Microbial Biology Research Articles

Decoupled Nutrient Status: a framework to disentangle host from microbial responses to diets that vary in digestibility

Diet shapes the gut microbiome, which in turn influences host phenotype. Accordingly, there is much interest in leveraging diet to modulate gut microbial communities and host biology. However, recent approaches have not fully appreciated that hosts and gut microbes experience diet differently. Whether dietary nutrients reach the gut microbiota, which primarily resides in the colon in humans and other hindgut fermenters, depends on nutrient absorption in the small intestine. That gut microbes utilize the fraction of diet that escapes host-driven digestion creates a paradigm where host nutrient status is decoupled from, and often negatively correlated with, gut microbiota nutrient status. Here, we present a framework based on this concept of decoupled nutrient status (DNS), which can be used to understand distinct host and gut microbial phenotypes that are ultimately mediated by the small intestinal digestibility of the diet. We evaluate our framework against existing research employing diets of varying digestibility and demonstrate convergence of host phenotypes and gut microbial signatures across studies. Further, we highlight that gut microbial signatures predicted by DNS manifest most strongly in humans living industrialized lifestyles and in captive animals that habitually consume diets with high host-driven digestibility. We posit that the evolutionary decoupling of nutritional status between hosts and their gut microbiota has likely been especially pronounced in humans due to our intensified pursuit of calorie-rich, easy-to-digest diets. We conclude by proposing future research directions to better capture diet as it appears to gut microbes, a perspective likely to deliver new understanding of diet-microbiome interactions.

Essential Genes Discovery in Microorganisms by Transposon-Directed Sequencing (Tn-Seq): Experimental Approaches, Major Goals, and Future Perspectives.

Essential genes are crucial for microbial viability, playing key roles in both the primary and secondary metabolism. Since mutations in these genes can threaten organism viability, identifying them is challenging. Conditionally essential genes are required only under specific conditions and are important for functions such as virulence, immunity, stress survival, and antibiotic resistance. Transposon-directed sequencing (Tn-Seq) has emerged as a powerful method for identifying both essential and conditionally essential genes. In this review, we explored Tn-Seq workflows, focusing on eubacterial species and some yeast species. A comparison of 14 eubacteria species revealed 133 conserved essential genes, including those involved in cell division (e.g., ftsA, ftsZ), DNA replication (e.g., dnaA, dnaE), ribosomal function, cell wall synthesis (e.g., murB, murC), and amino acid synthesis (e.g., alaS, argS). Many other essential genes lack clear orthologues across different microorganisms, making them specific to each organism studied. Conditionally essential genes were identified in 18 bacterial species grown under various conditions, but their conservation was low, reflecting dependence on specific environments and microorganisms. Advances in Tn-Seq are expected to reveal more essential genes in the near future, deepening our understanding of microbial biology and enhancing our ability to manipulate microbial growth, as well as both the primary and secondary metabolism.

Comprehensive profile of the companion animal gut microbiome integrating reference-based and reference-free methods.

The gut microbiome of companion animals is relatively underexplored, despite its relevance to animal health, pet owner health, and basic microbial community biology. Here, we provide the most comprehensive analysis of the canine and feline gut microbiomes to date, incorporating 2639 stool shotgun metagenomes (2272 dog and 367 cat) spanning 14 publicly available datasets (n = 730) and 8 new study populations (n = 1909). These are compared with 238 and 112 baseline human gut metagenomes from the Human Microbiome Project 1-II and a traditionally living Malagasy cohort, respectively, processed in a manner identical to the animal metagenomes. All microbiomes were characterized using reference-based taxonomic and functional profiling, as well as de novo assembly yielding metagenomic assembled genomes clustered into species-level genome bins. Companion animals shared 184 species-level genome bins not found in humans, whereas 198 were found in all three hosts. We applied novel methodology to distinguish strains of these shared organisms either transferred or unique to host species, with phylogenetic patterns suggesting host-specific adaptation of microbial lineages. This corresponded with functional divergence of these lineages by host (e.g., differences in metabolic and antibiotic resistance genes) likely important to companion animal health. This study provides the largest resource to date of companion animal gut metagenomes and greatly contributes to our understanding of the "One Health" concept of a shared microbial environment among humans and companion animals, affecting infectious diseases, immune response, and specific genetic elements.

Microbial production of methyl-uranium via the Wood-Ljungdahl pathway

The misuse of uranium is a major threat to human health and the environment. In microbial ecosystems, microbes deploy various strategies to cope with uranium-induced stress. However, the exact ecological strategies and mechanisms underlying uranium tolerance in microbes remain unclear. Therefore, this study aimed to investigate the survival strategies and tolerance mechanisms of microbial communities in uranium-contaminated soil and groundwater. Microbial co-occurrence networks and molecular biology techniques were used to analyze the properties of microbes in groundwater and soil samples from various depths of uranium-contaminated areas in Northwest China. Uranium pollution altered microbial ecological strategies. Uranium stress facilitated the formation of microbial community structures, leading to symbiosis. Furthermore, microbes primarily resisted uranium hazards by producing polysaccharides and phosphate groups that chelate uranium, releasing phosphate substances that precipitate uranium, and reducing U(VI) through sulfate- and iron-reducing processes. The relative abundance of metal-methylation genes in soil microorganisms positively correlated with uranium concentration, indicating that soil microorganisms can produce methyl uranium via the Wood-Ljungdahl pathway. Furthermore, soil and groundwater microorganisms demonstrated different responses to uranium stress. This study provides new insights into microbial responses to uranium stress and novel approaches for the bioremediation of uranium-contaminated sites.

Molecular and cellular level analysis of the mechanism of nutritional intervention in preventing epidemic virus infection

Molecular nutrition encompasses a wider range of investigations than nutritional genomics, which can be considered a scientific investigation of how different nutrients and dietary components influence the cellular and molecular mechanisms of the body and health. In effect, increasing antioxidant elements in daily diets can assist with combating the inflammatory response caused by cytokines in the human body. Antioxidants can impede the oxidation process and hence avoid the creation of free radicals in the cytoplasm that can damage the cells via chain reactions. Contamination sequences, batch effects, uneven sampling, unreported taxa, technological biases, and heteroscedasticity are all significant issues in molecular microbial biology. Artificial Intelligence (AI) methodologies to uncover hidden patterns, connections, and interactions within metabolomics data, allowing them to provide personalized food recommendations based on individual health profiles. A multi-scale convolutional neural network (MCNN) classifies cellular images into phenotypes in a single coherent step utilizing the image’s pixel intensity values. Hence, the proposed AI-MCNN has been an essential nutrient that assists the immune system in various ways, including acting as an antioxidant to protect healthy cells, promoting immune cell development and function, and creating antibodies. According to epidemiological research, people who are undernourished are more likely to get bacterial, viral, and other diseases. Nutritional epidemiology investigates dietary or nutritional parameters concerning illness prevalence in communities. Nutritional epidemiology results often add to the evidence that provides dietary recommendations for preventing disease and related disorders.

Identification, Design, and Application of Noncoding Cis-Regulatory Elements.

Cis-regulatory elements (CREs) play a pivotal role in orchestrating interactions with trans-regulatory factors such as transcription factors, RNA-binding proteins, and noncoding RNAs. These interactions are fundamental to the molecular architecture underpinning complex and diverse biological functions in living organisms, facilitating a myriad of sophisticated and dynamic processes. The rapid advancement in the identification and characterization of these regulatory elements has been marked by initiatives such as the Encyclopedia of DNA Elements (ENCODE) project, which represents a significant milestone in the field. Concurrently, the development of CRE detection technologies, exemplified by massively parallel reporter assays, has progressed at an impressive pace, providing powerful tools for CRE discovery. The exponential growth of multimodal functional genomic data has necessitated the application of advanced analytical methods. Deep learning algorithms, particularly large language models, have emerged as invaluable tools for deconstructing the intricate nucleotide sequences governing CRE function. These advancements facilitate precise predictions of CRE activity and enable the de novo design of CREs. A deeper understanding of CRE operational dynamics is crucial for harnessing their versatile regulatory properties. Such insights are instrumental in refining gene therapy techniques, enhancing the efficacy of selective breeding programs, pushing the boundaries of genetic innovation, and opening new possibilities in microbial synthetic biology.

Expansion of Auxiliary Activity Family 5 sequence space via biochemical characterization of six new copper radical oxidases.

Bacterial and fungal copper radical oxidases (CROs) from Auxiliary Activity Family 5 (AA5) are implicated in morphogenesis and pathogenesis. The unique catalytic properties of CROs also make these enzymes attractive biocatalysts for the transformation of small molecules and biopolymers. Despite a recent increase in the number of characterized AA5 members, especially from subfamily 2 (AA5_2), the catalytic diversity of the family as a whole remains underexplored. In the present study, phylogenetic analysis guided the selection of six AA5_2 members from diverse fungi for recombinant expression in Komagataella pfaffii (syn. Pichia pastoris) and biochemical characterization in vitro. Five of the targets displayed predominant galactose 6-oxidase activity (EC 1.1.3.9), and one was a broad-specificity aryl alcohol oxidase (EC 1.1.3.7) with maximum activity on the platform chemical 5-hydroxymethyl furfural (EC 1.1.3.47). Sequence alignment comparing previously characterized AA5_2 members to those from this study indicated various amino acid substitutions at active site positions implicated in the modulation of specificity.IMPORTANCEEnzyme discovery and characterization underpin advances in microbial biology and the application of biocatalysts in industrial processes. On one hand, oxidative processes are central to fungal saprotrophy and pathogenesis. On the other hand, controlled oxidation of small molecules and (bio)polymers valorizes these compounds and introduces versatile functional groups for further modification. The biochemical characterization of six new copper radical oxidases further illuminates the catalytic diversity of these enzymes, which will inform future biological studies and biotechnological applications.

First person – Kinga Rutowicz

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Kinga Rutowicz is first author on ‘ Multiscale chromatin dynamics and high entropy in plant iPSC ancestors’, published in JCS. Kinga is a Research Assistant in the lab of Célia Baroux at Department of Plant and Microbial Biology, University of Zurich, Switzerland. Her research focuses on better understanding the multifaceted role of chromatin in cellular reprogramming during both development and response to environmental stimuli.

CRISPR-Cas tools for simultaneous transcription & translation control in bacteria.

Robust control over gene translation at arbitrary mRNA targets is an outstanding challenge in microbial synthetic biology. The development of tools that can regulate translation will greatly expand our ability to precisely control genes across the genome. In Escherichia coli, most genes are contained in multi-gene operons, which are subject to polar effects where targeting one gene for repression leads to silencing of other genes in the same operon. These effects pose a challenge for independently regulating individual genes in multi-gene operons. Here, we use CRISPR-dCas13 to address this challenge. We find dCas13-mediated repression exhibits up to 6-fold lower polar effects compared to dCas9. We then show that we can selectively activate single genes in a synthetic multi-gene operon by coupling dCas9 transcriptional activation of an operon with dCas13 translational repression of individual genes within the operon. We also show that dCas13 and dCas9 can be multiplexed for improved biosynthesis of a medically-relevant human milk oligosaccharide. Taken together, our findings suggest that combining transcriptional and translational control can access effects that are difficult to achieve with either mode independently. These combined tools for gene regulation will expand our abilities to precisely engineer bacteria for biotechnology and perform systematic genetic screens.

Role of UDP-N-acetylmuramic acid in the regulation of MurA activity revealed by molecular dynamics simulations.

The peptidoglycan biosynthesis pathway plays a vital role in bacterial cells, and facilitates peptidoglycan layer formation, a fundamental structural component of the bacterial cell wall. The enzymes in this pathway are candidates for antibiotic development, as most do not have mammalian homologues. The UDP-N-acetylglucosamine (UNAG) enolpyruvyl transferase enzyme (MurA) in the peptidoglycan pathway cytoplasmic step is responsible for the phosphoenolpyruvate (PEP)-UNAG catalytic reaction, forming UNAG enolpyruvate and inorganic phosphate. Reportedly, UDP-N-acetylmuramic acid (UNAM) binds tightly to MurA forming a dormant UNAM-PEP-MurA complex and acting as a MurA feedback inhibitor. MurA inhibitors are complex, owing to competitive binding interactions with PEP, UNAM, and UNAG at the MurA active site. We used computational methods to explore UNAM and UNAG binding. UNAM showed stronger hydrogen-bond interactions with the Arg120 and Arg91 residues, which help to stabilize the closed conformation of MurA, than UNAG. Binding free energy calculations using end-point computational methods showed that UNAM has a higher binding affinity than UNAG, when PEP is attached to Cys115. The unbinding process, simulated using τ-random acceleration molecular dynamics, showed that UNAM has a longer relative residence time than UNAG, which is related to several complex dissociation pathways, each with multiple intermediate metastable states. This prevents the loop from opening and exposing the Arg120 residue to accommodate UNAG and potential new ligands. Moreover, we demonstrate the importance of Cys115-linked PEP in closed-state loop stabilization. We provide a basis for evaluating novel UNAM analogues as potential MurA inhibitors. PUBLIC SIGNIFICANCE: MurA is a critical enzyme involved in bacterial cell wall biosynthesis and is involved in antibiotic resistance development. UNAM can remain in the target protein's active site for an extended time compared to its natural substrate, UNAG. The prolonged interaction of this highly stable complex known as the 'dormant complex' comprises UNAM-PEP-MurA and offers insights into antibiotic development, providing potential options against drug-resistant bacteria and advancing our understanding of microbial biology.

Structure-function analysis of the cyclic β-1,2-glucan synthase from Agrobacterium tumefaciens

The synthesis of complex sugars is a key aspect of microbial biology. Cyclic β-1,2-glucan (CβG) is a circular polysaccharide critical for host interactions of many bacteria, including major pathogens of humans (Brucella) and plants (Agrobacterium). CβG is produced by the cyclic glucan synthase (Cgs), a multi-domain membrane protein. So far, its structure as well as the mechanism underlining the synthesis have not been clarified. Here we use cryo-electron microscopy (cryo-EM) and functional approaches to study Cgs from A. tumefaciens. We determine the structure of this complex protein machinery and clarify key aspects of CβG synthesis, revealing a distinct mechanism that uses a tyrosine-linked oligosaccharide intermediate in cycles of polymerization and processing of the glucan chain. Our research opens possibilities for combating pathogens that rely on polysaccharide virulence factors and may lead to synthetic biology approaches for producing complex cyclic sugars.

Pathogenic Rickettsia spp. as emerging models for bacterial biology.

Our understanding of free-living bacterial models like Escherichia coli far outpaces that of obligate intracellular bacteria, which cannot be cultured axenically. All obligate intracellular bacteria are host-associated, and many cause serious human diseases. Their constant exposure to the distinct biochemical niche of the host has driven the evolution of numerous specialized bacteriological and genetic adaptations, as well as innovative molecular mechanisms of infection. Here, we review the history and use of pathogenic Rickettsia species, which cause an array of vector-borne vascular illnesses, as model systems to probe microbial biology. Although many challenges remain in our studies of these organisms, the rich pathogenic and biological diversity of Rickettsia spp. constitutes a unique backdrop to investigate how microbes survive and thrive in host and vector cells. We take a bacterial-focused perspective and highlight emerging insights that relate to new host-pathogen interactions, bacterial physiology, and evolution. The transformation of Rickettsia spp. from pathogens to models demonstrates how recalcitrant microbes may be leveraged in the lab to tap unmined bacterial diversity for new discoveries. Rickettsia spp. hold great promise as model systems not only to understand other obligate intracellular pathogens but also to discover new biology across and beyond bacteria.

Massively parallel single-cell sequencing of diverse microbial populations.

Single-cell genetic heterogeneity is ubiquitous in microbial populations and an important aspect of microbial biology; however, we lack a broadly applicable and accessible method to study this heterogeneity in microbial populations. Here, we show a simple, robust and generalizable method for high-throughput single-cell sequencing of target genetic loci in diverse microbes using simple droplet microfluidics devices (droplet targeted amplicon sequencing; DoTA-seq). DoTA-seq serves as a platform to perform diverse assays for single-cell genetic analysis of microbial populations. Using DoTA-seq, we demonstrate the ability to simultaneously track the prevalence and taxonomic associations of >10 antibiotic-resistance genes and plasmids within human and mouse gut microbial communities. This workflow is a powerful and accessible platform for high-throughput single-cell sequencing of diverse microbial populations.

THIẾT KẾ DỰ ÁN HỌC TẬP TRONG DẠY HỌC CHỦ ĐỀ “SINH HỌC VI SINH VẬT” MÔN SINH HỌC 10 NHẰM PHÁT TRIỂN NĂNG LỰC TỰ HỌC CHO HỌC SINH

Knowledge changes every day and increases very rapidly, making high school curricula and textbooks unable to update and transmit knowledge to students promptly even when it is continuously innovative. In that situation, developing self-study capacity for students so that they can continuously supplement their knowledge and conduct lifelong self-study is an urgent requirement today. The study used theoretical research methods to review documents, thereby clarifying some concepts such as self-study capacity, project-based teaching, the structure of self-study capacity, and the role of project-based teaching in developing students' self-study capacity, propose the process of designing a learning project in teaching the topic “Microbial Biology” (Biology 10) to develop self-study capacity for students, and at the same time give an illustrative example for the process with learning project “Learning about products of fermentation technology” (Connecting knowledge to life - General education program 2018). The research results provide Biology teachers with important materials for designing lesson plans incorporating local practice to meet the requirements of the 2018 General Education Program.

Applications of Fourier Transform-Infrared spectroscopy in microbial cell biology and environmental microbiology: advances, challenges, and future perspectives.

Microorganisms play pivotal roles in shaping ecosystems and biogeochemical cycles. Their intricate interactions involve complex biochemical processes. Fourier Transform-Infrared (FT-IR) spectroscopy is a powerful tool for monitoring these interactions, revealing microorganism composition and responses to the environment. This review explores the diversity of applications of FT-IR spectroscopy within the field of microbiology, highlighting its specific utility in microbial cell biology and environmental microbiology. It emphasizes key applications such as microbial identification, process monitoring, cell wall analysis, biofilm examination, stress response assessment, and environmental interaction investigation, showcasing the crucial role of FT-IR in advancing our understanding of microbial systems. Furthermore, we address challenges including sample complexity, data interpretation nuances, and the need for integration with complementary techniques. Future prospects for FT-IR in environmental microbiology include a wide range of transformative applications and advancements. These include the development of comprehensive and standardized FT-IR libraries for precise microbial identification, the integration of advanced analytical techniques, the adoption of high-throughput and single-cell analysis, real-time environmental monitoring using portable FT-IR systems and the incorporation of FT-IR data into ecological modeling for predictive insights into microbial responses to environmental changes. These innovative avenues promise to significantly advance our understanding of microorganisms and their complex interactions within various ecosystems.

The short-chain fatty acid crotonate reduces invasive growth and immune escape of Candida albicans by regulating hyphal gene expression.

Macrophages curtail the proliferation of the pathogen Candida albicans within human body niches. Within macrophages, C. albicans adapts its metabolism and switches to invasive hyphal morphology. These adaptations enable fungal growth and immune escape by triggering macrophage lysis. Transcriptional programs regulate these metabolic and morphogenetic adaptations. Here we studied the roles of chromatin in these processes and implicate lysine crotonylation, a histone mark regulated by metabolism, in hyphal morphogenesis and macrophage interactions by C. albicans. We show that the short-chain fatty acid crotonate increases histone crotonylation, reduces hyphal formation within macrophages, and slows macrophage lysis and immune escape of C. albicans. Crotonate represses hyphal gene expression, and we propose that C. albicans uses diverse acylation marks to regulate its cell morphology in host environments. Hyphal formation is a virulence property of C. albicans. Therefore, a further importance of our study stems from identifying crotonate as a hyphal inhibitor.

Gene Expression in Cadmium Sulfide Biological-Nanoparticle Hybrids

Through millions of years of evolution, bacteria have developed unique and complex ways to survive, allowing them to inhabit ecosystems all over the Earth, including places with high metal ion concentrations. Bacteria have developed many survival mechanisms to evade metal ion toxicity. Survival mechanisms to evade metal toxicity include the ability to transform metal ions into nanoparticles. When metal ions bind to other constituents to form nanoparticles, the metal ion concentrations in the environment can be lowered, in turn lessening the likelihood of cells encountering toxic concentrations of metals. These nanoparticles can be expelled by the bacteria into the environment, remain inside the bacteria, or attached to the cell surface. Bacteria and metal nanoparticles have many useful functions on their own. Furthermore, these functions can be combined when the two come together. Cells that produce metal nanoparticles that remain attached to their surface are referred to as biological-nanoparticle hybrids (bionanohybrids), as shown in the scanning electron image in Fig. 1. Surface-associated nanoparticles (SANs) can enhance biological functions, enabling a variety of new applications related to bioremediation, energy production and storage, and agricultural and medical advances. Bionanohybrid research also creates new opportunities to investigate microbial communities, synthetic biology, and the origins of life. Metal-sulfide SANs are of particular interest due to their semi-conductor abilities and examples of their generation by multiple bacterial species. This includes bacteria inhabiting metal-rich extreme environments like the Mariana Trench, to bacteria found in the human gut (such as E. coli). While these bacteria are very different, they do share in common the cysteine desulfhydrase enzyme—which plays a crucial role in the formation of metal-sulfide bionanohybrids. Cysteine desulfhydrase converts the amino acid cysteine into sulfide that then reacts with environmental metal cations to create metal sulfide nanoparticles (Raouf Hosseini and Nasiri Sarvi 2015). Under the right conditions (e.g., optimal ratios of metal and cysteine to cell density and growth phase), the resulting nanoparticles remain attached to the surface of the cell, as shown in Fig. 1 (Barnes et al. 2022). Despite the emergence of bionanohybrid applications, very little is known about how the bionanohybrid lifestyle impacts cells. This project aims to uncover some of the fundamental questions regarding bionanohybrid gene expression by analyzing the RNA transcripts from E. coli K-12 cells with different degrees of cadmium sulfide (CdS) SAN coverage. Gene expression studies may reveal fundamental differences between bionanohybrids and uncoated bacteria, potentially informing development of industrially advantageous bacteria strains that can produce more SANs. Gel electrophoresis and/or density gradient centrifugation will be used to separate cells that are uncoated, lightly coated, medium coated, and heavily coated proir to RNA isolation and purification. Scanning electron microscopy will confirm SAN coverage in these different fractions. RNA sequencing will indicate if there are any differences in gene expression between uncoated cells and bionanoybrids, as well as examine if SAN cell coverage has any relationship to gene expression. This research promises to open doors to new applications related to bionanohybrids while expanding our knowledge of microbial biology.

Learning from the unknown: exploring the range of bacterial functionality.

Determining the repertoire of a microbe's molecular functions is a central question in microbial biology. Modern techniques achieve this goal by comparing microbial genetic material against reference databases of functionally annotated genes/proteins or known taxonomic markers such as 16S rRNA. Here, we describe a novel approach to exploring bacterial functional repertoires without reference databases. Our Fusion scheme establishes functional relationships between bacteria and assigns organisms to Fusion-taxa that differ from otherwise defined taxonomic clades. Three key findings of our work stand out. First, bacterial functional comparisons outperform marker genes in assigning taxonomic clades. Fusion profiles are also better for this task than other functional annotation schemes. Second, Fusion-taxa are robust to addition of novel organisms and are, arguably, able to capture the environment-driven bacterial diversity. Finally, our alignment-free nucleic acid-based Siamese Neural Network model, created using Fusion functions, enables finding shared functionality of very distant, possibly structurally different, microbial homologs. Our work can thus help annotate functional repertoires of bacterial organisms and further guide our understanding of microbial communities.

Trade-offs between the instantaneous growth rate and long-term fitness: Consequences for microbial physiology and predictive computational models.

Microbial systems biology has made enormous advances in relating microbial physiology to the underlying biochemistry and molecular biology. By meticulously studying model microorganisms, in particular Escherichia coli and Saccharomyces cerevisiae, increasingly comprehensive computational models predict metabolic fluxes, protein expression, and growth. The modeling rationale is that cells are constrained by a limited pool of resources that they allocate optimally to maximize fitness. As a consequence, the expression of particular proteins is at the expense of others, causing trade-offs between cellular objectives such as instantaneous growth, stress tolerance, and capacity to adapt to new environments. While current computational models are remarkably predictive for E. coli and S. cerevisiae when grown in laboratory environments, this may not hold for other growth conditions and other microorganisms. In this contribution, we therefore discuss the relationship between the instantaneous growth rate, limited resources, and long-term fitness. We discuss uses and limitations of current computational models, in particular for rapidly changing and adverse environments, and propose to classify microbial growth strategies based on Grimes's CSRframework.

Microbial synthetic biology for plant metabolite production: a strategy to reconcile human health with the realization of the UN Sustainable Development Goals

AbstractPlants produce a wide range of secondary metabolites that provide an array of benefits for human health. Challenges of native host production systems such as excessive land use, large carbon footprints, long production times, and high production costs often make plant‐based production of these critical metabolites inefficient and unsustainable. Engineered production through microbial‐based synthetic biology offers an alternative method of producing plant compounds that addresses the limitations encountered in plant‐based production. New technological and analytical tools such as bioprospecting, machine learning, and protein modeling can be used to explore biodiversity‐based data to identify more efficient enzymatic sequences for optimizing the production of plant derivatives. Ex planta production using microbial chassis systems provides a flexible, scalable metabolic platform that can more readily integrate new metabolic processes. Potential improvements include increased production rates and enhanced bioavailability of critical compounds, expanding the frontiers of metabolite production for optimized clinical applications. Microbial‐based synthetic biology also opens an avenue for sustainable production, with the capability of modifying the microbial chassis to accommodate a wide variety of substrates for feedstock. It includes the utilization of waste from human activities as carbon sources for production, presenting an opportunity to use cheap renewable resources for greener production methods. The benefits of ex planta production systems can potentially enable the efficient, scalable, and sustainable production of plant derivatives that may vastly improve health and help bring forward the realization of the 2030 UN Sustainable Development Goals.