Biology subjects

Andersen, S. B.

Publications and source records attributed to Andersen, S. B..

14 recordsLinked to original sources

bioRxiv2025

Host age at experimental Helicobacter pylori infection shapes epithelial development of mouse gastric organoids

The bacterium Helicobacter pylori colonises gastric glands, which triggers direct responses to bacterial activity and genetic modifications of the host. While most frequently asymptomatic, infection can cause stomach cancer through a stepwise sequence from chronic gastritis to carcinoma, involving induction of stem cell-like properties of epithelial cells. We tested the effect of host age at infection on epithelial development in a mouse organoid model, where mice were infected as neonates or adults, for one month. To isolate the effects of host genetic modification, gastric organoids were grown in the absence of H. pylori and sequenced and imaged. We found that H. pylori infection early in life resulted in a larger size of the derived organoids. The expression of marker genes in organoids for different cell types was dependent on host age, suggesting a decrease in pit cells and an increase in endocrine cells with age. H. pylori infection early in life accelerated this age dependent shift, and we propose that the cell type profile affects the host response to infection.

cell biology↗

bioRxiv2025

Evolutionary genomics reveals plant origins of acetic acid bacteria in fermented food

Humans have historically relied on acetic acid bacteria (AAB) for food fermentation, yet their origins must trace back to free-living species outside of human environments. In nature, plants, fruit flies, and social insects host AAB. However, the evolutionary transitions of AAB from symbiotic hosts to fermented foods remain ambiguous. Here, we conduct a comprehensive phylogenomic analysis of 570 publicly available AAB genomes. We find that the [~]170My evolutionary history of this group is concordant with the rise of angiosperms, corbiculate bees, and the consequential accelerated availability of environmental carbohydrates. Unlike other ferment-associated microbes, ferment-associated AAB have exclusively evolved from clades inhabiting flowers and fruits, but not insect hosts. Genomic features are similar in plant- and ferment-associated AAB, yet markers of early adaptation to ferments are also present. Conversely, social insect-associated AAB have reduced genome sizes, which may have limited their functional capability to disperse into ferments. Plant- and ferment-associated AAB coincide in the ability to metabolise diverse plant carbohydrates, though both have adapted to produce habitat-specific carbohydrate-active enzymes. In contrast, metabolic capacity is reduced in social insect-associated AAB. By tracing the phylogenomics of this clade, we understand how evolution forged AAB capable of performing metabolic work for humans, shaping the history and potential futures of fermentation.

evolutionary biology↗

bioRxiv2025

Neonatal infection with Helicobacter pylori affects stomach and colon microbiome composition and gene expression in mice

The stomach bacterium Helicobacter pylori is estimated to infect half of the worlds population, and the health implications are affected by the age at infection. Neonatal H. pylori infection of mice is a relevant model to investigate metabolic and immunological effects. We performed an explorative study at the dynamic first month of life, to compare the composition of the gastrointestinal tract microbiome and stomach gene expression of mice neonatally infected with H. pylori with that of uninfected mice. We found that H. pylori was present only in the stomach, and that H. pylori loads increase with age from one week after infection and onwards, especially after weaning. Stomach and colon microbiome composition was strikingly similar between sites at the same sampling time, but changed significantly over one week, with increased diversity at both sites. Despite that the relative abundance of H. pylori in the stomach was low and never exceeded 3%, the composition and alpha diversity of the gastrointestinal microbiome was significantly affected by infection. In a pathway enrichment analysis we found that stomach gene expression related to the extracellular matrix, muscle contraction, and metabolism was affected by infection. Expression of these key processes was, in infected mice, shifted away from that of control mice, towards that of all mice sampled the subsequent week, which we speculate represents accelerated development in infected mice.

evolutionary biology↗

bioRxiv2025

Early-life Helicobacter pylori infection worsens metabolic state in mice receiving a high-fat diet

Perturbations to early-life microbial colonization can shape immune and metabolic development, predisposing a host to obesity. We hypothesized that neonatal infection with the ancient human symbiont Helicobacter pylori exacerbates diet-induced metabolic responses and is accompanied by alterations in endocrine and inflammatory regulation. To test this, C57BL/6JRj neonatal mice were infected with H. pylori or left uninfected and, after weaning, exposed to a high-fat diet in a long-term (5-month) study of microbiome composition and a short-term (3-week) study of circulating biomarkers and microbiome composition. In the short-term intervention, infected mice showed increased visceral adiposity. Infection was associated with altered ghrelin and leptin responses across fasting conditions, accompanied by elevated MCP-1 and IL-6, particularly in males. H. pylori infection also reinforced diet-induced shifts in gastrointestinal microbiome composition. In the long-term study, there were no differences in adiposity between infected and control mice, suggesting that diet was the dominant determinant of adiposity at this stage. Together, our findings suggest that early-life H. pylori infection amplifies the initial endocrine, inflammatory, and adipose responses to a high-fat diet.

evolutionary biology↗

bioRxiv2024

Making yogurt with the ant holobiont uncovers bacteria, acids, and enzymes for food fermentation

Milk fermentation has a rich history in which food culture, the environment, and microbes intersect. However, the biocultural origins of fermentation practices and microbes have largely been replaced by industrial processes. Here, we consider a historical fermentation originating from Turkey and Bulgaria - ant yogurt. We revisit the traditional practices and modern gastronomic applications that use red wood ants (Formica rufa group) to initiate milk fermentation. Subsequently, we characterize the ants and experimental ant-derived yogurts. We uncover that the ant holobiont, which consists of the ants and their microbes, contributes key acids and enzymes to fermentation. Metabarcoding and culturing revealed that lactic and acetic acid bacteria, including species related to conventional sourdough, originate from the live ants and proliferate in the milk. The ants and bacteria consequently introduce formic, lactic, and acetic acid, advantageous for yogurt acidification and coagulation. Last, proteases with the potential to act on casein may alter yogurt texture and are produced by the ants and bacteria. The ant holobiont thus catalyses fermentation akin to the microbial consortia in other ferments. Our findings highlight the value of integrating traditional, gastronomic, and biological frameworks to uncover the origins and applications of microbes for fermented foods.

microbiology↗

bioRxiv2023

Sedimentary DNA can influence evolution:Establishing mineral facilitated horizontal gene transfer as a route to bacterial fitness

Horizontal gene transfer is one of the most important drivers of bacterial evolution. Transformation by uptake of extracellular DNA is traditionally not considered to be an effective mode of gene acquisition, simply because extracellular DNA is degraded in a matter of days when it is suspended in e.g. seawater. Mineral surfaces are, however, known to preserve DNA in the environment, and sedimentary ancient DNA studies have solidified that there are considerable amounts of fragmented DNA stored in sediments world-wide. Recently the age span of stored DNA was increased to at least 2 Ma. Here, we highlight that fragmented ancient DNA can be fueling the evolution of contemporary bacteria and advocate to consider this route for genetic variation in evolutionary history. We show that Acinetobacter baylyi can incorporate 60 bp DNA fragments adsorbed to a wide range of common sedimentary minerals and that the transformation frequencies scale with the mineral surface properties. Further, our results point to interfacial geochemical and sedimentologic processes as facilitators of evolutionary innovation where DNA-molecules are specific to the environment and the processes providing new DNA molecules may also provide the need to evolve. In contrast to heritable stochastic mutations as proposed by Darwin, the access by which bacteria acquire new genomic material at times with increased stress and also needs, would indicate a non-random mechanism that may propel evolution in a non-stochastic manner.

evolutionary biology↗

bioRxiv2022

Core and accessory effectors of type VI secretion systems contribute differently to the intraspecific diversity of Pseudomonas aeruginosa

Bacteria use type VI secretion systems (T6SSs) to deliver effector proteins into other cells or the extracellular space. Those effectors kill microbes1, manipulate eukaryotic cells2, and sequester nutrients3. Which T6SS-mediated functions are generalisable across bacteria of a species or are specific to particular strains is little known. Here, we use genomics to test for the intraspecific diversity of T6SS effectors in the opportunistic pathogen Pseudomonas aeruginosa. We found effectors that are omnipresent and conserved across strains acting as core effectors, while additional accessory effectors vary. In vitro and in vivo experiments demonstrate different roles of the two types of effectors in bacterial killing and virulence. Further, effectors compose various effector combinations. Within one local population of clinical isolates, we observed 36 combinations among 52 bacterial lineages. These findings show the distinct contribution of T6SS effectors to strain-level variation of a bacterial pathogen and might reveal conserved targets for novel antibiotics.

microbiology↗

bioRxiv2021

Substrate Specificity for Human Histidine Methyltransferase SETD3

Histidine methyltransferase SETD3 plays an important role in human biology and diseases. Previously, we showed that SETD3 catalyzes N3-methylation of histidine 73 in {beta}-actin (Kwiatkowski et al., 2018). Here we report integrated synthetic, biocatalytic, biostructural and computational analyses on human SETD3-catalyzed methylation of {beta}-actin peptides possessing histidine and its structurally and chemically diverse mimics. Our enzyme assays supported by biostructural analyses demonstrate that SETD3 has a broader substrate scope beyond histidine, including N-nucleophiles on the aromatic and aliphatic side chains. Quantum mechanical/molecular mechanical (QM/MM) molecular dynamics and free-energy simulations provide insight into binding geometries and the free energy barrier for the enzymatic methyl transfer to histidine mimics, further supporting experimental data that histidine is the superior SETD3 substrate over its analogs. This work demonstrates that human SETD3 has a potential to catalyze efficient methylation of several histidine mimics, overall providing mechanistic, biocatalytic and functional insight into {beta}-actin histidine methylation by SETD3.

biochemistry↗

bioRxiv2021

Long-term evolution of antibiotic persistence in P. aeruginosa lung infections

Pathogenic bacteria respond to antibiotic pressure with the evolution of resistance but survival can also depend on their ability to tolerate antibiotic treatment, known as persistence. While a variety of resistance mechanisms and underlying genetics are well characterised in vitro and in vivo, the evolution of persistence, and how it interacts with resistance in situ is less well understood. We assayed for persistence and resistance with three clinically relevant antibiotics: meropenem, ciprofloxacin and tobramycin, in isolates of Pseudomonas aeruginosa from chronic cystic fibrosis lung infections spanning up to forty years of evolution. We find evidence that persistence is under positive selection in the lung and that it can particularly act as an evolutionary stepping stone to resistance. However, this pattern is not universal and depends on the bacterial clone type and antibiotic used, indicating an important role for antibiotic mode of action.

evolutionary biology↗

bioRxiv2021

Single-molecule simultaneous profiling of DNA methylation and DNA-protein interactions with Nanopore-DamID

We present Nanopore-DamID, a method to simultaneously detect cytosine methylation and DNA-protein interactions from single molecules, via selective sequencing of adenine-labelled DNA. Assaying LaminB1 and CTCF binding with Nanopore-DamID, we identify escape from LAD-associated repression of hypomethylated promoters amidst generalised hypermethylation of LaminB1-associated regulatory elements. We detect novel CTCF binding sites in highly repetitive regions, and allele-specific CTCF binding to imprinted genes and the active X chromosome. Nanopore-DamID highlights the importance of DNA methylation to transcription factor activity.

genomics↗

bioRxiv2020

Spatially resolved transcriptome profiles of mammalian kidneys illustrate the molecular complexity of functional nephron segments, cell-to-cell interactions and genetic variants.

Understanding the molecular mechanisms underlying mammalian kidney function requires transcriptome profiling of the interplay between cells comprising nephron segments. Traditional transcriptomics requires cell dissociation, resulting in loss of the spatial context of gene expression within native tissue. To address this problem, we performed spatial transcriptomics (ST) to retain the spatial context of the transcriptome in human and mouse kidneys. The generated ST data allowed spatially resolved differential gene expression analysis, spatial identification of functional nephron segments, cell-to-cell interaction analysis, and chronic kidney disease-associated genetic variant calling. Novel ST thus provides an opportunity to enhance kidney diagnostics and knowledge, by retaining the spatial context of gene expression within intact tissue.

molecular biology↗

bioRxiv2020

Single-cell transcriptomics of allo-reactive CD4+ T cells over time reveals divergent fates during gut GVHD

Acute gastrointestinal Graft-versus-Host-Disease (GVHD) is a primary determinant of mortality after allogeneic hematopoietic stem-cell transplantation (alloSCT). It is mediated by alloreactive donor CD4+ T cells that differentiate into pathogenic subsets expressing IFN{gamma}, IL-17A or GM-CSF, and is regulated by subsets expressing IL-10 and/or Foxp3. Developmental relationships between T-helper states during priming in mesenteric lymph nodes (mLN) and effector function in the GI tract remain undefined at genome-scale. We used scRNA-seq and computational modelling to create an atlas of putative differentiation pathways during GVHD. Computational trajectory inference suggested emergence of pathogenic and regulatory states along a single developmental trajectory in mLN. Importantly, we identified an unexpected second trajectory, categorised by little proliferation or cytokine expression, reduced glycolysis, and high TCF1 expression. TCF1hi cells upregulated 4{beta}7 prior to gut migration and failed to express cytokines therein. Nevertheless, they demonstrated recall potential and plasticity following secondary transplantation, including cytokine or Foxp3 expression, but reduced TCF1. Thus, scRNA-seq revealed divergence of allo-reactive CD4+ T cells into quiescent and effector states during gut GVHD, reflecting putative heterogenous priming in vivo. These findings, the first at a single-cell level during GVHD over time, can now be used to interrogate T cell differentiation in patients undergoing alloSCT.

immunology↗

bioRxiv2018

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinsons Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

genetics↗

bioRxiv2018

Privatisation rescues function following loss of cooperation

A single cheating mutant can lead to the invasion and eventual eradication of cooperation from a population. Consequently, cheat invasion is often considered as \"game over\" in empirical and theoretical studies of cooperator-cheat dynamics, especially when cooperation is necessary for fulfilling an essential function. But is cheat invasion necessarily \"game over\" in nature? By following a population of bacteria through loss of cooperation and beyond, we observed that individuals evolved to replace cooperation with a selfish, or \"private\" behaviour. Specifically, we show that when cheating caused the loss of cooperative iron acquisition in a collection of Pseudomonas aeruginosa isolates from cystic fibrosis patients, a private uptake system that only benefits the focal individual was upregulated. This observation highlights the importance of social dynamics of natural populations and emphasizes the potential impact of past social interaction on the evolution of private traits.

evolutionary biology↗