Biology subjects

Cremer, J.

Publications and source records attributed to Cremer, J..

17 recordsLinked to original sources

bioRxiv2026

Quantifying the Resource Landscape That Shapes the Human Gut Microbiome

The microbial ecosystem in the human gut is fundamentally shaped by the resources it receives. Yet, while quantitative information is available for many individual resource fluxes, a comprehensive description of the overall resource landscape is lacking. Here, I systematically integrate physiological measurements and food composition data to map diet and digestion to the fluxes of more than 30 major resources entering the human large intestine, including carbohydrates, proteins, mucus, bile acids, ions, and electron acceptors. Applying this reconstruction across dietary variation in the U.S. population and analyzing the resulting influxes of biomass-forming elements, I find that microbial growth is carbon-limited for most individuals, whereas phosphorus is limiting for a subset; nitrogen, by contrast, is not limiting once host-derived urea recycling is accounted for. Resource supply also determines whether microbial auxotrophies impose physiological constraints. While amino acid dependencies can often be satisfied by protein-derived influx, characterized dietary cobamide influx is insufficient to account for the fecal cobamide pool, pointing to a much greater contribution from microbial production. Together, these results provide a quantitative resource landscape for the human gut, defining physiological constraints on microbial growth and providing a basis for predictive models of microbiome function and its impact on the host.

microbiology↗

bioRxiv2026

Order invariance of fitness makes evolution predictable despite strong history-dependent effects

Environmental change is ubiquitous in nature, yet understanding its effect on the predictability of evolution remains a challenge. Previous work in microbes has shown that growth and fitness in a particular environment can depend strongly on the environments encountered previously. If such history-dependent effects are large, then any sequence of environments must be thought of as unique, and even a modest number of environments could generate a combinatorially large number of evolutionary paths. This would make evolution in changing environments difficult to predict. Here, we use cycles of three environments, which is the smallest number of environments which allow for comparisons of different environmental orderings -- X [->] Y [->] Z [->] X vs X [->] Z [->] Y [->] X -- to empirically test how environmental order affects the fitness of S. cerevisiae mutants. We measured the fitness of ~900 adaptive mutants in distinct three-environment cycles, and find large history-dependent effects which cause fitness in individual environmental components to differ drastically across the two directions of the cycle. However, these effects tend to compensate for each other, resulting in similar overall fitness across the whole cycle. This is true even when we specifically conduct experimental evolution in both directions of the same three-environment cycle. Of the ~450 mutants we isolated, only a small number of strains showed higher fitness in the direction in which they evolved. By splitting the contribution of each environment on fitness into its effect on the current and next component, we show that the invariance of overall fitness to environment order emerges because the effect of an environment on the next component is largely independent of the identity of the subsequent component, and can be captured by an additive model. Despite this general pattern of compensation, we do find instances of non-additivity, some of which are partly due to history-dependent effects lasting beyond two growth components. Overall, these results suggest that despite large history-dependent effects, fitness across a sequence of environments can be surprisingly predictable.

evolutionary biology↗

bioRxiv2026

Quantifying Chemical Fluxes Underlying Gut Microbiota-Host Interactions

To resolve how the gut microbiota shapes human health, it is essential to quantify the exchange of chemicals between microbes and the host. Much as the dose of a drug determines its pharmacological effect, the magnitude of a specific chemical flux determines its impact. Here, we establish from first principles how fluxes can be estimated by integrating key parameters from human digestive physiology and microbial metabolism. We apply this framework to three cases: the exchange of fermentation products, the production of toxins by bacterial pathogens, and nitrogen homeostasis. Our analysis identifies three directly measurable host-level parameters which, in concert with microbial activity, shape flux magnitudes: intestinal transit time, absolute microbial abundance in feces, and fecal mass loss. The simultaneous quantification of these parameters provides a feasible yet essential step toward a mechanistic and quantitative description of gut microbiota-host interactions across health and disease.

systems biology↗

bioRxiv2025

Community coalescence reveals strong selection and coexistence within species in complex microbial communities

Complex microbial ecosystems harbor extensive intra-species diversity, but the fitness consequences of this genetic variation are poorly understood in community settings. Here we address this question by competing in vitro gut communities derived from different human donors, revealing the emergent fitness differences between conspecific strains as they competed within larger communities. Most pairs of strains experienced strong and context-dependent selection, even when their parent communities were originally selected in the same nutrient environment. However, these fitness differences typically attenuated over time due to biotic interactions within the community, leading to extended coexistence within many species, and competitive exclusion in others. These results support the view that conspecific strains can fulfill distinct ecological roles when competing within a diverse community, even when their genomic diversity exhibits the hallmarks of a single biological species.

evolutionary biology↗

bioRxiv2025

Diversity and prevalence of sulfate- and sulfite-reducing microorganisms in the human gut microbiome

Microorganisms capable of producing hydrogen sulfide have been associated with inflammatory diseases within the human gastrointestinal tract. Using a weighted protein homology search followed by phylogenetic fragment insertion, we sought to characterize the diversity and prevalence of microbial dissimilatory sulfite reduction genes (dsrAB) from over 70,000 human gut samples from publicly available metagenomic sequencing data. We found over 1,700 unique dsrAB sequences that were predominantly within two clades of sulfate- and sulfite-reducing microorganisms (SSRM): the well-studied Desulfovibrionaceae family and the Firmicutes group sensu lato (s.l.). We detected SSRM in over a third of adults, but very few children. Bilophila wadsworthia was the most prevalent SSRM, and along with other members of Desulfovibrionaceae, constituted the majority of SSRM found. About one fifth of people with SSRM contained members of the Firmicutes group s.l. Our study characterizes the overall diversity of SSRM in the human gut from different global populations while highlighting the potential importance of SSRM from the Firmicutes group, which have commonly been overlooked as contributors to microbial hydrogen sulfide production in the human gut.

microbiology↗

bioRxiv2025

It is Not Always Crystal Clear: In-Pocket Analysis for Understanding Binding Site Microenvironment Properties

Structural biology enabled key advances in biochemistry, drug discovery, and AI-driven three-dimensional structure modelling. Despite its importance, reliable and general computational tools for chemical validation of structural models remain limited, especially when small-molecule ligands are involved. This challenge is exacerbated when experimental resolution is insufficient to define interaction chemistry, leaving critical interpretations ambiguous. We introduce In-Pocket, a quantum mechanical optimisation method biased by experimental data that evaluates the chemical nature of protein-ligand binding interfaces. In-Pocket improves model quality, corrects chemically inconsistent structures, and identifies the energetically most favourable ligand-conformers within biomacromolecular complexes. The approach is generally applicable to a wide range of systems, including those containing transition metals. Benchmarking demonstrates that In-Pocket enhances the reliability of legacy and newly solved structures. With automated, user-friendly routine chemical validation, In-Pocket offers unique opportunities to improve the integrity of structural databases and impact diverse domains: from molecular biology to rational drug design and application of generative AI.

bioinformatics↗

bioRxiv2025

A mismatch between slow protein synthesis and fast environmental fluctuations determines tradeoffs in bacterial proteome allocation strategies

Microbes live in environments that fluctuate faster than they can adjust their cellular machinery. To survive these fluctuations, they must dynamically regulate protein synthesis--a resource-intensive process that is often slower than environmental changes. Here, we develop a mechanistic model coupling antibiotic kinetics with dynamic proteome allocation to understand how limitations in translational capacity shape acclimation strategies. Using translation-inhibiting antibiotics and resistance proteins, we show that the temporal mismatch between environmental perturbations (seconds) and protein synthesis responses (hours) creates a growth advantage for anticipatory strategies where cells pre-synthesize resistance proteins before antibiotic exposure. Further, we find that the largest benefits of anticipation and the largest protein fractions reserved for anticipation are realized in environments with multiple antibiotics, suggesting that anticipation is most important in complex environments. This work establishes a framework for quantifying the costs and benefits of various acclimation strategies in dynamical environments based on the fundamental constraints of protein synthesis, with implications for microbial ecology, antibiotic resistance, and biotechnology applications.

microbiology↗

bioRxiv2024

Diurnal variations in microbial population dynamics along the human large intestine

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, Ne [~] 107 - 1011, 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. Our findings underscore the highly intertwined population dynamics of the gut microbiota, determined by the physics of fluid flow and growth with strong consequences for the microbiome and the host. Significance statementThe density of microbial biomass within the large intestine is a key determinant of microbiome-host interactions and their impact on the human body. Studies with animal models have suggested highly intertwined population dynamics with strong variations of microbial densities over time and space. To elucidate the physiological drivers of these spatiotemporal dynamics along the human large intestine, we introduce a biophysical modeling framework that considers at its core the diurnal variation of digestion and fluid flow. Our analysis reveals how nutrient supply and the rapid movement of luminal content cause strong fluctuations in microbial biomass turnover throughout the day. The intertwined dynamics provide the host with ample mechanisms to control the microbiota, suppressing, for example, the emergence of slow-growing cross-feeding microbes.

microbiology↗

bioRxiv2024

Quantifying the daily harvest of fermentation products from the human gut microbiota

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.

microbiology↗

bioRxiv2023

The differing prevalences of propionate and butyrate producing bacteria in the human gut microbiota

Propionate and butyrate are major fermentation products released during the anaerobic growth of bacteria in the large intestine with strong implications on host health. While the different metabolic pathways leading to the release of these products are biochemically well characterized, less is known about their relative abundances across hosts and conditions. Here, we introduce a bioinformatics pipeline which connects pathway analyses, gene identification via sequence homology, and the screening of metagenomic samples to systematically identify the abundances of propionate producing pathways across individuals and in relation to butyrate producing pathways. We found that on average 36% of all genomes of a gut microbiota carried propionate producing pathways with the sodium-pumping succinate pathway being the most prevalent. This pathway abundance was anti-correlated to the abundance of butyrate pathways and greatly depended on host physiology. For example, propionate pathway abundance varied strongly among infants with a substantially higher abundance in vaginally than C-section born infants, increased in early adulthood, and decreased again with higher ages. This is in strong contrast to the known variation of butyrate pathway abundance, which is close to zero in infants and steadily increases with age. These results highlight the contrasting prevalence of both fermentation products at the individual level with shifts in microbiota composition resulting in strong consequences on the amount of butyrate and propionate available to the host.

microbiology↗

bioRxiv2023

Stringent Control Over Cytoplasmic and Membrane Densities Defines Regulation of Cell Geometry in Escherichia coli

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.

microbiology↗

bioRxiv2023

Cardiopulmonary structural, functional and immune-alterations in a Down syndrome mouse model and upon modulation of EGCG

In individuals with Down syndrome (DS), cardiovascular and pulmonary diseases are the most common health problem and result in increased mortality and morbidity. Although these clinical comorbidities are well described, no preclinical models for DS are fully characterized for cardiopulmonary alterations, preventing research to understanding the development and pharmacological modulation of lungs, heart and immune system. Our objective is to characterize the cardiopulmonary and immunological phenotype in Ts65Dn mice and investigate the modulatory effects green tea extract enriched in epigallocatechin 3 gallate (GTE-EGCG). GTE-EGCG administration started at embryonic day 9 and was discontinued at postnatal day (PD) 180. Newborns were longitudinally monitored until PD210 using micro-computed tomography. At endpoint, we characterized the structural, functional and immunological alterations and persistent effects of GTE-EGCG administration. This study revealed normal lung development in the Ts65Dn mice and highlighted RV hypertrophy and immunological alterations. GTE-EGCG administration resulted in genotype-specific and genotype-independent alterations resulting in lung immaturation and airway hyperreactivity. Our results highlight the cardiovascular and immunological phenotype of Ts65Dn mice and potential use for safety studies of therapeutic agents in a DS-specific context. Summary statementThis study longitudinally follows respiratory and cardiac alterations in the Ts65Dn mouse model and describes the impact of prenatal EGCG modulation on the euploid and trisomic phenotype

systems biology↗

bioRxiv2022

Changing flows balance nutrient absorption and bacterial growth along the gut

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, independently 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.

biophysics↗

bioRxiv2022

An Optimal Regulation of Fluxes Dictates Microbial Growth In and Out of Steady-State

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 control 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 {approx} 60 data sets from Escherichia coli establishes this regulatory mechanisms 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.

microbiology↗

bioRxiv2021

Coordination of gene expression with cell size enables Escherichia coli to efficiently maintain motility across conditions

To swim and navigate, motile bacteria synthesize a complex motility machinery involving flagella, motors, and a sensory system. A myriad of studies has elucidated the molecular processes involved, but less is known about the coordination of motility expression with cellular physiology: In Escherichia coli, motility genes are strongly upregulated in nutrient-poor conditions compared to nutrient-replete conditions; yet a quantitative link to cellular motility has not been developed. Here, we systematically investigate gene expression, swimming behavior, and cell growth across a broad spectrum of exponential growth condition. We establish that E. coli up-regulates the expression of motility genes at slow growth to compensate for reduction in cell size, such that the number of flagella per cell is maintained across conditions. The observed 4-5 flagella per cell is the minimum number needed to keep the majority of cells motile. This simple regulatory objective allows E. coli cells to remain motile across a broad range of growth conditions while keeping the biosynthetic and energetic demands to establish and drive the motility machinery at the minimum needed. Given the strong reduction in flagella synthesis resulting from cell size increases at fast growth, our findings also provide a novel physiological perspective on bacterial cell size control: A larger cell-size at fast growth is an efficient strategy to increase the allocation of cellular resources to the synthesis of those proteins required for fast growth, while maintaining processes such as motility which are only needed on a per-cell basis.

microbiology↗

bioRxiv2021

Suboptimal proteome allocation during changing environments constrains bacterial response and growth recovery

To sustain growth in fluctuating environments microbial organisms must respond appropriately. The response generally requires the synthesis of novel proteins, but this synthesis can be impeded due to the depletion of biosynthetic precursors when growth conditions vary. Microbes must thus devise effective response strategies to manage depleting precursors. To better understand these strategies, we here investigate the active response of Escherichia coli to changes in nutrient conditions, connecting transient gene-expression behavior to growth phenotypes. By synthetically modifying the gene expression during changing growth conditions, we show how the competition by genes for the limited protein synthesis capacity constrains the cellular response. Despite this constraint, cells substantially express genes that are not required, severely slowing down the response. These findings highlight that cells do not optimize growth and recovery in every encountered environment but rather exhibit hardwired response strategies that may have evolved to promote growth and fitness in their native environment and include the regulation of multiple genes. The constraint and the suboptimality of the cellular response uncovered in this study provides a conceptual framework relevant for many research applications, from the prediction of evolution and adaptation to the improvement of gene circuits in biotechnology.

microbiology↗

bioRxiv2020

Molecular epidemiology of mumps viruses detected in the Netherlands, 2017-2019

Mumps cases continue to occur, also in countries with a relatively high vaccination rate. The last major outbreaks of mumps in the Netherlands were from 2009-2012 and thereafter, only small clusters and single cases were reported. Molecular epidemiology can provide insights in the circulation of mumps viruses. The aims of the present study were to analyze the molecular epidemiology of mumps viruses in the Netherlands in 2017-2019 and to elucidate whether complete genome sequencing adds to the molecular resolution of mumps viruses when compared to sequencing of the mumps SH gene and non-coding regions (SH+NCRs). To this end, Sanger sequence data from the SH+NCRs were analyzed from 82 mumps genotype G viruses. In addition, the complete genomes were obtained from 10 mumps virus isolates using next-generation sequencing. Analysis of SH+NCRs of mumps viruses revealed the presence of two major lineages in the Netherlands, which was confirmed by analysis of complete genomes. Comparison of molecular resolution obtained with SH+NCRs and complete genomes clearly indicated that additional molecular resolution can be obtained by analyzing complete genomes. In conclusion, analysis of SH + NCRs sequence data from recent mumps genotype G viruses indicate that mumps viruses continue to circulate in the Netherlands and surrounding countries. However, to understand exact transmission trees and to compare mumps viruses on a large geographic scale, analysis of complete genomes is a very useful approach.

microbiology↗