Biology subjects

Donia, M. S.

Publications and source records attributed to Donia, M. S..

11 recordsLinked to original sources

bioRxiv2026

Community Curation of Microbial Metabolites Enables Biological Insights of Metabolomics Data

Microbial metabolites play a critical role in regulating ecosystems, including the human body and its microbiota. However, understanding the physiologically relevant role of these molecules, especially through liquid chromatography tandem mass spectrometry (LC-MS/MS)-based untargeted metabolomics, poses significant challenges and often requires manual parsing of a large amount of literature, databases, and webpages. To address this gap, we established the Collaborative Microbial Metabolite Center knowledgebase (CMMC-KB), a platform that fosters collaborative efforts within the scientific community to curate knowledge about microbial metabolites. The CMMC-KB aims to collect comprehensive information about microbial molecules originating from microbial biosynthesis, drug metabolism, exposure-related molecules, food, host-derived molecules, and, whenever available, their known activities. Molecules from other sources, including host-produced, dietary, and pharmaceutical compounds, are also included. By enabling direct integration of this knowledgebase with downstream analytical tools, including molecular networking, we can deepen insights into microbiota and their metabolites, ultimately advancing our understanding of microbial ecosystems.

bioinformatics↗

bioRxiv2025

Many circulating indole and phenol metabolites are host derived

Indole and phenol metabolites are typically thought to be products of bacterial digestion of tryptophan (indoles) and phenylalanine or tyrosine (phenols). Interest in controlling gut microbial production of these metabolites has continually grown as they have important physiological impacts, with indoles agonizing AhR signaling, and phenols being associated with healthy body weight. While there is a growing wealth of research into which bacteria produce these metabolites, host contribution to their circulating pools has not been adequately characterized. Here, through stable isotope tracing in cell culture and mice, we show that mammalian cells can make aryl-pyruvates, -lactates, -acetates, and -carboxylic acids. Levels of these metabolites in mice and human patients are insensitive to perturbations of the microbiome. In contrast, bacterial metabolism is required to synthesize aryl-propionates and free indole, phenol, and cresol. Overall, we show that host metabolism is a primary contributor to circulating indole and phenol metabolite pools.

molecular biology↗

bioRxiv2025

When is microbial cross-feeding evolutionarily stable?

Cross-feeding, a phenomenon in which organisms share metabolites, is frequently observed in microbial communities across the natural world. One of the most common forms is waste-product cross-feeding, a unidirectional interaction in which the waste products of one microbe support the growth of another. Despite its ubiquity, it is not well-understood why waste-product cross-feeding persists when a single organism could in principle perform both the producer and consumer role. To address this question, we first analyze cross-feeding evolution in a minimal model of microbial metabolism. The model describes multi-step extraction of energy from a substrate in a simple but thermodynamically correct formulation. Surprisingly, we find that cross-feeding is never evolutionarily stable in this model. By analyzing models with more complex growth functions, we identify a novel mechanism for the evolutionary stability of waste-product cross-feeding, namely, generalized intracellular metabolite toxicity. Such toxicity arises because, in excess, the same intracellular metabolites that cells require for metabolism can be detrimental to growth (e.g., due to osmotic stress). We show that some but not all forms of such toxicity can lead to evolutionarily stable consortia of microbes that cross-feed waste products. This stability results from the potential of such consortia to divide the burden of toxic metabolites among a larger population, allowing them to perform their collective metabolism more efficiently than non-cross-feeders. More generally, we predict that growth penalties that scale nonlinearly with intracellular metabolite levels promote cross-feeding. We find that this mechanism for cross-feeding evolutionary stability implies nontrivial population dynamics, such as a discontinuity in population biomass at the onset of cross-feeding. Significance statementThe chemical reactions performed by microbes have large impacts on our world: from nitrification within the nitrogen cycle to the breakdown of fiber in animal digestive tracts. A striking commonality in many of these processes is that the chemical reactions are a collective effort, with the complete reaction subdivided between many microbes. This phenomenon is known as cross-feeding, and its origins are poorly understood. Understanding the eco-evolutionary forces promoting cross-feeding have the potential to not only enhance our understanding of natural ecosystems, but also improve our ability to engineer such distributed reactions in biotechnology. Here, we develop mathematical theory for the evolution of a common type of cross-feeding and provide predictions for what metabolic and environmental conditions promote this behavior.

microbiology↗

bioRxiv2025

A nutrient bottleneck limits antibiotic efficacy in structured bacterial populations

Antibiotic resistance is a growing global health threat. Therefore, it is critically important to optimize how existing antibiotics act against bacterial infections. Although antibiotic activity is well studied at the single cell level, many infections are caused by spatially structured multicellular populations. In such populations, cellular consumption of scarce nutrients establishes strong spatial variations in their abundance. These nutrient variations have long been hypothesized to help bacterial populations tolerate antibiotics, since single-cell studies show that antibiotic tolerance depends on metabolic activity, and thus, local nutrient availability. Here, we directly test this hypothesis by visualizing cell death in Escherichia coli populations with defined structures upon exposure to nutrient (glucose) and antibiotic (fosfomycin). We find that nutrient availability acts as a bottleneck to antibiotic killing, causing death to propagate through the population as a traveling front--a phenomenon predicted over 20 years ago, but never verified until now. By integrating our measurements with biophysical theory and simulations, we establish quantitative principles that explain how collective nutrient consumption can limit the progression of this "death front," protecting a population from a nominally deadly antibiotic dose. While increasing nutrient supply can overcome this bottleneck, our work reveals that in some cases, excess nutrient can unexpectedly promote the regrowth of resistant cells. Altogether, this work provides a key step toward predicting and controlling antibiotic treatment of spatially structured bacterial populations, yielding fundamental biophysical insights into collective behavior and helping to guide strategies for more effective antibiotic stewardship.

biophysics↗

bioRxiv2024

Cathelicidin antimicrobial peptides mediate immune protection of marsupial neonates

Marsupial neonates are born with immature immune systems, making them vulnerable to pathogens. While neonates receive maternal protection, they can also independently combat pathogens, though the mechanisms remain unknown. Using the sugar glider (Petaurus breviceps) as a model, we investigated immunological defense strategies of marsupial neonates. Cathelicidins - a family of antimicrobial peptides expanded in the genomes of marsupials - are highly expressed in developing neutrophils. Sugar glider cathelicidins reside in two genomic clusters and their coordinated expression is achieved by enhancer sharing within clusters and long-range physical interactions between clusters. These cathelicidins modulate immune responses and have potent antimicrobial effects, sufficient to provide protection in a mouse model of sepsis. Lastly, cathelicidins have a complex evolutionary history, where marsupials and monotremes are the only tetrapods that retained two cathelicidin clusters. Thus, cathelicidins are critical mediators of marsupial immunity, and their evolution reflects the life history-specific immunological needs of these animals.

evolutionary biology↗

bioRxiv2024

A meta-analysis of the gut microbiome in inflammatory bowel disease patients identifies disease-associated small molecules

Changes in the gut microbiome have been associated with several human diseases, but the molecular and functional details underlying these associations remain largely unknown. Here, we performed a multi-cohort analysis of small molecule biosynthetic gene clusters (BGCs) in 5,306 metagenomic samples of the gut microbiome from 2,033 Inflammatory Bowel Disease (IBD) patients and 833 matched healthy subjects and identified a group of Clostridia-derived BGCs that are significantly associated with IBD. Using synthetic biology, we discovered and solved the structures of six fatty acid amides as the products of the IBD-enriched BGCs. Using two mouse models of colitis, we show that the discovered small molecules disrupt gut permeability and exacerbate inflammation in chemically and genetically susceptible mice. These findings suggest that microbiome-derived small molecules may play a role in the etiology of IBD and represent a generalizable approach for discovering molecular mediators of microbiome-host interactions in the context of microbiome-associated diseases.

microbiology↗

bioRxiv2022

Gut bacterial nutrient preferences quantified in vivo

Great progress has been made in understanding gut microbiomes products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber, and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate and urea (but not glucose or amino acids) feed the gut microbiome. To determine nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We find systematic differences in nutrient use: Most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.

molecular biology↗

bioRxiv2020

Pseudomonas aeruginosa detachment from surfaces via a self-made small molecule

Pseudomonas aeruginosa is a significant threat in both healthcare and industrial biofouling. Surface attachment of P. aeruginosa is particularly problematic as surface association induces virulence and biofilm formation, which hamper later antibiotic treatments. Previous efforts have searched for biofilm dispersal agents, but there are no known factors that specifically disperse surface-attached P. aeruginosa. In this study we develop a quantitative surface-dispersal assay and use it to show that P. aeruginosa itself produces factors that can stimulate its dispersal. Through bioactivity-guided fractionation, Mass Spectrometry, and Nuclear Magnetic Resonance, we elucidated the structure of one such factor, 2-methyl-4-hydroxyquinoline (MHQ). MHQ is an alkyl-quinolone with a previously unknown activity and is synthesized by the PqsABC enzymes. Pure MHQ is sufficient to disperse P. aeruginosa, but the dispersal activity of natural P. aeruginosa conditioned media requires additional factors. Whereas other alkyl quinolones have been shown to act as antibiotics or membrane depolarizers, MHQ lacks these activities and known antibiotics do not induce dispersal. In contrast, we show that MHQ inhibits the activity of Type IV Pili (TFP) and that TFP targeting can explain its dispersal activity. Our work thus identifies surface dispersal as a new activity of P. aeruginosa-produced small molecules, characterizes MHQ as a promising dispersal agent, and establishes TFP inhibition as a viable mechanism for P. aeruginosa dispersal. Significance StatementWe discovered that the clinically relevant human bacterial pathogen P. aeruginosa, typically associated with surface-based infections, is dispersed by a small molecule that the bacteria themselves produce. We elucidate the chemical structure of this molecule and find that mechanistically it functions to inhibit the activity of the P. aeruginosa extra cellular surface motility appendage, the type IV pilus.

microbiology↗

bioRxiv2020

Integration of machine learning and pan-genomics expands the biosynthetic landscape of RiPP natural products

Most clinical drugs are based on microbial natural products, with compound classes including polyketides (PKS), non-ribosomal peptides (NRPS), fluoroquinones and ribosomally synthesized and post-translationally modified peptides (RiPPs). While variants of biosynthetic gene clusters (BGCs) for known classes of natural products are easy to identify in genome sequences, BGCs for new compound classes escape attention. In particular, evidence is accumulating that for RiPPs, subclasses known thus far may only represent the tip of an iceberg. Here, we present decRiPPter (Data-driven Exploratory Class-independent RiPP TrackER), a RiPP genome mining algorithm aimed at the discovery of novel RiPP classes. DecRiPPter combines a Support Vector Machine (SVM) that identifies candidate RiPP precursors with pan-genomic analyses to identify which of these are encoded within operon-like structures that are part of the accessory genome of a genus. Subsequently, it prioritizes such regions based on the presence of new enzymology and based on patterns of gene cluster and precursor peptide conservation across species. We then applied decRiPPter to mine 1,295 Streptomyces genomes, which led to the identification of 42 new candidate RiPP families that could not be found by existing programs. One of these was studied further and elucidated as a novel subfamily of lanthipeptides, designated Class V. Two previously unidentified modifying enzymes are proposed to create the hallmark lanthionine bridges. Taken together, our work highlights how novel natural product families can be discovered by methods going beyond sequence similarity searches to integrate multiple pathway discovery criteria. Code and data availabilityThe source code of DecRiPPter is freely available online at https://github.com/Alexamk/decRiPPter. Results of the data analysis are available online at http://www.bioinformatics.nl/~medem005/decRiPPter_strict/index.html and http://www.bioinformatics.nl/~medem005/decRiPPter_mild/index.html (for the strict and mild filters, respectively). All training data and code used to generate these, as well as outputs of the data analyses, are available on Zenodo at doi:10.5281/zenodo.3834818.

microbiology↗

bioRxiv2019

Cutibacterium acnes antibiotic production shapes niche competition in the human skin microbiome

The composition of the skin microbiome varies widely among individuals sampled at the same body site. A key question is which molecular factors determine strain-level variability within sub-ecosystems of the skin. We used a genomics-guided approach to identify an antibacterial biosynthetic gene cluster in Cutibacterium acnes (formerly Propionibacterium acnes) that is widely distributed across individuals and skin sites. Experimental characterization of this cluster enabled the identification of a new thiopeptide antibiotic, cutimycin. Analysis of individual human skin hair follicles showed that cutimycin is an important factor regulating colonization resistance against Staphylococcus species.\n\nOne Sentence SummaryCutimycin, a thiopeptide antibiotic produced by a widespread skin commensal, reduces Staphylococcus colonization of human follicles.

microbiology↗

bioRxiv2019

Systematic mapping of drug metabolism by the human gut microbiome

The human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities, making it one of natures highest density, highest diversity bioreactors. Several drugs have been previously shown to be directly metabolized by the gut microbiome, but the extent of this phenomenon has not been systematically explored. Here, we develop a systematic screen for mapping the ability of the complex human gut microbiome to biochemically transform small molecules (MDM-Screen), and apply it to a library of 575 clinically used oral drugs. We show that 13% of the analyzed drugs, spanning 28 pharmacological classes, are metabolized by a single microbiome sample. In a proof-of-principle example, we show that microbiome-derived metabolism occurs in vivo, identify the genes responsible for it, and provide a possible link between its consequences and clinically observed features of drug bioavailability and toxicity. Our findings reveal a previously underappreciated role for the gut microbiome in drug metabolism, and provide a comprehensive framework for characterizing this important class of drug-microbiome interactions.

microbiology↗