Biology subjects

Rosenstiel, P.

Publications and source records attributed to Rosenstiel, P..

At least 19 recordsLinked to original sources

bioRxiv2026

A symbiont-derived biosurfactant couples bacterial surface behavior and host peristalsis to control colonization

Hosts must control symbiont abundance to ensure stable associations with their beneficial microbes, while also minimizing potentially harmful unrestricted microbial proliferation. Yet, the microbial stimuli and involved host responses that shape this colonization control, are usually unknown, in spite of their central role in shaping host-microbe and, more broadly, host-microbiota interactions. Here, using the natural association between Caenorhabditis elegans and its symbiont Pseudomonas lurida MYb11, we combine an unbiased bacterial genetic screen with a host response reporter to identify the biosurfactant massetolide as a key regulator of host-microbe interaction. Our subsequent host functional genetic analyses revealed that massetolide triggers host TGF-beta and serotonergic signaling to promote intestinal peristalsis, limiting colonization. Indeed, massetolide deficiency enhances colonization, while its presence specifically facilitates serotonin-dependent expulsion. Together, our findings reveal a symbiont-derived biosurfactant that links host neuroimmune control of intestinal peristalsis with bacterial susceptibility to expulsion, coupling host and microbial physiology to regulate symbiont abundance.

microbiology↗

bioRxiv2026

STING safeguards epithelial genome integrity and protects from carcinogenesis via mitotic checkpoint control

STING is canonically known for mediating interferon responses to cytosolic DNA, yet its cell-intrinsic role in genome maintenance beyond the immune context is unknown. Here we show that epithelial STING functions as a type I interferon-independent genome-integrity checkpoint. STING loss impairs homologous recombination repair, attenuates ATM-associated damage signaling, elevates CDK1 activity, and causes chromosomal instability revealed by single-cell Strand-seq, culminating in spontaneous intestinal adenocarcinoma. These defects arise before tumor formation and confer selective vulnerability to CDK inhibition in tumor organoids and human colorectal cancer cells. Our findings identify STING as a cell-autonomous guardian of epithelial genome stability that restrains chromosomal instability-driven tumor evolution beyond its canonical immune function.

cancer biology↗

bioRxiv2025

Systematic screening of tryptophan metabolism identifies site- and microbial-specific signatures of tryptophan utilization in experimental colitis

BackgroundAltered tryptophan (Trp) metabolism and disrupted nicotinamide adenine dinucleotide (NAD) synthesis are hallmarks of IBD, yet how intestinal microbiota contribute to these metabolic shifts during intestinal inflammation remains poorly understood. MethodsWe used targeted metabolomics to systematically profile Trp- and NAD-related metabolites across multiple biological compartments - including tissues, luminal contents, stool, and serum - in mice treated with dextran sulfate sodium (DSS) alone or in combination with a broad-spectrum antibiotic (ABX) cocktail. ResultsMicrobial depletion significantly attenuated colitis and increased host Trp bioavailability, implicating the gut microbiota as a competitive Trp consumer. In DSS colitis, Trp degradation along the kynurenine pathway (KP) was exaggerated but blocked at the key KP enzyme quinolinate phosphoribosyltransferase (QPRT), resulting in mucosal NAD(H) depletion. ABX co-treatment normalized metabolite conversion along the KP and restored mucosal NAD(H) levels, revealing a dual role of the gut microbiota during colitis: while they compete with the host for Trp utilization, they simultaneously shape host KP regulation and NAD de novo synthesis, supporting host energy homeostasis. ConclusionOur findings demonstrate that mucosal NAD de novo synthesis is a microbially regulated metabolic process that alleviates intestinal inflammation and may represent a novel therapeutic target in IBD through modulation of the gut microbiota or their metabolites.

immunology↗

bioRxiv2025

Long-Term Intestinal Epithelial Remodeling Induced by Acute Protein-Energy Malnutrition

Protein-energy malnutrition (PEM) is a global health burden with lasting effects that extend well beyond the initial nutrient deficiency. To systematically investigate the long-term effects of a single episode of PEM on the structure and function of the intestinal epithelium and its associated microbiota, we employed a comprehensive multi-omics approach, including (spatial) transcriptomics, DNA methylation analysis, fecal metagenomics, and metabolomics. Our findings show that PEM persistently alters the intestinal epithelium by depleting Paneth cells and suppressing antimicrobial gene expression - changes linked to DNA methylation that persist despite dietary recovery. In germ-free mice, the sustained epithelial phenotype after was absent. We identified the microbial lipid metabolite 9-HODE and epigenetically deregulated PPAR-driven GDF15 expression as key molecular drivers of the persistent PEM-induced Paneth cell dysfunction. Targeting microbial lipid production and its link to the host GDF15 pathway could offer novel therapeutic strategies for long-term consequences of malnutrition and other Paneth cell-associated diseases.

immunology↗

bioRxiv2025

Association of ulcerative colitis with atopic dermatitis: identification of shared and unique mechanisms by construction and computational analysis of disease maps

Background and AimsUlcerative colitis (UC) and atopic dermatitis (AD) are immune-mediated inflammatory diseases with limited treatment options. They are known to be related which may explain higher risk of development of UC in patients with AD. The goal of this work is to review and analyse molecular mechanisms of UC in comparison to AD towards insights into UC complexity, potential comorbidities and novel therapies. MethodsWe developed graphical computational models of UC and AD molecular mechanisms (disease maps) by integrating information from over 800 manually curated articles. The maps are available online at https://imi-immuniverse.elixir-luxembourg.org. Disease-specific risk variants and gene expression profiles are visualised to identify signatures specific to UC, and shared with AD. Computational analysis shows key proteins, their interactions and pathways shared between UC and AD. ResultsUC and AD maps include more than 2000 molecular interactions. Systematic computational comparison shows that both disorders exhibit epithelial barrier dysfunction, immune dysregulation involving abnormal Th2, Th1 and ILC response, common inflammatory pathways and biomarkers such as IL-13, IL-4R, IFNG, and IL-18. Visualisation and analysis of omics data demonstrates UC map usability. ConclusionsWe developed the first computational graphic model of UC molecular mechanisms. Its content focuses on mechanisms of epithelial barrier disruption and downstream immune dysregulation through cytokines and other mediators. The comparison of UC to AD mechanisms demonstrates common signalling pathways and biomarkers, and supports potential drug repurposing and treatment options. The workflow can be reused and new findings can be dynamically integrated into the maps. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/650149v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@1c4c80eorg.highwire.dtl.DTLVardef@2a1e66org.highwire.dtl.DTLVardef@131ece3org.highwire.dtl.DTLVardef@b74971_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG

bioinformatics↗

bioRxiv2024

Deletion of epithelial HKDC1 decelerates cellular proliferation and impairs mitochondrial function of tumorous epithelial cells thereby protecting from intestinal carcinogenesis in mice

BackgroundA metabolic switch favoring glycolysis over aerobic oxidative phosphorylation, namely the "Warburg effect", represents a hallmark of cancer cells. Hexokinases (HK) catalyze the first step of glycolysis, thereby regulating its rate. Dysregulated HKDC1 (HK domain containing 1) expression has been associated with various cancer types and blocking HKDC1 prevents disease progression for hepatic carcinoma T cell lymphoma and lung adenocarcinoma, but its implication for colorectal cancer (CRC) remained unknown. Here, we functionally investigated the role of HKDC1 for intestinal carcinogenesis. MethodsFirst, we analyzed HKDC1 expression in the intestinal mucosa of healthy controls (HC) and CRC patients and in different tumor tissues using transcriptomic data from publicly available databases. We then generated HKDC1-deficient human and murine colonic epithelial cell lines as well as intestinal organoids and profiled their phenotypic functions. Next, we screened for proteins interacting with HKDC1 by immunoprecipitation. Finally, we generated tumor-bearing ApcMin/+ mice with a conditional deletion of HKDC1 in intestinal epithelial cells and also performed a xenograft mouse model to test the role of HKDC1 for intestinal carcinogenesis in vivo. ResultsHKDC1 was found to be overexpressed in tumor compared to normal tissue of CRC patients. In vitro, HKDC1-deficient human Caco-2 and murine CMT-93 cells displayed reduced proliferation, altered susceptibility to cell death induction, and disrupted mitochondrial functions, particularly mitochondrial respiration. These altered cancer hallmarks were then corroborated in HKDC1-deficient normal and tumor-derived ApcMin/+ intestinal organoids. Immunoprecipitation and mass spectometry proteomic analyses revealed interactions of HKDC1 with several mitochondria-related proteins. In vivo, two distinct mouse models demonstrated that epithelial deletion of HKDC1 protected from carcinogenesis. First, ApcMin/+-Hkdc1{Delta}IEC mice showed mildly improved disease phenotypes in the colon accompanied with reduced numbers of Ki67-positive proliferating epithelial cells. Finally, HKDC1-deficient Caco-2 cells completely failed to form any tumor mass in a xenograft model when implanted into immunodeficient mice. ConclusionsWe demonstrate that HKDC1 influences cancer cell proliferation and susceptibility to cell death, potentially through interactions with mitochondrial proteins that regulate membrane permeability, ultimately impacting intestinal carcinogenesis. Collectively, these findings highlight the significance of HKDC1 for CRC pathobiology, presenting it as a promising target for further investigation and potential therapeutic interventions.

cancer biology↗

bioRxiv2024

Metabolic modeling reveals a multi-level deregulation of host-microbiome metabolic networks in IBD

Inflammatory bowel diseases (IBDs) are chronic disorders involving dysregulated immune responses. Despite the role of disrupted host-microbial interaction in the pathophysiology of IBD, the underlying metabolic principles are not fully understood. We densely profiled microbiome, transcriptome and metabolome signatures from longitudinal IBD cohorts before and after advanced drug therapy initiation and reconstructed metabolic models of the gut microbiome and the host intestine to study host-microbiome metabolic cross-talk in the context of inflammation. We identified concomitant changes in metabolic activity across data layers involving NAD, amino acid, one-carbon and phospholipid metabolism. In particular on the host level, elevated tryptophan catabolism depleted circulating tryptophan, thereby impairing NAD biosynthesis. Reduced host transamination reactions disrupted nitrogen homeostasis and polyamine/glutathione metabolism. The suppressed one-carbon cycle in patient tissues altered phospholipid profiles due to limited choline availability. Simultaneously, microbiome metabolic shifts in NAD, amino acid and polyamine metabolism exacerbated these host metabolic imbalances. Leveraging host and microbe metabolic models, we predicted dietary interventions remodeling the microbiome to restore metabolic homeostasis, suggesting novel therapeutic strategies for IBD.

systems biology↗

bioRxiv2024

Neonatal microbiota colonization drives maturation of primary and secondary goblet cell mediated protection in the pre-weaning colon

In the distal colon, mucus secreting goblet cells primarily confer protection from luminal microorganisms via generation of a sterile inner mucus layer barrier structure. Bacteria-sensing sentinel goblet cells provide a secondary defensive mechanism that orchestrates mucus secretion in response to microbes that breach the mucus barrier. Previous reports have identified mucus barrier deficiencies in adult germ-free mice, thus implicating a fundamental role for the microbiota in programming mucus barrier generation. In this study, we have investigated the natural neonatal development of the mucus barrier and sentinel goblet cell-dependent secretory responses upon postnatal colonization. Combined in vivo and ex vivo analyses of pre- and post-weaning colonic mucus barrier and sentinel goblet cell maturation demonstrated a sequential microbiota-dependent development of these primary and secondary goblet cell-intrinsic protective functions, with dynamic changes in mucus processing dependent on innate immune signalling via MyD88, and development of functional sentinel goblet cells dependent on the NADPH/Dual oxidase family member Duox2. Our findings therefore identify new mechanisms of microbiota-goblet cell regulatory interaction and highlight the critical importance of the pre-weaning period for the normal development of colonic barrier function.

immunology↗

bioRxiv2024

Epithelial Hexokinase 2 expression is a marker for intestinal inflammation

BackgroundInflammation is characterized by a metabolic switch promoting glycolysis and lactate production. Hexokinases (HK) catalyze the first reaction of glycolysis and inhibition of epithelial HK2 protected from colitis in mice. HK2 expression has been described as elevated in patients with intestinal inflammation, however there is conflicting data from few cohorts especially with severely inflamed individuals, thus systematic studies linking disease activity with HK2 levels are needed. MethodsWe examined the relationship between HK2 expression and inflammation severity using bulk transcriptome data derived from the mucosa of thoroughly phenotyped patients suffering from intestinal inflammation of two independent cohorts. Analyzing publicly available single cell RNA sequencing data and performing immunofluorescence on colonic biopsies of unrelated patients with intestinal inflammation confirmed the RNA-based findings on cellular and protein level. ResultsHK2 expression gradually increased from mild to intermediate inflammation, yet strongly declined at high inflammation scores. Expression of epithelial marker genes also declined at high inflammation scores, whereas that of candidate immune marker genes increased, indicating a cellular remodeling of the mucosa during inflammation with an infiltration of HK2-negative immune cells and a loss of the apical epithelium - the main site of HK2 expression. Normalizing for the enterocyte loss clearly identified epithelial HK2 expression as gradually increasing with disease activity and remaining elevated at high inflammation scores. HK2 protein expression was mostly restricted to brush border enterocytes and these cells along with HK2 levels vanished with increasing disease severity. ConclusionsOur findings clearly define dysregulated epithelial HK2 expression as an indicator of disease activity in intestinal inflammation and suggest targeted HK2-inhibition as a potential therapeutic avenue.

immunology↗

bioRxiv2023

Intestinal epithelial Atg16l1 influences pregnancy-induced fecal microbiota shifts in mice

Throughout gestation, the female body undergoes a series of transformations, including profound alterations in intestinal microbial communities. Changes gradually increase towards the end of pregnancy and comprise reduced -diversity of microbial communities and an increased propensity for energy harvest. Despite the importance of the intestinal microbiota for the pathophysiology of inflammatory bowel diseases, very little is known about the relationship between these microbiota shifts and pregnancy-associated complications of the disease. Here, we explored the longitudinal dynamics of gut microbiota composition and functional potential during pregnancy and after lactation in Atg16l1{Delta}IECmice carrying an intestinal epithelial deletion of the Croh[n]s disease risk gene Atg16l1. Using 16S rRNA amplicon and shotgun metagenomic sequencing, we demonstrated divergent temporal shifts in microbial composition between Atg16l1 wildtype and Atg16l1{Delta}IECpregnant mice in trimester 3, which was validated in an independent experiment. Observed differences included microbial genera implicated in IBD such as Lachnospiraceae, Roseburia, Ruminococcus, and Turicibacter. Changes partially recovered after lactation. In addition, functional inference of metagenomic data suggest a reduced potential to biosynthesize mucosal protective polyamines and reduced capacity to metabolize acidic polysaccharides (ketogluconate metabolism). On the host side, we found that the immunological response of Atg16l1{Delta}IEC mice is characterized by higher colonic mRNA levels of TNFA, and CXCL1 in trimester 3 and a lower weight of offspring at birth. Understanding pregnancy-dependent microbiome changes in the context of IBD may constitute the first step in the identification of fecal microbial biomarkers and microbiota-directed therapies that could help improving precision care for managing pregnancies in IBD patients.

microbiology↗

bioRxiv2023

ATF6 activation alters colonic lipid metabolism causing tumor-associated microbial adaptation

Endoplasmic reticulum unfolded protein responses (UPRER) contribute to cancer development and the activating transcription factor 6 (ATF6) is involved in microbiota-dependent tumorigenesis. Here, we substantiate the clinical relevance of ATF6 in early-onset and late colorectal cancer patient cohorts. Transcriptional analysis in intestinal epithelial cells (IEC) of ATF6 transgenic mice (nATF6IEC) identified bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics and isotype-labeling confirmed ATF6-related enrichment of long chain fatty acids in colonic tissue of patients, mice and organoid cultures. FASN inhibition and microbiota transfer in germ-free nATF6IEC mice confirmed the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumor-relevant microbial taxa was mechanistically linked to long chain fatty acid exposure, using bioorthogonal non-canonical amino acid tagging (BONCAT) and growth analysis of Desulfovibrio isolates. We postulate chronic ATF6 signaling in the epithelium to select for tumor-promoting microbiota by altering lipid metabolism. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/565267v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@be3756org.highwire.dtl.DTLVardef@231da4org.highwire.dtl.DTLVardef@16f3aaeorg.highwire.dtl.DTLVardef@1758fe3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Chronic ATF6 signaling in the colonic epithelium alters lipid metabolism to select a tumor-promoting microbiota C_FIG O_LIBiallelic expression of activated ATF6 (p50 nuclear fragment) in intestinal epithelial cells (nATF6IEC) induces spontaneous colon tumors in SPF but not GF mice C_LIO_LIMechanistically, biallelic SPF nATF6IEC mice alter colonic lipid metabolism, including the upregulation of LCFAs and Fasn C_LIO_LIInhibition of FASN prevents colon tumor formation in mice, and reduces the tumor-promoting potential of the intestinal microbiota (FMT) C_LIO_LIExposure of fl/fl control mouse microbiota to LCFAs ex vivo translationally activates tumor-associated bacteria, including Desulfovibrio fairfieldensis C_LIO_LIHuman CRC patients show ATF6 upregulation, FASN co-occurrence and increased LCFAs in T tissue C_LIO_LIATF6 activity links with CRC-associated microbiota in patients, including Desulfovibrio C_LI Created with BioRender.com nATF6: activated activating transcription factor 6; LCFA: long-chain fatty acids; SAFA: saturated fatty acids; Fasn: fatty acid synthase; C75 i.p.: intraperitoneal injection of the Fasn inhibitor C75.

cancer biology↗

bioRxiv2023

Tryptophan wasting and disease activity as a systems phenomenon in inflammation - an analysis across 13 chronic inflammatory diseases.

Chronic inflammatory diseases (CID) are systems disorders affecting various organs including the intestine, joint and skin. The essential amino acid tryptophan (Trp) is not only used for protein synthesis but can also be catabolized to various bioactive derivatives that are important for cellular energy metabolism and immune regulation. Increased Trp catabolism via the kynurenine pathway is seen across individual CID entities1-5. Here, we assessed the levels of Trp and tryptophan derivatives across 13 CID to investigate the extent and nature of Trp wasting as a systems phenomenon in CID. We found reduced serum Trp levels across the majority of CID and a prevailing negative relationship between Trp and systemic inflammatory marker C-reactive protein (CRP). Increases in the kynurenine-to-Trp ratio (Kyn:Trp) indicate that the kynurenine pathway is a major route for CID-related Trp wasting. However, the extent of Trp depletion and its relationship with disease activity varies by disease, indicating potential differences in Trp metabolism. In addition, we find that amino acid catabolism in chronic inflammation is specific to tryptophan wasting, whereas other proteinogenic amino acids are not affected. Hence, our results suggest that increased Trp catabolism is a common metabolic occurrence in CID that may directly affect systemic immunity. Grant supportThis work was supported by the DFG Cluster of Excellence 1261 "Precision medicine in chronic inflammation" (KA, SSchr, PR, BH, SWa), the BMBF (e:Med Juniorverbund "Try-IBD" 01ZX1915A and 01ZX2215, the e:Med Network iTREAT 01ZX2202A, and GUIDE-IBD 031L0188A), DFG RU5042 (PR, KA), and Innovative Medicines Initiative 2 Joint Undertakings ("Taxonomy, Treatments, Targets and Remission", No. 831434, "ImmUniverse", grant agreement No. 853995, "BIOMAP", grant agreement No. 821511).

immunology↗

bioRxiv2023

Evolution of E. coli in a mouse model of inflammatory bowel disease leads to a disease-specific bacterial genotype and trade-offs with clinical relevance

Inflammatory bowel disease (IBD) is a persistent inflammatory condition that affects the gastrointestinal tract and presents significant challenges in its management and treatment. Despite the knowledge that within-host bacterial evolution occurs in the intestine, the disease has rarely been studied from an evolutionary perspective. In this study, we aimed to investigate the evolution of resident bacteria during intestinal inflammation and whether- and how disease-related bacterial genetic changes may present trade-offs with potential therapeutic importance. Here, we perform an in vivo evolution experiment of E. coli in a gnotobiotic mouse model of IBD, followed by multiomic analyses to identify disease-specific genetic and phenotypic changes in bacteria that evolved in an inflamed versus a non-inflamed control environment. Our results demonstrate distinct evolutionary changes in E. coli specific to inflammation, including a single nucleotide variant that independently reached high frequency in all inflamed mice. Using ex vivo fitness assays, we find that these changes are associated with a higher fitness in an inflamed environment compared to isolates derived from non-inflamed mice. Further, using large-scale phenotypic assays, we show that bacterial adaptation to inflammation results in clinically relevant phenotypes, which intriguingly include collateral sensitivity to antibiotics. Bacterial evolution in an inflamed gut yields specific genetic and phenotypic signatures. These results may serve as a basis for developing novel evolution-informed treatment approaches for patients with intestinal inflammation.

evolutionary biology↗

bioRxiv2023

FixNCut: Single-cell genomics through reversible tissue fixation and dissociation

The use of single-cell technologies for clinical applications requires disconnecting sampling from downstream processing steps. Early sample preservation can further increase robustness and reproducibility by avoiding artifacts introduced during specimen handling. We present FixNCut, a methodology for the reversible fixation of tissue followed by dissociation that overcomes current limitations. We applied FixNCut to human and mouse tissues to demonstrate the preservation of RNA integrity, sequencing library complexity, and cellular composition, while diminishing stress-related artifacts. Besides single-cell RNA sequencing, FixNCut is compatible with multiple single-cell and spatial technologies, making it a versatile tool for robust and flexible study designs.

bioinformatics↗

bioRxiv2023

Amino acid auxotrophies in human gut bacteria are linked to higher microbiome diversity and long-term stability

Amino acid auxotrophies are prevalent among bacteria. They can govern ecological dynamics in microbial communities and indicate metabolic cross-feeding interactions among coexisting genotypes. Despite the ecological importance of auxotrophies, their distribution and impact on the diversity and function of the human gut microbiome remain poorly understood. This study performed the first systematic analysis of the distribution of amino acid auxotrophies in the human gut microbiome using a combined metabolomic, metagenomic, and metabolic modeling approach. Results showed that amino acid auxotrophies are ubiquitous in the colon microbiome, with tryptophan auxotrophy being the most common. Auxotrophy frequencies were higher for those amino acids that are also essential to the human host. Moreover, a higher overall abundance of auxotrophies was associated with greater microbiome diversity and stability, and the distribution of auxotrophs was found to be related to the human hosts metabolome, including trimethylamine oxide, small aromatic acids, and secondary bile acids. Thus, our results suggest that amino acid auxotrophies are important factors contributing to microbiome ecology and host-microbiome metabolic interactions.

microbiology↗

bioRxiv2023

Recurrent phases of strict protein limitation inhibit tumor growth and restore lifespan in a Drosophila intestinal cancer model

Diets that restrict caloric or protein intake offer a variety of benefits, including decreasing the incidence of cancer. However, whether such diets pose a substantial therapeutic benefit as auxiliary cancer treatments remains unclear. We determined the effects of severe protein depletion on tumorigenesis in a Drosophila melanogaster intestinal tumor model, using a human RAF gain-of-function allele. Severe and continuous protein restriction significantly reduced tumor growth but resulted in premature death. Therefore, we developed a diet in which short periods of severe protein restriction alternated cyclically with periods of complete feeding. This nutritional regime reduced tumor mass, restored gut functionality, and normalized the lifespan of oncogene-expressing flies to the levels observed in healthy control flies. Furthermore, this diet reduced the chemotherapy-induced stem cell activity associated with tumor recurrence. Transcriptome analysis revealed long-lasting changes in the expression of key genes involved in multiple major developmental signaling pathways. Overall, the data suggest that recurrent severe protein depletion effectively mimics the health benefits of continuous protein restriction, without undesired nutritional shortcomings. This provides seminal insights into the mechanisms of the transcriptomic memory effect required to maintain the positive effects of protein restriction throughout the phases of a full diet.

cancer biology↗

bioRxiv2022

Adaptation to ER-stress via serine glycine metabolism licences STING signalling and CMV control in intestinal epithelial cells

Inflammatory bowel diseases (IBD) are characterized by chronic relapsing inflammation of the gastrointestinal tract. While the molecular causality between endoplasmic reticulum (ER) stress and intestinal inflammation is widely accepted, the metabolic consequences of chronic ER-stress on the pathophysiology of IBD remain unclear. By using in vitro, ex vivo, in vivo mouse models and patient datasets, we identified a distinct polarisation of the mitochondrial one-carbon (1C) metabolism and a fine-tuning of the amino acid uptake in intestinal epithelial cells tailored to support GSH and NADPH metabolism upon chronic ER-stress. This metabolic phenotype strongly correlates with IBD severity and therapy-response. Mechanistically, we uncover that both chronic ER-stress and serine limitation disrupt cGAS/STING-signalling, impairing the epithelial response against viral and bacterial infection, fuelling experimental enteritis. Consequently, antioxidant treatment restores STING function and virus control. Collectively, our data highlight the importance of the plasticity of serine metabolism to allow proper cGAS/STING-signalling and innate immune responses upon chronic inflammation in the gut.

cell biology↗

bioRxiv2021

Impact of antibiotic perturbation on intestinal viral communities in mice

Viruses and bacteriophages have a strong impact on intestinal barrier function and the composition and functional properties of commensal bacterial communities. To improve our understanding of the role of the enteric intestinal virome, we longitudinally characterized the virome in fecal samples from wild-type (WT) C57BL/6J and knock-out (KO) NOD2 mice in response to an antibiotic perturbation. Sequencing of viral-like-particles (VLPs) demonstrated both a high diversity and high inter-individual variation of the murine gut virome composed of eukaryotic viruses and bacteriophages. Antibiotics also had a significant impact on the gut murine virome causing a delayed resilience independent of genotype. However, compositional shifts in the virome and bacteriome were highly correlated, suggesting that the loss of specific phages may contribute to a dysregulation of the bacterial community composition. Bacteriophage species may be playing an important role in either upregulating or downregulating the bacterial community, and restoring a healthy virome may therefore be a central goal of microbiota-targeted therapies.

microbiology↗