The human gut microbiota
The human gut microbiota is a central focus of the lab. We connect fundamental principles of bacterial physiology with intestinal physiology, diet, and host metabolism to quantify the exchange of chemical fluxes between the microbiota and the human host. Towards a mechanistic understanding, we tightly integrate in-vitro experimentation with mathematical modeling and the analysis of food intake and digestion. Building on these quantitative foundations, we investigate how the microbiome's metabolic activities vary across individuals and health conditions, aiming to reveal the mechanistic role of the microbiome in disease development and progression.
Recent work
Quantifying the varying harvest of fermentation products from the human gut microbiota (2025)
Cell
Fermentation products released by the gut microbiota provide energy and regulatory functions to the host. Yet, little is known about the magnitude of this metabolic flux and its quantitative dependence on diet and microbiome composition. Here, we establish orthogonal approaches to consistently quantify this flux, integrating data on bacterial metabolism, digestive physiology, and metagenomics. From the nutrients fueling microbiota growth, most carbon ends up in fermentation products and is absorbed by the host. This harvest varies strongly with the amount of complex dietary carbohydrates and is largely independent of bacterial mucin and protein utilization. It covers 2-5% of human energy demand for Western, and up to 10% for non-Western diets. Microbiota composition has little impact on the total harvest but determines the amount of specific fermentation products. This consistent quantification of metabolic fluxes by our analysis framework is crucial to elucidate the gut microbiotas mechanistic functions in health and disease.
DOI
Diurnal Variations in Digestion and Flow Drive Microbial Dynamics in the Gut (2025)
PRX Life
The human large intestine harbors a highly dynamic microbial ecosystem in which growing microbes regularly replenish biomass lost via feces. Understanding this population dynamics is biomedically important but remains a significant challenge due to rapid changes in microbial biomass and intestinal fluid flows. Leveraging experimental data on fluid turnover, nutrient supply, and microbial growth, we here derive a biophysical model of population dynamics. We show how the digestion of meals in batches triggers strong fluctuations in fluid movement and bacteria growth along the proximal large intestine. Comparing different model scenarios, we further analyze how the expandable nature of the proximal large intestine, the presence of a pouch-like cecum off major flow paths, and the periodic exit of luminal content via mass movements are required in combination to maintain the high microbial population observed in the proximal large intestine. Since the microbial population undergoes several bottlenecks followed by rapid growth each day, the effective population size in the proximal large intestine is small, promoting the fast evolution of microbes. The diurnal fluctuations in flow also hamper the accumulation of slower-growing bacteria and lead to substantial variations in the uptake of fermentation products by the host.
DOI
Changing flows balance nutrient absorption and bacterial growth along the gut (2022)
Physical Review Letters
Small intestine motility and its ensuing flow of luminal content impact both nutrient absorption and bacterial growth. To explore this interdependence we introduce a biophysical description of intestinal flow and absorption. Rooted in observations of mice we identify the average flow velocity as the key control of absorption efficiency and bacterial growth, independent of the exact contraction pattern. We uncover self-regulation of contraction and flow in response to nutrients and bacterial levels to promote efficient absorption while restraining detrimental bacterial overgrowth.
DOI
Microbial cell physiology
How do microbial cells coordinate thousands of enzymes and molecular processes to grow and replicate? We seek the essential physiological principles governing microbial growth by combining controlled culturing experiments across conditions with omics approaches, including proteomics and transcriptomics, and mathematical modeling. To generate biological insights into growth, we use low-dimensional modeling approaches building on and expanding the idea of resource allocation. We work primarily with E. coli, but increasingly also include other microbes across biological domains.
Recent work
Maintenance of cytoplasmic and membrane densities shapes cellular geometry in Escherichia coli (2025)
Nature Communications
Microbes exhibit precise control over their composition and geometry in order to adapt and grow in diverse environments. However, the mechanisms that orchestrate this simultaneous regulation, and how they are causally linked, remains poorly understood. In this work, we derive and experimentally test a biophysical model of cell size regulation in Escherichia coli which relates the cellular surface-to-volume ratio to the total macromolecular composition and partitioning of the proteome between cellular compartments. Central to this model is the observation that the macromolecular density of the cytoplasm and the protein density within the cell membranes are maintained at a constant ratio across growth conditions. Using quantitative mass spectrometry, single-cell microscopy, and biochemical assays, we show this model quantitatively predicts a non-linear relationship between the surface-to-volume ratio, proteome localization, and the total ribosome content of the cell. This model holds under perturbations of intracellular ppGpp concentrations — thereby changing the ribosomal content — demonstrating that cellular geometry is not strictly determined by the cellular growth rate. These findings provide a biophysical link between the coregulation of proteome organization and cellular geometry, offering a quantitative framework for understanding bacterial size regulation across conditions.
DOI
An optimal regulation of fluxes dictates microbial growth in and out of steady-state (2023)
eLife
Effective coordination of cellular processes is critical to ensure the competitive growth of microbial organisms. Pivotal to this coordination is the appropriate partitioning of cellular resources between protein synthesis via translation and the metabolism needed to sustain it. Here, we extend a low-dimensional allocation model to describe the dynamic regulation of this resource partitioning. At the core of this regulation is the optimal coordination of metabolic and translational fluxes, mechanistically achieved via the perception of charged- and uncharged-tRNA turnover. An extensive comparison with approximately 60 data sets from Escherichia coli establishes this regulatory mechanism's biological veracity and demonstrates that a remarkably wide range of growth phenomena in and out of steady state can be predicted with quantitative accuracy. This predictive power, achieved with only a few biological parameters, cements the preeminent importance of optimal flux regulation across conditions and establishes low-dimensional allocation models as an ideal physiological framework to interrogate the dynamics of growth, competition, and adaptation in complex and ever-changing environments.
DOI
Suboptimal resource allocation during changing environments constrains bacterial response and growth recovery (2021)
Molecular Systems Biology
To respond to fluctuating conditions, microbes typically need to synthesize novel proteins. As this synthesis relies on sufficient biosynthetic precursors, microbes must devise effective response strategies to manage depleting precursors. To better understand these strategies, we investigate the active response of Escherichia coli to changes in nutrient conditions, connecting transient gene expression to growth phenotypes. By synthetically modifying gene expression during changing conditions, we show how the competition by genes for the limited protein synthesis capacity constrains cellular response. Despite this constraint cells substantially express genes that are not required, trapping them in states where precursor levels are low and the genes needed to replenish the precursors are outcompeted. Contrary to common modeling assumptions, our findings highlight that cells do not optimize growth under changing environments but rather exhibit hardwired response strategies that may have evolved to promote fitness in their native environment.
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Physiology, ecology, and evolution
Incorporating ecological and evolutionary considerations with our physiological studies, we explore how fundamental cell-physiological constraints shape adaptation to specific environments and habitats. For example, systematic omics studies have revealed that large fractions of the proteome account for proteins not immediately required for growth in probed conditions. We aim to understand the role of these conditionally unutilized proteins, how they shape growth and how they reflect ecological adaptation. Are they part of an anticipatory adaptation strategy, poised for rapid deployment when conditions shift? How does the expression of these proteins reflect the ecological niche of a species, and what does this tell us about the physiological identity of a species and its evolutionary history?
Recent work
Conditionally unutilized proteins and their profound effects on growth and adaptation across microbial species (2023)
Current Opinion in Microbiology
Protein synthesis is an important determinant of microbial growth and response that demands a high amount of metabolic and biosynthetic resources. Despite these costs, microbial species from different taxa and habitats massively synthesize proteins that are not utilized in the conditions they currently experience. Based on resource allocation models, recent studies have begun to reconcile the costs and benefits of these conditionally unutilized proteins (CUPs) in the context of varying environmental conditions. Such massive synthesis of CUPs is crucial to consider in different areas of modern microbiology, from the systematic investigation of cell physiology, via the prediction of evolution in laboratory and natural environments, to the rational design of strains in biotechnology applications.
DOI
Chemotaxis as a navigation strategy to boost range expansion (2019)
Nature
Bacterial chemotaxis, the directed movement of cells along gradients of chemoattractants, is among the best-characterized subjects in molecular biology, but much less is known about its physiological roles. It is commonly seen as a starvation response when nutrients run out, or as an escape response from harmful situations. Here we identify an alternative role of chemotaxis by systematically examining the spatiotemporal dynamics of Escherichia coli in soft agar. Chemotaxis in nutrient-replete conditions promotes the expansion of bacterial populations into unoccupied territories well before nutrients run out in the current environment. Low levels of chemoattractants act as aroma-like cues in this process, establishing the direction and enhancing the speed of population movement along the self-generated attractant gradients. This process of navigated range expansion spreads faster and yields larger population gains than unguided expansion and is therefore a general strategy to promote population growth in spatially extended, nutrient-replete environments.
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An evolutionarily stable strategy to colonize spatially extended habitats (2019)
Nature
The ability of a species to colonize newly available habitats is crucial to its overall fitness. In general, motility and fast expansion are expected to be beneficial for colonization and hence for the fitness of an organism. Here we apply an evolution protocol to investigate phenotypical requirements for colonizing habitats of different sizes during range expansion by chemotaxing bacteria. Contrary to the intuitive expectation that faster is better, we show that there is an optimal expansion speed for a given habitat size. Our analysis showed that this effect arises from interactions among pioneering cells at the front of the expanding population, and revealed a simple, evolutionarily stable strategy for colonizing a habitat of a specific size: to expand at a speed given by the product of the growth rate and the habitat size. These results illustrate stability-to-invasion as a powerful principle for the selection of phenotypes in complex ecological processes.
DOI