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Designer microbial consortia are an emerging frontier in synthetic biology that enable versatile microbiome engineering. However, the utilization of such consortia is hindered by our limited capacity in rapidly creating ecosystems with desired dynamics. Here we present the development of synthetic communities through social interaction engineering that combines modular pathway reconfiguration with model creation. Specifically, we created six two-strain consortia, each possessing a unique mode of interaction, including commensalism, amensalism, neutralism, cooperation, competition and predation. These consortia follow distinct population dynamics with characteristics determined by the underlying interaction modes. We showed that models derived from two-strain consortia can be used to design three- and four-strain ecosystems with predictable behaviors and further extended to provide insights into community dynamics in space. This work sheds light on the organization of interacting microbial species and provides a systematic framework—social interaction programming—to guide the development of synthetic ecosystems for diverse purposes.

Lactic acid bacteria (LAB) are fundamental in the production of fermented foods and several strains are regarded as probiotics. Large quantities of live LAB are consumed within fermented foods, but it is not yet known to what extent the LAB we ingest become members of the gut microbiome. By analysis of 9445 metagenomes from human samples, we demonstrate that the prevalence and abundance of LAB species in stool samples is generally low and linked to age, lifestyle, and geography, with Streptococcus thermophilus and Lactococcus lactis being most prevalent. Moreover, we identify genome-based differences between food and gut microbes by considering 666 metagenome-assembled genomes (MAGs) newly reconstructed from fermented food microbiomes along with 154,723 human MAGs and 193,078 reference genomes. Our large-scale genome-wide analysis demonstrates that closely related LAB strains occur in both food and gut environments and provides unprecedented evidence that fermented foods can be indeed regarded as a possible source of LAB for the gut microbiome. Here, Pasolli et al. perform a large-scale genome-wide comparative analysis of publicly available and newly sequenced food and human metagenomes to investigate the prevalence and diversity of lactic acid bacteria (LAB), indicating food as a major source of LAB species in the human gut.

Lactococcus lactis has progressed a long way since its discovery and initial use in dairy product fermentation, to its present biotechnological applications in genetic engineering for the production of various recombinant proteins and metabolites that transcends the heterologous species barrier. Key desirable features of this gram-positive lactic acid non-colonizing gut bacteria include its generally recognized as safe (GRAS) status, probiotic properties, the absence of inclusion bodies and endotoxins, surface display and extracellular secretion technology, and a diverse selection of cloning and inducible expression vectors. This have made L. lactis a desirable and promising host on par with other well established model bacterial or yeast systems such as Escherichia coli, Salmonella cerevisiae and Bacillus subtilis . In this article, we review recent technological advancements, challenges, future prospects and current diversified examples on the use of L. lactis as a microbial cell factory. Additionally, we will also highlight latest medical-based applications involving whole-cell L. lactis as a live delivery vector for the administration of therapeutics against both communicable and non-communicable diseases.

Abstract It is almost a century since nisin was discovered in fermented milk cultures, coincidentally in the same year that penicillin was first described. Over the last 100 years this small, highly modified pentacyclic peptide has not only found success in the food industry as a preservative but has also served as the paradigm for our understanding of the genetic organization, expression, and regulation of genes involved in lantibiotic biosynthesis—one of the few cases of extensive post-translation modification in prokaryotes. Recent developments in understanding the complex biosynthesis of nisin have shed light on the cellular location of the modification and transport machinery and the co-ordinated series of spatio-temporal events required to produce active nisin and provide resistance and immunity. The continued unearthing of new natural variants from within human and animal gastrointestinal tracts has sparked interest in the potential application of nisin to influence the microbiome, given the growing recognition of the role the gastrointestinal microbiota plays in health and disease. Moreover, interdisciplinary approaches have taken advantage of biotechnological advancements to bioengineer nisin to produce novel variants and expand nisin functionality for applications in the biomedical field. This review will discuss the latest progress in these aspects of nisin research. The highly post-translationally modified peptide nisin has been studied over the course of the last 100 years, and although it has been employed successfully as a food preservative, its potent activity against multidrug resistant microbes, long safety record, lack of any significant resistance development, and amenability to bioengineering approaches to improve its antimicrobial and physicochemical properties has meant that the focus on nisin-related research is shifting from food preservation towards therapeutic use for the treatment of bacterial infections.

Herein, we sought to evaluate the potential of a recombinant Lactococcus lactis strain secreting the Yersinia pseudotuberculosis low-calcium response V (LcrV) antigen for mucosal vaccination against Yersinia infections. We showed that the recombinant strain induced specific systemic and mucosal antibody and cellular immune responses after intranasal immunization and protected mice against both oral and systemic Y. pseudotuberculosis infections. This constitutes the first proof of principle for a novel anti- Yersinia mucosal vaccination strategy using recombinant lactic acid bacteria.

Cheese fermentation and flavour formation are the result of complex biochemical reactions driven by the activity of multiple microorganisms. Here, we studied the roles of microbial interactions in flavour formation in a year-long Cheddar cheese making process, using a commercial starter culture containing Streptococcus thermophilus and Lactococcus strains. By using an experimental strategy whereby certain strains were left out from the starter culture, we show that S. thermophilus has a crucial role in boosting Lactococcus growth and shaping flavour compound profile. Controlled milk fermentations with systematic exclusion of single Lactococcus strains, combined with genomics, genome-scale metabolic modelling, and metatranscriptomics, indicated that S. thermophilus proteolytic activity relieves nitrogen limitation for Lactococcus and boosts de novo nucleotide biosynthesis. While S. thermophilus had large contribution to the flavour profile, Lactococcus cremoris also played a role by limiting diacetyl and acetoin formation, which otherwise results in an off-flavour when in excess. This off-flavour control could be attributed to the metabolic re-routing of citrate by L. cremoris from diacetyl and acetoin towards α -ketoglutarate. Further, closely related Lactococcus lactis strains exhibited different interaction patterns with S. thermophilus , highlighting the significance of strain specificity in cheese making. Our results highlight the crucial roles of competitive and cooperative microbial interactions in shaping cheese flavour profile. Cheese fermentation and flavour formation are the result of complex biochemical reactions driven by the activity of multiple microorganisms. Here, the authors identify microbial interactions as a mechanism underlying flavour formation in Cheddar cheese.

ABSTRACT Lactococcus lactis serves as a paradigm organism for the lactic acid bacteria (LAB). Extensive research into the molecular biology, metabolism and physiology of several model strains of this species has been fundamental for our understanding of the LAB. Genomic studies have provided new insights into the species L. lactis, including the resolution of the genetic basis of its subspecies division, as well as the control mechanisms involved in the fine-tuning of growth rate and energy metabolism. In addition, it has enabled novel approaches to study lactococcal lifestyle adaptations to the dairy application environment, including its adjustment to near-zero growth rates that are particularly relevant in the context of cheese ripening. This review highlights various insights in these areas and exemplifies the strength of combining experimental evolution with functional genomics and bacterial physiology research to expand our fundamental understanding of the L. lactis lifestyle under different environmental conditions. The lifestyles of Lactococcus lactis in different environmental niches and their adaptation under dynamic conditions.

Maintenance of a high degree of biodiversity in homogeneous environments is poorly understood. A complex cheese starter culture with a long history of use was characterized as a model system to study simple microbial communities. Eight distinct genetic lineages were identified, encompassing two species: Lactococcus lactis and Leuconostoc mesenteroides. The genetic lineages were found to be collections of strains with variable plasmid content and phage sensitivities. Kill-the-winner hypothesis explaining the suppression of the fittest strains by density-dependent phage predation was operational at the strain level. This prevents the eradication of entire genetic lineages from the community during propagation regimes (back-slopping), stabilizing the genetic heterogeneity in the starter culture against environmental uncertainty.

The complex microbiota of cheese starters plays a key role in determining the structure and flavour of the final product, primarily through their acid-forming capacity, protease activity, and exopolysaccharide synthesis. However, the specific microbial communities underlying the unique qualities of artisanal cheeses remain poorly understood. This study presents the microbiological and molecular genetic characterisation of the microbiome isolated from an artisanal cheese starter in Kosh-Agach, Altai, Russia. Metagenomic analysis of this starter revealed the presence of three bacterial genomes corresponding to those of Lactococcus lactis. Pure cultures from this starter were obtained by sequential subculture, and seventeen colonies displaying distinct characteristics on differential media were selected. Genome sequencing was performed for each colony. Bioinformatic analysis based on the rpoB gene grouped the isolates into three clusters, each corresponding to a distinct strain of Lactococcus lactis subsp. diacetilactis. This classification was further confirmed by microbiological and microscopic analyses. A notable finding was that none of the strains produced the characteristic aroma compounds of L. l. subsp. diacetilactis, namely, diacetyl and CO2. The functional properties and metabolic characteristics of this starter consortium are discussed.

Non-model bacteria like Pseudomonas putida , Lactococcus lactis and other species have unique and versatile metabolisms, offering unique opportunities for Synthetic Biology (SynBio). However, key genome editing and recombineering tools require optimization and large-scale multiplexing to unlock the full SynBio potential of these bacteria. In addition, the limited availability of a set of characterized, species-specific biological parts hampers the construction of reliable genetic circuitry. Mining of currently available, diverse bacteriophages could complete the SynBio toolbox, as they constitute an unexplored treasure trove for fully adapted metabolic modulators and orthogonally-functioning parts, driven by the longstanding co-evolution between phage and host. Non-model bacteria offer unique and versatile metabolisms for synthetic biology. In this Perspective, the authors explore the limited availability of well-characterised biological parts in these species and argue that bacteriophages represent a diverse trove of orthogonal parts.