Biology subjects

Fuhrer, T.

Publications and source records attributed to Fuhrer, T..

5 recordsLinked to original sources

bioRxiv2026

A perturbation atlas of mouse neural organoids resolves macroglial reactivity and nominates drivers of degeneration

Understanding neuro-glial roles in homeostasis and disease requires scalable central nervous system (CNS) models, particularly as macroglia like astrocytes and Muller glia remain challenging to study in slow-developing human systems. Here, we generate and map the cellular diversity of mouse neural organoids spanning multiple brain regions and the retina. Benchmarking transcriptomic maturation against in vivo references captures postnatal neuro-macroglial states within a month. We show that macroglia are highly responsive to inflammatory cues and adopt specific transcriptomic states also found in vivo. Through a single-cell perturbation screen targeting 13 Muller-glia-specific pathways, we map how certain inflammatory cytokines drive degeneration-like stress programs in photoreceptors and distinct reactive states in Muller glia, including an Oncostatin M-driven chaperone-associated state. Mechanistically, we identify gp130-STAT3 signaling as a targetable driver of macroglial reactivity and photoreceptor distress. Together, these single-cell atlases provide a foundation for dissecting cellular crosstalk and neuro-glial pathology in the mature CNS.

neuroscience↗

bioRxiv2021

Distinct N and C cross-feeding networks in a synthetic mouse gut consortium

The complex interactions between gut microbiome and host or pathogen colonization resistance cannot solely be understood from community composition. Missing are causal relationships such as metabolic interactions among species to better understand what shapes the microbiome. Here, we focused on metabolic niches generated and occupied by the Oligo-Mouse-Microbiota consortium, a synthetic community composed of 12 members that is increasingly used as a model for the mouse gut microbiome. Combining mono-cultures and spent medium experiments with untargeted metabolomics uncovered broad metabolic diversity in the consortium, constituting a dense cross-feeding network with more than 100 pairwise interactions. Quantitative analysis of the cross-feeding network revealed distinct C and N food webs that highlight the two Bacteroidetes consortium members B. caecimuris and M. intestinale as primary suppliers of carbon, and a more diverse group as nitrogen providers. Cross-fed metabolites were mainly carboxylic acids, amino acids, and the so far not reported nucleobases. In particular the dicarboxylic acids malate and fumarate provided a strong physiological benefit to consumers, presumably as anaerobic electron acceptors. Isotopic tracer experiments validated the fate of a subset of cross-fed metabolites, in particular the conversion of the most abundant cross-fed compound succinate to butyrate. Thus, we show that this consortium is tailored to produce the anti-inflammatory metabolite butyrate. Overall, we provide evidence for metabolic niches generated and occupied by OMM members that lays a metabolic foundation to facilitate understanding of the more complex in vivo behavior of this consortium in the mouse gut. ImportanceThis article maps out the cross-feeding network amongst 10 members of a synthetic consortium that is increasingly used as the model mouse gut microbiota. Combining metabolomics with in vitro cultivations, two dense networks of carbon and nitrogen exchange are described. The vast majority of the about 100 interactions are synergistic in nature, in several cases providing distinct physiological benefits to the recipient species. These networks lay the ground work towards understanding gut community dynamics and host-gut microbe interactions.

microbiology↗

bioRxiv2020

Redox stress reshapes carbon fluxes of Pseudomonas putida for cytosolic glucose oxidation and NADPH generation

The soil bacterium and metabolic engineering platform Pseudomonas putida tolerates high levels of endogenous and exogenous oxidative stress, yet the ultimate reason of such property remains unknown. To shed light on this question, NADPH generation routes--the metabolic currency that fuels redox stress responses--were assessed when P. putida KT2440 was challenged with H2O2 as proxy of oxidative conditions. 13C-tracer experiments, metabolomics and flux analysis, together with inspection of physiological parameters and measurement of enzymatic activities, revealed a substantial flux reconfiguration under oxidative stress. In particular, periplasmic glucose processing was rerouted to cytoplasmic oxidation, and cyclic operation of the pentose phosphate pathway led to significant NADPH fluxes, exceeding biosynthetic demands by ~50%. This NADPH surplus, in turn, fuelled the glutathione system for H2O2 reduction. These properties not only contribute to the tolerance of P. putida to environmental stresses, but they also highlight the value of this host for harsh biotransformations.

microbiology↗

bioRxiv2018

Synthesis and degradation of FtsZ determines the first cell division in starved bacteria

In natural environments, microbes are typically non-dividing. Such quiescent cells manage fleeting nutrients and gauge when intra- and extracellular resources permit division. Quantitative prediction of the division event as a function of nutritional status is currently achieved through phenomenological models for nutrient-rich, exponentially growing cultures. Such models, however, cannot predict the first division of cells under limiting nutrient availability. To address this, we analyzed the metabolic capability of starved Escherichia coli that were fed pulsed glucose at defined frequencies. Real-time metabolomics and microfluidic single-cell microscopy revealed unexpected, rapid protein and nucleic acid synthesis already in non-dividing cells. Additionally, the lag time to first division shortened as pulsing frequency increased. Here, we demonstrate that the first division from a non-dividing state occurs when the facilitating protein FtsZ reaches division-supporting concentration. A dynamic model quantitatively relates lag time to FtsZ synthesis from nutrient pulses and its protease-dependent degradation. Consistent with model predictions, lag time shortened when FtsZ synthesis was supplemented or protease inhibitors were added. Lag time prolonged when ftsZ was repressed or FtsZ degradation rate was increased. Thus, we provide a basis to quantitatively predict bacterial division using information about molecular determinants and the nutrient input.

microbiology↗

bioRxiv2017

Antibodies set boundaries limiting microbial metabolite penetration and the resultant mammalian host response

Although the mammalian microbiota is well-contained within the intestine and on other body surfaces, it profoundly shapes development and metabolism of almost every host organ, presumably through pervasive microbial metabolite penetration. The challenge is that most metabolites can be of both host and microbial origin. We developed a model to distinguish between microbial and host metabolites by stable isotope tracing using fully 13C-labelled live non-replicating Escherichia coli, differentiating 12C and 13C isotopes with high-resolution mass spectrometry. Hundreds of microbial compounds penetrated across 23 host tissues and fluids after intestinal exposure: subsequent 12C host metabolome signatures included lipidemia, reduced glycolysis and inflammation. Mucosal barrier maturation with transient microbial exposure increased early clearance of penetrant bacterial metabolites from the small intestine into the urine, independently of antibody induction. Induced antibodies curtailed microbial metabolite exposure at the intestinal surface, by accelerating intestinal bacterial transit into the colon where metabolite transport mechanisms are limiting.

immunology↗