewirtschaftete Eichen-Mischwälder des Betulo-Quercetum auf sandigen Partien der Geestplatten südlich des Aller-Urstromtals. Vierzehn eigene, in den Jahren 1990 und 1991 angefertigte Vegetationsaufnahmen in neun Waldgebieten wurden im Jahr 2015 wiederholt. Veränderungen in der Struktur und Bewirtschaftung gaben Anlass, die Nutzungsgeschichte der Bestände seit Ende des 18. Jahrhunderts anhand von historischen Kar-ten und durch Befragung von Lokalhistorikern, Waldbesitzern und Förstern zu dokumentieren. Folgende zwei Hypothesen bilden die Grundlage der Studie: (1) Bestandesschluss nach Aufgabe der historischen Niederwaldnutzung führte zu einem Rückgang lichtliebender Pflanzenarten. (2) Stickstoffdeposition aus der Luft hatte auf den relativ nährstoffarmen, grundwasserfernen Standorten die Zunahme von stickstoffliebenden Pflanzen und mesophilen Waldarten zur Folge. Anhand veränderter Häufigkeiten in den 14 Vegetationsaufnahmen wurden „Gewinner- und Verliererarten“ ermittelt; außerdem wurden Artenzahlen und mittlere Ellenberg-Zeigerwerte der rezenten und historischen Vegetationsaufnahmen verglichen. Im Verlauf von 25 Jahren waren alle Flächen, von denen neun historisch alte Wälder und fünf Aufforstungen oder Vorwälder auf ehemaligen Heide- und Ackerflächen waren, noch Eichen-Mischwälder des Betulo-Quercetum. Fast alle der acht noch 1990/91 niederwaldartigen Bestände hatten diesen Charakter verloren, indem bei Durchforstung nur ein Eichenstamm mehrstämmi-ger Stockausschläge belassen wurde. Insgesamt nahmen Birken als Pioniergehölze ab, und die Strauchschicht wurde u.a. durch die Zunahme der neophytischen Spätblühenden Traubenkirsche dichter. In Übereinstimmung mit Hypothese 1 konnte eine Entwicklung zu schattentoleranterer 120 Vegetation nachgewiesen werden; viele ehemals vorhandene Lichtzeiger – vor allem charakteristische Arten der Birken-Eichenwälder– gingen zurück oder verschwanden. Die mittleren Lichtzahlen der Flächen nahmen ab und die mittleren Feuchtezahlen infolge des ausgeglicheneren Bestandesklimas zu. Auch Hypothese 2 konnte bestätigt werden, denn eine Reihe von Stickstoffzeigern und mesophilen Waldarten nahm zu. Dies brachte eine Zunahme von obligaten Waldarten auf Kosten von auch auf mageren Offenlandstandorten verbreiteten Arten sowie bei den Zeigerwerten eine Erhöhung der mittleren Stickstoffzahlen mit sich. Neben Stickstoffeinträgen dürfte die Regeneration der Standorte durch geringere Biomasseentnahme hierfür eine Rolle spielen. Diese Entwicklungen sind in jüngerer Zeit auch in anderen Regionen Mitteleuropas nachgewiesen worden, doch war der Zeitraum seit der Erstaufnahme dort meist deutlich länger. Die Geschwindigkeit der Veränderungen überrascht daher. Die Ergebnisse unterstreichen, dass die Birken- Eichenwälder der Region nicht der potenziell natürlichen Vegetation entsprechen, sondern kulturgeschichtlich interessante Nutzungsrelikte sind. Eine weitere Bewirtschaftung als Eichenwald und ein beispielhafter Erhalt niederwaldartiger Nutzung ist wünschenswert; eine Erhaltung bzw. Wiederherstellung des früheren Vegetationszustands ist aber angesichts fortwährender Stickstoffeinträge und fehlenden Nährstoffentzugs unrealistisch.Resurveying historical permanent or quasi-permanent vegetation plots in Central European forest ecosystems often revealed strong vegetation changes over the past decades due to different environmental drivers. Subject of this study were acidic mixed oak forests (Betulo-Quercetum) on sandy soils on glacial deposits south of the Aller glacial valley (Lower Saxony, Germany), most of which have been historically used as coppice forests. Fourteen own relevés from the years 1990 and 1991 were resurveyed in 2015. Changes in structure and forest management gave reason to document the land use history of the forest stands since the second half of the 18th century, using historical maps and questioning of local historians, land owners and foresters. The following hypotheses were tested: (1) Canopy closure after abandonment of historical land use led to a decrease of heliophilous plant species. (2) Airborne nitrogen deposition led to an increase of nitrophilous plant species and mesophilous forest species on the relatively nutrientpoor and dry sites. Using frequency and cover changes winner and loser species were identified. Also species numbers as well as mean Ellenberg indicator values for actual and historical relevés were compared. During 25 years all stands, of which nine were ancient forests and five afforestations or pioneer forests on former heathland or farmland, were still mixed oak forests belonging to the Betulo- Quercetum. However, nearly all of the eight stands still recognizable as coppice forest in 1990/91 had lost this character due to conversion to high forest by cutting of side shoots from trunks. Altogether birch as pioneer tree decreased and the shrub canopy became denser, partly due to the spread of the neophyte Prunus serotina. In agreement with existing literature and hypothesis (1) a shift towards more shade-tolerant communities was proved. Light indicators, among them many characteristic plant species of acidic mixed oak forests, decreased or disappeared. This resulted not only in a decrease of mean Ellenberg light values, but also an increase of moisture values of Thilo Heinken: Vom bodensauren Niederwald zum mesophilen Hochwald – Vegetationsveränderungen in Eichenmischwäldern im Flachland südlich der Aller im Verlauf von 25 Jahren 121 the plots due to a more mesic microclimate. Also hypothesis (2) was confirmed, as a number of nitrogen indicators and mesophilous forest species increased, indicating a ‘mesophication’ of the studied forests. This resulted in an increase of strict forest species at the expense of species which also occur on nutrient-poor sites in the open land, and of mean nutrient values of the plots. Besides nitrogen deposition a soil recovery process due to a lower biomass removal may play a role for this effect. All trends have been recently described in other regions of Central Europe, but the time span between the first census and the resurvey was mostly much longer in these studies. The speed of vegetation change is thus surprising. The results emphasize that mixed oak forests do not correspond with the potential natural vegetation, but are interesting relicts of former landuse in cultural heritage terms. In the future a management as oak forest and an exemplary conservation of coppice forest stands is desirable, but a conservation or restoration of the former vegetation state is not realistic, given the continuous nitrogen deposition and missing removal of nutrients

Estudio de las reacciones diagnósticas del embarazo : Variaciones del hierro no hemínico, en el estado de gravidez

Índice - Estudio del método y la determinación de su sensibilidad con distintas concentraciones de sal férrica - Sensibilidad del método para una solución determinada de hierro. - Sensibilidad del método con un suero. - Variaciones fisiológicas del hierro no hemínico en mujeres no embarazadas - Variaciones del hierro en suero de mujeres embarazadas - Estudio cooperativo - Conclusiones - BibliografíaTesis digitalizada en SEDICI gracias a la Biblioteca Central de la Facultad de Ciencias Exactas (UNLP).Facultad de Ciencias Exacta

Microbiome Modelling Toolbox 2.0: efficient, tractable modelling of microbiome communities

Motivation: Constraint-Based Reconstruction and Analysis (COBRA) is a widely used approach for the interrogation and stratification of microbiome samples, yet applications to large-scale cohorts are hampered by limited scalability and efficiency of simulations. Results: We substantially improved the computation speed and scalability of a previous implementation for the construction and interrogation of personalized constraint-based microbiome models as well as implemented additional functionalities for analysis and visualization. Availability and implementation: Microbiome Modelling Toolbox and tutorials are freely available as part of the COBRA Toolbox at https://git.io/microbiomeModelingToolbox

Quantitative systems pharmacology and the personalized drug–microbiota–diet axis

Precision medicine is an emerging paradigm that aims at maximizing the benefits and minimizing the adverse effects of drugs. Realistic mechanistic models are needed to understand and limit heterogeneity in drug responses. While pharmacokinetic models describe in detail a drug's absorption and metabolism, they generally do not account for individual variations in response to environmental influences, in addition to genetic variation. For instance, the human gut microbiota metabolizes drugs and is modulated by diet, and it exhibits significant variation among individuals. However, the influence of the gut microbiota on drug failure or drug side effects is under-researched. Here, we review recent advances in computational modeling approaches that could contribute to a better, mechanism-based understanding of drug–microbiota–diet interactions and their contribution to individual drug responses. By integrating systems biology and quantitative systems pharmacology with microbiology and nutrition, the conceptually and technologically demand for novel approaches could be met to enable the study of individual variability, thereby providing breakthrough support for progress in precision medicine

The contribution of gut bacterial metabolites in the human immune signaling pathway of non-communicable diseases

The interaction disorder between gut microbiota and its host has been documented in different non-communicable diseases (NCDs) such as metabolic syndrome, neurodegenerative disease, and autoimmune disease. The majority of these altered interactions arise through metabolic cross-talk between gut microbiota and host immune system, inducing a low-grade chronic inflammation that characterizes all NCDs. In this review, we discuss the contribution of bacterial metabolites to immune signaling pathways involved in NCDs. We then review recent advances that aid to rationally design microbial therapeutics. A deeper understanding of these intersections between host and gut microbiota metabolism using metabolomics-based system biology platform promises to reveal the fundamental mechanisms that drive metabolic predispositions to disease and suggest new avenues to use microbial therapeutic opportunities for NCDs treatment and prevention.Analytical BioScience

The Microbiome Modeling Toolbox: from microbial interactions to personalized microbial communities

The application of constraint-based modeling to functionally analyze metagenomic data has been limited so far, partially due to the absence of suitable toolboxes. To address this gap, we created a comprehensive toolbox to model i) microbe-microbe and host-microbe metabolic interactions, and ii) microbial communities using microbial genome-scale metabolic reconstructions and metagenomic data. The Microbiome Modeling Toolbox extends the functionality of the COBRA Toolbox. The Microbiome Modeling Toolbox and the tutorials at https://git.io/microbiomeModelingToolbox

Personalized whole-body models integrate metabolism, physiology, and the gut microbiome

Comprehensive molecular-level models of human metabolism have been generated on a cellular level. However, models of whole-body metabolism have not been established as they require new methodological approaches to integrate molecular and physiological data. We developed a new metabolic network reconstruction approach that used organ-specific information from literature and omics data to generate two sex-specific whole-body metabolic (WBM) reconstructions. These reconstructions capture the metabolism of 26 organs and six blood cell types. Each WBM reconstruction represents whole-body organ-resolved metabolism with over 80,000 biochemical reactions in an anatomically and physiologically consistent manner. We parameterized the WBM reconstructions with physiological, dietary, and metabolomic data. The resulting WBM models could recapitulate known inter-organ metabolic cycles and energy use. We also illustrate that the WBM models can predict known biomarkers of inherited metabolic diseases in different biofluids. Predictions of basal metabolic rates, by WBM models personalized with physiological data, outperformed current phenomenological models. Finally, integrating microbiome data allowed the exploration of host-microbiome co-metabolism. Overall, the WBM reconstructions, and their derived computational models, represent an important step toward virtual physiological humans.Analytical BioScience

Adaptation of the Human Gut Microbiota Metabolic Network During the First Year After Birth

Predicting the metabolic behavior of the human gut microbiota in different contexts is one of the most promising areas of constraint-based modeling. Recently, we presented a supra-organismal approach to build context-specific metabolic networks of bacterial communities using functional and taxonomic assignments of meta-omics data. In this work, this algorithm is applied to elucidate the metabolic changes induced over the first year after birth in the gut microbiota of a cohort of Spanish infants. We used metagenomics data of fecal samples and nutritional data of 13 infants at five time points. The resulting networks for each time point were analyzed, finding significant alterations once solid food is introduced in the diet. Our work shows that solid food leads to a different pattern of output metabolites that can be potentially released from the gut microbiota to the host. Experimental validation is presented for ferulate, a neuroprotective metabolite involved in the gut-brain axis.IA was supported by a Basque Government predoctoral grant (PRE_2017_2_0028). SP-B was supported by a Spanish Government predoctoral grant (FPU14/01192). This manuscript will form part of the doctoral thesis of SP-B conducted within the context of the “Nutrition and Food Sciences Programme” at the University of Granada. This work was supported by the EU Project STANCE4HEALTH (contract number 816303) and the Ministry of Economy and Competitiveness of Spain (BIO2016-77998-R, SAF2009-13032-C02-02, CSD2009-00006 and SAF2012-31187)