Biology subjects

Drotleff, B.

Publications and source records attributed to Drotleff, B..

12 recordsLinked to original sources

bioRxiv2026

Cross-generational characterization of paternal Low Protein Diet effects in mice

The impact of diet on the physiology of organisms and their progeny has been well documented across phyla. Using the established paternal Low Protein (LP) diet paradigm in mice, here we assess the robustness of the diet-induced intergenerational responses upon variation of genetic background and dietary history of tested animals. Protein restriction in FVB/NCrl resulted in mild, but specific hepatic responses in exposed animals, as well as their F1 progeny, affecting fatty acid metabolism and cholesterol biosynthesis, respectively. These phenotypes were qualitatively conserved between FVB/NCrl and C56BL/6J mice, suggesting the existence of shared molecular mechanisms underlying metabolic reprogramming, modulated in magnitude by genetic background. Unexpectedly, we uncover cumulative intergenerational inheritance effects that get reshaped at every generation, and a sex-specific priming of cholesterol metabolism of LP-sired F1 offspring, evident upon dietary challenge. Together, our data, spanning multigenerational physiology, transcriptomics and lipidomics, indicate that the phenotypic consequences of paternal LP consumption depend on the duration and/or on the interaction of dietary exposure across generations, leading to distinct trajectories in hepatic energy metabolism.

molecular biology↗

bioRxiv2026

Age-dependent disease tolerance to SARS-CoV-2 infection

Disease tolerance limits infectious disease severity through tissue damage control mechanisms that do not target pathogens directly. Here we demonstrate that age-dependent decline in adipose tissue lipolysis compromises disease tolerance to SARS-CoV-2 infection. Young adult mice exhibited robust adipocyte lipolysis and 80% survival, whereas old mice showed impaired adipocyte lipolysis and only 20% survival. Genetic repression of adipocyte lipolysis eliminated this age-dependent survival advantage without affecting viral titers, revealing that adipocyte lipolysis is essential for disease tolerance to SARS-CoV-2 in young adults. Impaired adipocyte lipolysis in aged mice was associated with a plasma lipidomic signature that predicts COVID-19 severity and mortality in three independent human cohorts. Mechanistically, adipocyte lipolysis provides free fatty acids (FFA) to support bone marrow emergency myelopoiesis, through CD36- and CPT1-dependent FFA cellular uptake and mitochondrial import, respectively. Bone marrow derived monocytes migrate to the lung via CCL2/CCR2-dependent mechanism where they enforce an immune-metabolic communication network with parenchymal cells to sustain lung structure and function. This circuit is not required to confer protection against influenza infection, revealing pathogen-specific disease tolerance mechanisms. These findings reveal adipose tissue catabolism as a central age-dependent factor responsible for exacerbated COVID-19 mortality in aged populations. One-Sentence SummarySARS-CoV-2 infection induces adipose tissue lipolysis to release fatty acids that drive myelopoiesis and monocyte production for lung protection and COVID-19 disease tolerance, but this protective circuit declines with age, increasing disease severity in the elderly.

immunology↗

bioRxiv2026

13C flux ratio analysis with FRAPPPE reveals differences in metabolic fluxes between gut Bacteroidota and Escherichia coli

Gut bacteria shape the metabolism of their host and play an important role in human health. However, systems biology approaches to study their intracellular metabolic fluxes are largely underdeveloped. We present an experimental and computational workflow to quantify metabolic flux ratios in gut bacteria using 13C-labeled nutrient supplementation and a newly developed machine learning-based Flux Ratio Prediction Python PackagE (FRAPPPE). We apply FRAPPPE to investigate central carbon metabolism in two prevalent gut Bacteroidota, Bacteroides uniformis and Phocaeicola vulgatus, in comparison to Escherichia coli. FRAPPPE revealed altered tricarboxylic acid cycle bifurcation in Bacteroidota compared to E. coli under anaerobic conditions. Further, we used FRAPPPE to investigate co-metabolism of nucleosides and carbohydrates by B. uniformis and P. vulgatus. We found distinct species-specific patterns in how nucleosides affected growth and were utilized depending on the co-fed compound. We quantified co-metabolism and showed that the tested nucleosides were mainly contributing to anabolic metabolism closely related to the specific co-fed nucleoside. Together, these findings provide insights into central and nucleoside metabolism of two gut Bacteroidota, and showcase FRAPPPE as a generalizable workflow to investigate metabolic fluxes in gut bacteria.

microbiology↗

bioRxiv2026

From the lung to the muscle: Systemic insights from an integrative MultiOmics analysis of harbour porpoises in poor respiratory health

Harbour porpoises (Phocoena phocoena) in the North and Baltic Seas are increasingly impacted by anthropogenic pressures, including underwater noise, fisheries and pollution. These pressures correlate with declining population health, particularly affecting the respiratory system. Growing pathological lesions, partly resulting from high prevalence of parasitic infestations and subsequent diseases, can impair tissue function and oxygen supply to distant end-organs. In this study, we applied an integrative MultiOmics approach (proteomics, metabolomics, lipidomics) to analyse the lungs and muscles of 12 wild harbour porpoises with compromised respiratory health. Our aim was to identify dysregulated biological pathways across omics layers to advance insights into adaptive physiological responses and to define disease-associated molecular signatures that could assist health assessments. Our analysis revealed pronounced immune system and antioxidative responses in the lungs and muscles, indicated by enhanced immunoglobulins, plasmalogens and glutathione-related proteins. In the lungs, high cardiolipin levels and reduced collagen suggest impaired tissue structure and function, while tissue maintenance processes were elevated in the muscle. Both tissues exhibited metabolic alterations suggestive of energetic imbalance, including increased purine metabolism in the lung and decreased lipid metabolism in the muscle. Several dysregulated molecules were shared across tissues, pointing to pathophysiological effects. The proposed disease-associated molecular signatures included the protein SLC25A4, the metabolite O-phosphoethanolamine and the lipid TG O-16:0_16:0_20:4 for the lung, and the protein SPEG, the metabolite pipecolic acid, and the lipid BMP 18:1_22:6 in the muscle. Our findings elucidate the complexity of molecular mechanisms linking anthropogenic and environmental stressors with vulnerability and resilience in a marine sentinel species. Furthermore, this study highlights the potential of integrative omics to define disease-related marker panels, thereby supporting ongoing and future health monitoring and conservation efforts.

systems biology↗

bioRxiv2026

An ancient monoaminergic signaling system coordinates contractility in a nerveless sponge

Chemical neurotransmission was a key animal innovation, enabling multicellular coordination of physiology and locomotion. Sponges are early-diverging animals that lack neurons and muscles, yet still coordinate contraction and relaxation of their filter-feeding water canals. Here, we show that Spongilla lacustris synthesizes the monoamines tryptamine, phenethylamine, and tyramine to elicit distinct canal behaviors. We identify previously uncharacterized decarboxylases and vesicular transporters coexpressed in secretory neuroid and metabolic cells. Using phosphoproteomics and label-free 3D imaging, we show that tryptamine activates GPCR signaling and Rho GTPases, remodeling adhesion and actomyosin networks in contractile canal epithelia to drive localized constrictions and whole-body deflations. Together, these findings define an ancestral monoaminergic system linking secretory and contractile cell types that predate neurons and was later elaborated for neuromodulation of synaptic transmission.

evolutionary biology↗

bioRxiv2025

A deep, quantitative lipid atlas of extracellular vesicles across multiple cell lines

Extracellular vesicles (EVs) are subcellular particles surrounded by a lipid bilayer membrane and incorporating various additional biomolecules derived from their donor cell. In many disease contexts circulating EVs have received increasing scientific attention due to their potential diagnostic and prognostic value. Additionally, EVs have been ascribed multiple biological functions, ranging from cellular waste disposal to sophisticated, intercellular communication. Consequently, EVs involved in pathological processes may represent therapeutic targets, whereas EV-based therapeutics are being developed for targeted delivery of molecular cargoes in vivo. Detailed knowledge of the molecular content of natural EVs derived from diverse cellular origins is crucial to identify biomarkers, dissect EV functions, and optimize EV engineering for therapeutic purposes. Although the lipid composition of biological membranes has a significant impact on their biophysical and -chemical properties and may affect signaling and interactions at the molecular and cellular level, relatively little is known about the lipid composition of EV membranes. Here, we applied high resolution mass spectrometry to deeply and quantitatively characterize the lipidome of EVs isolated from a panel of malignant and non-malignant cell lines, providing a comprehensive data resource for biomarker research and EV engineering efforts. Furthermore, subset comparisons indicate striking differences between lipid profiles of EVs isolated from cells of different tissue origin, suggesting distinct membrane characteristics that could affect EV biodistribution and function in vivo.

cell biology↗

bioRxiv2025

A bioenergetic basis for multiorgan dysfunction in sepsis

Sepsis is a life-threatening multiorgan dysfunction that develops from a maladaptive host response to infection1. With an estimated 49 million cases per year and [~]11 million related deaths2, sepsis is a global WHO health priority3. Failure to overcome sepsis morbidity and lethality4,5 calls for alternative therapeutic approaches6-8. Here we report that adipocyte lipolysis is vital to prevent the pathogenesis of sepsis in mice. This protective response is evolutionary conserved, producing a plasma lipidomic profile9,10 that reflects on the severity of clinical sepsis. Mechanistically, adipocyte lipolysis fuels energy metabolism to sustain adaptive thermoregulation to infection, via insulin production and insulin receptor (INSR) signaling in adipocytes. This metabolic-based defense strategy does not impact on bacterial burden, establishing disease tolerance to infection11-14. In conclusion, adipocyte lipolysis induces insulin to rewire energy metabolism and support organ function in response to infection.

pathology↗

bioRxiv2025

Regulation of the branched-chain amino acid pathway and its crosstalk to carbon metabolism in yeast

In Saccharomyces cerevisiae, the TORC1 pathway regulates the transition from rapid fermentative growth to respiration during the diauxic shift, by tightly coordinating energy- and biomass-producing pathways. Although leucine and other components of the branched-chain amino acid (BCAA) pathway are known TORC1 regulators, how the BCAA pathway is controlled across this transition and influences the crosstalk between central carbon and amino acid metabolism remains unclear. By integrating high-throughput flow cytometry and untargeted LC-MS metabolomics into a thermodynamically curated genome-scale model, we profiled protein levels, metabolite dynamics, and cellular context during the diauxic shift of a GFP-tagged strain library of the BCAA pathway in wild-type and mutants lacking non-essential genes for BCAA biosynthesis. This analysis revealed that the BCAA pathway operates in two branches, with only the leucine-committed branch exhibiting a fermentative signature aligned with TORC1 activity. We further identified key regulatory elements and showed that dysregulation of the BCAA pathway disrupts distant metabolic circuits, including central carbon metabolism. Our findings highlight the dynamic role of the BCAA pathway in metabolic network integration during the diauxic shift.

systems biology↗

bioRxiv2025

A Metabolite-Based Resistance Mechanism Against Malaria

Whether jaundice, a common presentation of Plasmodium (P.) falciparum malaria (1-3) arising from the accumulation of circulating bilirubin, represents an adaptive or maladaptive response to Plasmodium spp. infection is not understood (1-3). We found that asymptomatic P. falciparum infection was associated with a >10-fold higher ratio of unconjugated bilirubin over parasite burden, compared to symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) (4) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, via genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1) (5), was protective against malaria in mice. Unconjugated bilirubin inhibited P. falciparum proliferation in red blood cells (RBC) via a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin (Hz) crystallization and compromised the parasites food vacuole. In conclusion, jaundice represents a metabolic response to Plasmodium spp. infection that limits malaria severity.

immunology↗

bioRxiv2024

HT SpaceM: A High-Throughput and Reproducible Method for Small-Molecule Single-Cell Metabolomics

Single-cell metabolomics promises to resolve metabolic cellular heterogeneity, yet current methods struggle with detecting small molecules, throughput, and reproducibility. Addressing these gaps, we developed HT SpaceM, a high-throughput single-cell metabolomics method with novel cell preparation, custom glass slides, small-molecule MALDI imaging mass spectrometry protocol, and batch processing. We propose a unified framework covering essential data analysis steps including quality control, characterization, differential analysis, structural validation and functional analysis. Interrogating human HeLa and mouse NIH3T3 cells, we detected 73 diverse small-molecule metabolites validated by bulk LC-MS/MS, achieving high reproducibility across wells and slides. Interrogating nine NCI-60 cancer cells and HeLa, we identified cell-type markers in small subpopulations. Functional analysis revealed overrepresented metabolic pathways, co-abundant metabolites, and metabolic hubs. We demonstrate the ability of SCM to analyze over 120,000 cells from over 112 samples, and provide guidance to interpret single-cell metabolic heterogeneity, revealing metabolic insights beyond population averages.

molecular biology↗

bioRxiv2023

Molecular profiling of sponge deflation reveals an ancient relaxant-inflammatory response

A hallmark of animals is the coordination of whole-body movement. Neurons and muscles are central to this, yet coordinated movements also exist in sponges that lack these cell types. Sponges are sessile animals with a complex canal system for filter-feeding. They undergo whole-body movements resembling "contractions" that lead to canal closure and water expulsion. Here, we combine 3D optical coherence microscopy, pharmacology, and functional proteomics to elucidate anatomy, molecular physiology, and control of these movements. We find them driven by the relaxation of actomyosin stress fibers in epithelial canal cells, which leads to whole-body deflation via collapse of the incurrent and expansion of the excurrent system, controlled by an Akt/NO/PKG/A pathway. A concomitant increase in reactive oxygen species and secretion of proteinases and cytokines indicate an inflammation-like state reminiscent of vascular endothelial cells experiencing oscillatory shear stress. This suggests an ancient relaxant-inflammatory response of perturbed fluid-carrying systems in animals. HighlightsO_LISponge deflation is driven by tension release in actomyosin stress fibers of epithelial pinacocytes C_LIO_LIAkt kinase/Nitric oxide/Protein kinase G/A regulate actomyosin relaxation C_LIO_LIAgitation-induced deflation coincides with an inflammatory state C_LIO_LIThe sponge relaxant-inflammatory response is evolutionary related to similar responses in the vertebrate vascular system C_LI

molecular biology↗

bioRxiv2022

To start or to discontinue the pill - changes in progestogens reflected by resting-state connectivity and positive mood

Oral contraceptive (OC) intake has been associated with alterations in functional brain architecture and socio-affective processes. However, most previous studies have been limited by cross-sectional designs and/or did not account for synthetic sex hormone concentrations. The aim of this longitudinal study was to determine the effects of starting vs discontinuing OCs on socio-affective functions such as mood and emotion cognition, and to identify their possible neuroendocrinological substrates. To this end, 88 young healthy women performed the behavioral and fMRI measures twice, three to eight months apart: 26 natural cycling women twice during menstruation, 26 OC users twice during OC intake, 25 OC discontinuers and 11 OC starters before and after discontinuation or start, respectively. In addition to mean-based analyses, we used intersubject representational similarity analyses to determine relationships between interindividual variability in within-subject changes of hormone profiles, including concentrations of endogenous and synthetic hormones, region-specific resting state functional connectivity (parcelwise RSFC) and socio-affective measures. Across the whole sample, interindividual patterns of changes in RSFC of fronto-parietal regions, parts of the left hippocampus and the right cerebellum reflected change patterns of progestogen levels. For the right superior orbitofrontal gyrus (OFG), a trinity of idiosyncratic patterns was found in changes of progestogens, RSFC and positive mood. Active OC intake was associated with higher self-reported depressive symptoms in OC discontinuers (and starters). Emotion recognition performance was not associated with changes in hormone profiles or RSFC. Overall, progestogens rather than estrogens appear to be associated with functional brain architecture of the frontal and subcortical/cerebellar regions and positive mood. The right superior OFG represents a possible neural substrate for progestogen-induced changes in positive mood. This study indicates the importance of a multidimensional, longitudinal approach when being interested in effects of hormonal contraception on womens brain and behavior.

neuroscience↗