22 December 2023

2023: the NCCR Microbiomes publishing year in review

Understanding how microbiomes assemble, change and function

In its first consortium review article (37 authors from all work packages), the NCCR proposes a step-by-step dissection of microbiome assembly and functioning. The review lays out the systematic approach championed by the consortium: the addition or removal of one particular strain at a time from the microbiome (the N+1/N−1 concept). This approach aims to reveal mechanisms driving community structure and functions, which are examined through the multifaceted lens of classical microbiology, ecology and evolution, synthetic engineering, and computational biology.

To enable hypothesis-testing in microbiome research, the NCCR develops reproducible synthetic and natural communities in its various model systems, including core gut microbiota members in honey bees, synthetic phyllosphere consortia to study pathogen protection (N−1), as well as soil and rhizosphere microbial communities to test biocontrol inoculants (N+1). Molecular mechanisms and colonization processes are also investigated in more detail in animal models. In insects (honey bee), researchers identified an integration host factor key to gut colonization by a bacterial symbiont. Recent work in the honeybee gut microbiome also highlights the importance of strain-level diversity in modulating community functional traits. Mouse models are other essential tools to study gut colonization, and revealed that auto-inducer signalling and chemotaxis promote colonization by gut commensals, that the complex interplay between microbiota and opportunistic pathogens modulates both colonization resistance and selection of virulence factors, and that strain-specific metabolic capacity promotes HGT and strains co-existence. Finally, the NCCR is developing innovative experimental tools and techniques to investigate microbiome ecological and evolutionary processes in situ: the engineering of new bioreporters for the honeybee gut, genetically barcoded gut microbiome strains to study within-host population dynamics in mice, and workflows for the automated image tracking of bacterial cells.

Illuminating microbe-microbe and microbe-host interactions with computational and experimental models

Genome-scale metabolic models are central to the NCCR aim to predict the outcome of interspecies interactions, with the latest technical advances offering new insights into enzymatic dynamics and large-scale kinetic models. Application in the plant leaf microbiome with more than 200 curated genome-scale models showed that metabolic interactions can be predicted to high precision between species pairs. In addition to genome-scale models, other mathematical frameworks have been succesfully applied to examine competitive growth and metabolite cross-feeding, environment-organism feedbacks influencing interactions, or the role of spatial encounters and aggregation behaviors.

Methods to quantify microbial interspecies interactions have been developed in controlled artificial environments such as microfluidics, microbeads, or picoliter droplets, as well as in more complex habitats (e.g. plant leaves). We examine mechanisms of microbial warfare that rely on toxic arsenic compounds or phage tail-like bacteriocins. Controlled laboratory systems permit us to tease out environmental factors modulating competition or facilitation. Building on both experimental and computational knowledge, a theoretical concept for the spatial arrangement of metabolic reactions and species has been proposed.

Microbe-host interactions are now also examined thanks to innovative techniques such as the non-invasive monitoring of metabolites with mass spectrometry, while the use of NanoSIMS has successfully demonstrated the role of host-produced metabolites in facilitating colonization by bacterial symbionts in the bee gut. Honey bees have also now emerged as a useful model to study the role of the microbiome in the gut–brain axis.

New bioinformatic tools for microbiome research and clinical diagnostics

Taxonomic profiling from metagenomic data keeps breaking new ground with mOTUs (version 3), which is independent from reference genomes of cultivated organisms, reduces the number of unassigned sequences in a sample, and offers species-level resolution. This year also saw the release of the new versatile tool mBARq for the analysis of DNA barcoding data. For the comparison of whole genomes, the new tool zDB will facilitate bacterial comparative genomics by providing integration and visualization features, in clinical or environmental studies. Finally, the new open-source database of mass spec profiles CLOSTRI-TOF expands the identification of intestinal clostridia for clinical diagnostics.

Progress in delineating healthy and dysbiosed microbiomes

The NCCR aims to better characterize unbalanced microbiomes, as well as better understand processes maintaining or restoring healthy ones, in a wide variety of hosts or environmental habitats. A new longitudinal observational study describing the gut microbiota profile in COVID-19 patients shed light on the interplay between the human microbiome and SARS-CoV-2 disease response. Focusing on infants, the new VITERBI GUT project will investigate how malnutrition and dysbiosed microbiomes intertwine and associate with later life health issues, while a new study on Ethiopian children reveals how pastoral life and low fiber diet influence the microbiome. In the plant microbiome, which allows for more controlled experimentation, dysbiosis could be mechanistically linked to both the absence of a plant host enzyme and the presence of a specific opportunistic pathogen in the microbiota.

Innovative therapeutic microbiota interventions in animals and humans

Development of strategies for pathogen clearance (N−1) has shown resounding successes: the development of an inactived Salmonella vaccine demonstrates efficacy and excellent safety in pigs, live auxtrophic vaccines against enteropathogens in poultry are currently being developed by the NCCR spin-off Santella, and in humans personalized phage therapy has achieved clinically significant improvement in a patient suffering from chronic lung infection.

Promoting or restoring specific functions in the microbiome

The N+1 concept of the NCCR explores interventions such as bioaugmentation that promote desired functions in the target host or habitat, and progress has been made notably in identifying bacterial fitness-conditional genes for soil adaptation. Plant-beneficial bacteria and fungi are also tested as biocontrol inoculants in crops, highlighting the key role of nutrient availability in assembly processes. Finally, artificial selection of microbial communities is another strategy that can potentially improve a given function, and currently under study with computational models

Access our full list of NCCR publications here