Multiscale Evolutionary Dynamics of Host-Associated Microbiomes

Ferreiro, Aura; Crook, Nathan; Gasparrini, Andrew J.; Dantas, Gautam

doi:10.1016/j.cell.2018.02.015

Cited by 95 publications

(94 citation statements)

References 89 publications

(101 reference statements)

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“…The few available data on temporal dynamics of genetic polymorphism in species of human gut commensals is starting to confirm this prediction, at least for some species [5][6][7][8]59]. As genetic diversity can impact community composition [82], more time series data, similar to that obtained here, is needed towards a full understanding of the selective mechanisms that shape the eco-evolutionary dynamics within the microbiota [83,84].…”

Section: Resultssupporting

confidence: 54%

Low Mutational Load Allows for High Mutation Rate Variation in Gut Commensal Bacteria

Ramiro

Durão

Bank

et al. 2019

Preprint

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Bacteria generally live in species-rich communities, such as the gut microbiota. Yet, little is known about bacterial evolution in natural ecosystems. Here, we followed the long-term evolution of commensal Escherichia coli in the mouse gut. We observe the emergence of polymorphism for mutation rate, ranging from wild-type levels to 1000-fold higher. By combining experiments, whole-genome sequencing and in silico simulations, we identify the molecular causes and evolutionary conditions that allow these hypermutators to emerge and coexist within a complex microbiota. The hypermutator phenotype is caused by mutations in DNA polymerase III, which increase mutation rate by~1000-fold (a mutation in the proofreading subunit) and stabilize hypermutator fitness (mutations in the catalytic subunit). The strong mutation rate variation persists for >1000 generations, with coexistence between lineages carrying 4 to >600 mutations. This in vivo molecular evolution pattern is consistent with deleterious mutations of~0.01-0.001% fitness effects, 100 to 1000-fold lower than current in vitro estimates. Despite large numbers of deleterious mutations, we identify multiple beneficial mutations that do not reach fixation over long periods of time. This indicates that the dynamics of beneficial mutations are not shaped by constant positive Darwinian selection but by processes leading to negative frequency-dependent or temporally fluctuating selection. Thus, microbial evolution in the gut is likely characterized by partial sweeps of beneficial mutations combined with hitchhiking of very slightly deleterious mutations, which take a long time to be purged but impose a very weak mutational load. These results are consistent with the pattern of genetic polymorphism that is emerging from metagenomics studies of the human gut microbiota, suggesting that we identified key evolutionary processes shaping the genetic composition of this community.

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Section: Resultssupporting

confidence: 54%

Low Mutational Load Allows for High Mutation Rate Variation in Gut Commensal Bacteria

Ramiro

Durão

Bank

et al. 2019

Preprint

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“…To parse this complexity, gnotobiotic mouse models are attractive to explore the behavior of microbes in defined gut ecologies. Thus, we first measured S. boulardii’ s residence time in the germ-free gut by delivering S. boulardii (10 8 , 10 7 , or 10 6 colony-forming units) to germ-free mice via oral gavage (Supplementary Figure S12). No deleterious effects on mouse health were apparent during the experiment.…”

Section: Resultsmentioning

confidence: 99%

“…Next-generation probiotics offer unique attributes for the delivery of biomolecules to the gut 3 . By leveraging decades of work in metabolic engineering 4 , engineered probiotics have enabled the conversion of unused dietary material to beneficial products for the host 5–7 . Furthermore, the ongoing development of synthetic biological sensors advance the concept of drug synthesis tailored to the severity and location of disease within the host 8–11 .…”

Section: Introductionmentioning

confidence: 99%

Establishing Probiotic Saccharomyces boulardii as a Model Organism for Synthesis and Delivery of Biomolecules

Durmusoglu

Al'Abri

Collins

et al. 2020

Preprint

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12Saccharomyces boulardii is a widely used yeast probiotic which can counteract various 13 gastrointestinal disorders 1 . As a relative of Saccharomyces cerevisiae, S. boulardii exhibits rapid 14 growth and is easy to transform 2 and thus represents a promising chassis for the engineered 15 secretion of biomolecules. To establish S. boulardii as a platform for delivery of biomolecules to 16 the mammalian gut, we measured the amount and variance in protein expression enabled by 17 promoters, terminators, selective markers, and copy number control elements in this organism. 18These genetic elements were characterized in plasmidic and genomic contexts, revealing 19 strategies for tunable control of gene expression and CRISPR-mediated genome editing in this 20 strain. We then leveraged this set of genetic parts to combinatorially assemble pathways 21 enabling a wide range of drug and vitamin titers. Finally, we measured S. boulardii's residence 22 time in the gastrointestinal tracts of germ-free and antibiotic-treated mice, revealing the 23 relationships between dosing strategy and colonization level. This work establishes S. boulardii 24 as a genetically tractable commensal fungus and provides a set of strategies for engineering S. 25 boulardii to synthesize and deliver biomolecules during gut colonization. 26 27 abundant in the human gut, 21 and difficulty in producing high levels of post-translationally-42 modified proteins 22 . 43 44In addition to bacteria, a diverse fungal population also exists in the human gastrointestinal tract 45 (GIT) [23][24][25][26] . While the numerical abundance of fungal cells in the GIT is much lower than bacterial 46 cells, fungal cells are on average 100-fold larger, indicating that their biomass and role in the gut 47 may be larger than metagenomic surveys indicate 25,27 . Recent studies have shown that while 48 3 commensal fungi play important roles in the development of inflammatory bowel diseases, they 49 also provide protective heterologous immunity to pathogenic organisms by training the immune 50 system 28,29 . Furthermore, fungi are not susceptible to bacteriophage predation and are easily 51 engineered to secrete high titers of proteins that are post-translationally modified. Thus, in this 52 study, we established a pipeline to engineer the only eukaryotic probiotic that is approved by the 53 FDA: Saccharomyces boulardii 30 . 54 55 S. boulardii is a non-pathogenic yeast that was originally isolated from lychee and mangosteen in 56 1923 and has since been used to treat ulcerative colitis, diarrhea, and recurrent Clostridium 57 difficile infection 1,31 . S. boulardii is closely related to the famous budding yeast Saccharomyces 58 cerevisiae, indicating that it may be similarly amenable to engineering for the production of 59 biomolecules, including biologics requiring post-translational modifications 2,32 . Supporting this, 60 S. cerevisiae expression vectors can be transformed and propagated in S. boulardii, and 61 CRISPR/Cas9-mediated genome editing is functional in both ...

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“…In stressful environments, hosts may leverage locally adapted microbes. Microbes with larger effective population sizes, rapid generation time, and pangenomes may evolve novel functions faster than their hosts [75][76][77][78] . If hosts can capitalize on locally adapted microbes, then hosts can increase survivorship and rapidly adapt to novel environments.…”

Section: Hosts Leverage Locally Adapted Microbesmentioning

confidence: 99%

Can the microbiome influence host evolutionary trajectories?

Henry

Bruijning

Forsberg

et al. 2019

Preprint

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The microbiome shapes many traits in hosts, but we still do not understand how it influences host evolution. To impact host evolution, the microbiome must be heritable and have phenotypic effects on the host. However, the complex inheritance and context-dependence of the microbiome challenges traditional models of organismal evolution. Here, we take a multifaceted approach to identify conditions in which the microbiome influences host evolutionary trajectories. We explore quantitative genetic models to highlight how microbial inheritance and phenotypic effects can modulate host evolutionary responses to selection. We synthesize the literature across diverse taxa to find common scenarios of microbiome driven host evolution. First, hosts may leverage locally adapted microbes, increasing survivorship in stressful environments. Second, microbial variation may increase host phenotypic variation, enabling exploration of novel fitness landscapes. We further illustrate these effects by performing a meta-analysis of artificial selection in Drosophila, finding that bacterial diversity also frequently responds to host selection. We conclude by outlining key avenues of research and experimental procedures to improve our understanding of the complex interplay between hosts and microbiomes. By synthesizing perspectives through multiple conceptual and analytical approaches, we show how microbiomes can influence the evolutionary trajectories of hosts.

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Multiscale Evolutionary Dynamics of Host-Associated Microbiomes

Cited by 95 publications

References 89 publications

Low Mutational Load Allows for High Mutation Rate Variation in Gut Commensal Bacteria

Low Mutational Load Allows for High Mutation Rate Variation in Gut Commensal Bacteria

Establishing Probiotic Saccharomyces boulardii as a Model Organism for Synthesis and Delivery of Biomolecules

Can the microbiome influence host evolutionary trajectories?

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