Role of metabolism and ecology in the emergence of microbial communities

Polymicrobial communities often show complex patterns of metabolic and ecological interactions, yet our understanding of how the properties of communities emerge from the metabolic rules of species interactions is still limited. A central feature of metabolic interactions within microbial communities is ‘cross-feeding’, where one species or lineage consumes the metabolic by-products of another. Cross-feeding bacteria excrete and consume a wide range of metabolites and this sets the stage for diverse intra- and inter-specific metabolic interactions. In this thesis, I use ecological and evolutionary theory to address a number of critical questions posed by cross-feeding bacteria, with a particular focus on the role played by microbial metabolism in driving the emergence and dynamics of microbial interactions. First, I explore the conditions that favour the emergence and maintenance of cooperative cross-feeding and show that the evolutionary outcome depends strongly on the shape of the trade-off curves between the costs and benefits of cooperation. Second, I investigate the origins of cross-feeding interactions via single lineage diversification and derive new predictions on the physiological mechanisms that may explain the stable coexistence of a cross-feeding polymorphism that evolved from a single clone. Third, I investigate what are the ecological consequences of cross-feeding metabolic interactions and demonstrate theoretically that a simple mechanism of trade can generate a diverse array of ecological relationships. Furthermore, I show the importance of the metabolic by-product properties in determining the ecological outcome. Fourth, I investigate how metabolic constraints of individual species shape the emergent functional and structural relationships among species. I show that strong metabolic interdependence drives the emergence of mutualism, robust interspecific mixing, and increased community productivity. Furthermore, I show that these emergent community properties are driven by demographic feedbacks. In general, these findings support the idea that bridging microbial ecology and metabolism is a critical step toward a better understanding of the factors governing the emergence and dynamics of polymicrobial interactions

Evolution of Cooperative Cross-Feeding Could Be Less Challenging Than Originally Thought

The act of cross-feeding whereby unrelated species exchange nutrients is a common feature of microbial interactions and could be considered a form of reciprocal altruism or reciprocal cooperation. Past theoretical work suggests that the evolution of cooperative cross-feeding in nature may be more challenging than for other types of cooperation. Here we re-evaluate a mathematical model used previously to study persistence of cross-feeding and conclude that the maintenance of cross-feeding interactions could be favoured for a larger parameter ranges than formerly observed. Strikingly, we also find that large populations of cross-feeders are not necessarily vulnerable to extinction from an initially small number of cheats who receive the benefit of cross-feeding but do not reciprocate in this cooperative interaction. This could explain the widespread cooperative cross-feeding observed in natural populations

From Metabolism to Ecology:Cross-Feeding Interactions Shape the Balance between Polymicrobial Conflict and Mutualism

Polymicrobial interactions are widespread in nature, and play a major role in maintaining human health and ecosystems. Whenever one organism uses metabolites produced by another organism as energy or nutrient sources, this is called cross-feeding. The ecological outcomes of cross-feeding interactions are poorly understood and potentially diverse: mutualism, competition, exploitation or commensalism. A major reason for this uncertainty is the lack of theoretical approaches linking microbial metabolism to microbial ecology. To address this issue, we explore the dynamics of a one-way interspecific cross-feeding interaction, in which food can be traded for a service (detoxification). Our results show that diverse ecological interactions (competition, mutualism, exploitation) can emerge from this simple cross-feeding interaction, and can be predicted by the metabolic, demographic and environmental parameters that govern the balance of the costs and benefits of association. In particular, our model predicts stronger mutualism for intermediate by-product toxicity because the resource-service exchange is constrained to the service being neither too vital (high toxicity impairs resource provision) nor dispensable (low toxicity reduces need for service). These results support the idea that bridging microbial ecology and metabolism is a critical step towards a better understanding of the factors governing the emergence and dynamics of polymicrobial interactions

Emergent simplicity in microbial community assembly

Published in final edited form as: Science. 2018 August 03; 361(6401): 469–474. doi:10.1126/science.aat1168.A major unresolved question in microbiome research is whether the complex taxonomic architectures observed in surveys of natural communities can be explained and predicted by fundamental, quantitative principles. Bridging theory and experiment is hampered by the multiplicity of ecological processes that simultaneously affect community assembly in natural ecosystems. We addressed this challenge by monitoring the assembly of hundreds of soil- and plant-derived microbiomes in well-controlled minimal synthetic media. Both the community-level function and the coarse-grained taxonomy of the resulting communities are highly predictable and governed by nutrient availability, despite substantial species variability. By generalizing classical ecological models to include widespread nonspecific cross-feeding, we show that these features are all emergent properties of the assembly of large microbial communities, explaining their ubiquity in natural microbiomes.The funding for this work partly results from a Scialog Program sponsored jointly by the Research Corporation, for Science Advancement and. the Gordon and Betty Moore Foundation through grants to Yale University and Boston University by the Research Corporation and by the Simons Foundation. This work was also supported by a young; investigator award from the Human Frontier Science Program to A.S. (RGY0077/2016) and by NIH NIGMS grant 1R35GM119461 and a Simons Investigator as in the Mathematical Modeling of Living Systems (MMLS) to P.M.; D.S. and J.E.G. additionally acknowledge funding from the Defense Advanced Research Projects Agency (purchase request no. HR0011515303, contract no.. HR0011-15-0-0091), the U.S. Department of Energy (DE-SC0012627), the NIH (T32GM100842, 5R01DE024468, R01GM121950, and Sub_P30DK036836_P&F), the National Science Foundation (1457695), the Human Frontier Science Program (RGP0020/2016) and the Boston University Interdisciplinary Biomedical Research Office. (Research Corporation, for Science Advancement; Gordon and Betty Moore Foundation; Boston University by the Research Corporation; Simons Foundation.; RGY0077/2016 - uman Frontier Science Program; 1R35GM119461 - NIH NIGMS grant; Simons Investigator as in the Mathematical Modeling of Living Systems (MMLS); HR0011515303 - Defense Advanced Research Projects Agency; HR0011-15-0-0091 - Defense Advanced Research Projects Agency; T32GM100842 - NIH; 5R01DE024468 - NIH; R01GM121950 - NIH; ub_P30DK036836 - NIH; 1457695 - National Science Foundation; RGP0020/2016 - Human Frontier Science Program; Boston University Interdisciplinary Biomedical Research Office)Accepted manuscrip

Functional characterization of the novel sequence variant p.S304R in the hinge region of TSHR in a congenital hypothyroidism patients and analogy with other formerly known mutations of this gene portion

Context: Thyroid dysgenesis may be associated with loss-of-function mutations in the thyrotropin receptor (TSHR) gene. Objectives: The aim of this study was to characterize a novel TSHR gene variant found in one patient harboring congenital hypothyroidism (CH) from a cohort of patients with various types of thyroid defects. Materials and methods: This cross-sectional cohort study involved 118 patients with CH and their family members, including 45 with familial and 73 with sporadic diseases. The thyroid gland was normal in 23 patients, 25 patients had hypoplasia, 25 hemithyroid agenesis, 21 had athyreosis, and 21 had ectopy. Genomic DNA was extracted, and 10 exons of the TSHR gene were amplified and sequenced. Mutations in other candidate genes were investigated. Ortholog alignment was performed, and TSHR functional assays were evaluated. Results: We identified one previously unknown missense variation in the hinge region (HinR) of the TSHR gene (p.S304R) in one patient with thyroid hypoplasia. This variant is conserved in our ortholog alignment. However, the p.S304R TSHR variant presented a normal glycosylation pattern and signal transduction activity in functional analysis. Conclusion: We report the ocurrence of a novel nonsynonymous substitution in the HinR of the large N-terminal extracellular domain of the TSHR gene in a patient with thyroid hypoplasia. In contrast with four others in whom TSHR mutations of the hinge portion were previously identified, the p.S304R TSHR variation neither affected TSH binding nor cAMP pathway activation. This TSHR gene variant was documented in a CH patient, but the current data do not support its role in the clinical phenotype

Within-Host Dynamics of Multi-Species Infections: Facilitation, Competition and Virulence

Host individuals are often infected with more than one parasite species (parasites defined broadly, to include viruses and bacteria). Yet, research in infection biology is dominated by studies on single-parasite infections. A focus on single-parasite infections is justified if the interactions among parasites are additive, however increasing evidence points to non-additive interactions being the norm. Here we review this evidence and theoretically explore the implications of non-additive interactions between co-infecting parasites. We use classic Lotka-Volterra two-species competition equations to investigate the within-host dynamical consequences of various mixes of competition and facilitation between a pair of co-infecting species. We then consider the implications of these dynamics for the virulence (damage to host) of co-infections and consequent evolution of parasite strategies of exploitation. We find that whereas one-way facilitation poses some increased virulence risk, reciprocal facilitation presents a qualitatively distinct destabilization of within-host dynamics and the greatest risk of severe disease

Metabolic and demographic feedbacks shape the emergent spatial structure and function of microbial communities

Microbes are predominantly found in surface-attached and spatially structured polymicrobial communities. Within these communities, microbial cells excrete a wide range of metabolites, setting the stage for interspecific metabolic interactions. The links, however, between metabolic and ecological interactions (functional relationships), and species spatial organization (structural relationships) are still poorly understood. Here, we use an individual-based modelling framework to simulate the growth of a two-species surface-attached community where food (resource) is traded for detoxification (service) and investigate how metabolic constraints of individual species shape the emergent structural and functional relationships of the community. We show that strong metabolic interdependence drives the emergence of mutualism, robust interspecific mixing, and increased community productivity. Specifically, we observed a striking and highly stable emergent lineage branching pattern, generating a persistent lineage mixing that was absent when the metabolic exchange was removed. These emergent community properties are driven by demographic feedbacks, such that aid from neighbouring cells directly enhances focal cell growth, which in turn feeds back to neighbour fecundity. In contrast, weak metabolic interdependence drives conflict (exploitation or competition), and in turn greater interspecific segregation. Together, these results support the idea that species structural and functional relationships represent the net balance of metabolic interdependencies

Multi-Replicated Enrichment Communities as a Model System in Microbial Ecology

Recent advances in robotics and affordable genomic sequencing technologies have made it possible to establish and quantitatively track the assembly of enrichment communities in high-throughput. By conducting community assembly experiments in up to thousands of synthetic habitats, where the extrinsic sources of variation among replicates can be controlled, we can now study the reproducibility and predictability of microbial community assembly at different levels of organization, and its relationship with nutrient composition and other ecological drivers. Through a dialog with mathematical models, high-throughput enrichment communities are bringing us closer to the goal of developing a quantitative predictive theory of microbial community assembly. In this short review, we present an overview of recent research on this growing field, highlighting the connection between theory and experiments and suggesting directions for future work