Biology subjects

Seo, Y.

Publications and source records attributed to Seo, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

In vivo Quantitative Tomography of 225Ac Daughters in a Prostate Cancer Mouse Model with a Compton Camera

Targeted alpha therapy with 225Ac is a promising modality for cancer treatment, as shown in recent preclinical and clinical studies. Preclinical imaging of 225Ac is essential to fully understand the biokinetics of developmental 225Ac radiopharmaceuticals. Although single photon emission computed tomography (SPECT) is typically used to achieve this in vivo, conventional preclinical scanners struggle to provide high contrast and accurate quantification for 225Ac imaging due to the very low injected activities (below 1 kBq/g), the unfavorable gamma-ray branching ratios (<26%), and its complex decay chain with several gamma-ray emissions. In this work, we employ a compact CZT-based Compton camera to achieve quantitative tomography of 225Ac daughters in live mice at 18.5 kBq (0.5 Ci) injected activities. Three mice bearing 22Rv1 prostate cancer subcutaneous xenografts were scanned in a single bed position for 30 minutes following intravenous administration of 18.5 kBq of the Anti-CD46 225Ac-Macropa-PEG4-YS5 conjugate. We successfully visualized the in vivo biodistributions of the 225Ac daughters 221Fr and 213Bi, distinguishing between the tumor xenograft and the central organs. Quantification of the tumor uptake from the images revealed an activity as low as 1.1 kBq. In vivo activity quantification computed from the images was compared to ex vivo biodistribution measurements using a gamma counter after harvesting the tissue, showing strong agreement.

bioengineering↗

bioRxiv2026

Hyperactivation of the AXL-ICD/SIRT2 axis by Amyloid-β impairs astrocytic autophagic flux and exacerbates neuroinflammation

Autophagy dysfunction and neuroinflammation are central to Alzheimer's disease (AD), yet how extracellular amyloid-{beta} (A{beta}) couples to impaired autophagic flux and heightened neuroinflammation remains unknown. Here, we identify the TAM receptor AXL as a molecular transducer that couples A{beta} sensing to the regulation of autophagy and neuroinflammation in astrocytes. A{beta} induces {gamma}-secretase-dependent cleavage of AXL, generating a nuclear intracellular domain (AXL-ICD) that forms phase-separated condensates and activates autophagy gene transcription through SIRT2-mediated recruitment of the RUVBL1/2-INO80 chromatin-remodeling complex. This axis is activated in astrocytes of postmortem AD brains. Concurrently, AXL-ICD binds to the SIRT2 catalytic domain and suppresses its deacetylase activity, increasing -tubulin acetylation and altering microtubule dynamics. While moderate AXL-ICD levels promote autophagic flux, excessive elevation paradoxically triggers microtubule hyperstabilization, thereby impairing autophagosome-lysosome fusion and causing pathological accumulation of autophagosomes and H2O2. The inhibitory peptide AxSBiP disrupts the AXL-ICD/SIRT2 interaction, restores autophagic flux, reduces plaque burden, and normalizes A{beta}-induced H2O2 production and astrogliosis in APP/PS1 mice. We propose the AXL-ICD/SIRT2 axis as an effective therapeutic target to reduce A{beta} burden and neuroinflammation in AD

neuroscience↗

bioRxiv2026

Repurposing native non-homologous end joining for multicopy random integration in Wickerhamomyces ciferrii

Wickerhamomyces ciferrii is a non-model diploid yeast that naturally produces tetraacetyl phytosphingosine (TAPS), a sphingoid base used in cosmetic and dermatological applications. However, its strong preference for non-homologous end joining (NHEJ) over homologous recombination (HR) limits conventional genome editing, while disruption of LIG4, a core NHEJ gene, compromises cellular fitness. Here, we repurposed native NHEJ activity to develop a homology-independent multicopy genome integration platform for W. ciferrii. The platform combines three optimized donor-design features: telomeric end-shielding with two tandem copies of an 11 bp repeat to improve linear donor persistence, a defective URA5 auxotrophic marker to enrich multicopy integrants, and 5'-phosphorylated donor termini to enhance transformant recovery and integration output. These features were consolidated into the platform vector pTdmVU5. As a metabolic engineering demonstration, multicopy integration of LCB1 and LCB2, encoding the two subunits of serine palmitoyltransferase, increased TAPS titer by 2.7-fold. This work converts the native NHEJ bias of W. ciferrii from a barrier to precise genome editing into a practical tool for pathway amplification and establishes a framework for engineering NHEJ-dominant non-model yeasts.

synthetic biology↗

bioRxiv2026

Whole-genome 3D architectural screen reveals modulators of brain DNA structure

Three-dimensional (3D) genome architecture is the foundation of gene regulation, and plays a critical role in normal physiology and disease. However, our understanding of its biochemical determinants has long been limited by technology: imaging-based screens only profile a small number of loci, while sequencing-based studies rarely exceed 100 samples or conditions. Here we present "in-plate chromosome conformation capture" (Plate-C), a high-throughput, cost-effective platform that profiles thousands of whole-genome architectures in a day. Plate-C enabled the first chemical screen for whole-genome structural changes--profiling 2,956 samples from 834 conditions across 5 neuronal and glial types, accompanied by 6,081 single cells using "easy diploid chromosome conformation capture" (Easy Dip-C) and 200,893 single-cell transcriptomes. We discovered that diverse, dose/time-dependent, and cell type/species-specific modes of DNA structural changes can be rapidly induced by manipulating epigenetic (HDAC, BET), metabolic (mTOR), proteostatic (UPR), developmental (GSK3/Wnt, Hedgehog), immune (cGAS/STING), and neurotransmission pathways. To validate our finding in vivo, we demonstrated in newborn mice that HDAC inhibition drives brain-wide genome rewiring within hours, highly correlated with changes in vitro and inducing a latent structural and transcriptional state orthogonal to normal differentiation. By enabling massively parallel profiling of whole-genome structures, Plate-C paves the way for systematic discovery of DNA folding principles to better understand and engineer the human genome in 3D.

genomics↗

bioRxiv2026

Systemic hypoxia suppresses solid tumor growth

Local hypoxia is a hallmark of solid tumors and a negative prognostic factor in the progression and treatment of cancer. Here, we showed that systemic hypoxia, in contrast to localized tumor hypoxia, decreases tumor growth in vivo across multiple cancer types and preclinical models. The reduced tumor growth in systemic hypoxia was not explained by hypoglycemia, hypoinsulinemia, or HIF activation. Instead, metabolite profiling in tumors and tumor interstitial fluid revealed extensive perturbations in purine-related metabolites. Stable isotope tracing demonstrated that systemic hypoxia caused tumors to suppress de novo purine synthesis. Furthermore, tumors did not develop resistance to systemic hypoxia therapy, and when used in combination with chemotherapy or immunotherapy, systemic hypoxia dramatically suppressed tumor growth. Finally, we showed that systemic hypoxia can be achieved pharmacologically with the small molecule HypoxyStat. These findings challenge the long-held paradigm of hypoxia as a negative prognostic factor in cancer progression, and they suggest a potential therapeutic role for systemic hypoxia in suppressing solid tumor growth.

cancer biology↗

bioRxiv2026

NFATc3 enhances DREAM complex-driven tumorigenesis

The nuclear factor of activated T cells (NFAT) transcription factors, activated by calcium-calcineurin signaling, regulate various cellular processes, including cell differentiation, angiogenesis, and immune cell activation. Nonetheless, their roles in tumor cells remain largely undefined. The dimerization partner, RB-like, E2F, and multi-vulval class B (DREAM) complex orchestrates cell quiescence and proliferation. Pharmacological mimicry of DREAM-activated transcriptional signatures identified two calcium signaling inhibitors that suppressed lung adenocarcinoma (LUAD) cell proliferation. Among the five NFAT members, NFATc3/NFAT4 was predominantly expressed in LUAD cells and required for both LUAD cell proliferation and DREAM target gene transactivation. NFATc3 was enriched at DREAM target promoters and associated with the DREAM complex, possibly via LIN9, a scaffolding protein of the Multi-Vulva class B (MuvB) core proteins. These findings reveal an unexpected role for NFATc3 in promoting DREAM target gene transactivation and suggest the calcium-NFATc3 axis as a molecular target in LUAD, enriched by DREAM complex activation.

molecular biology↗

bioRxiv2025

Comparative single-cell transcriptomics of orthotopic and subcutaneous gastric tumors reveal immune and stromal heterogeneity

Preclinical cancer models often use subcutaneous (SC) implantation, which fails to recapitulate the native tumor microenvironment (TME) of orthotopic (ORT) sites. To resolve these differences, we used single-cell RNA sequencing (scRNA-seq) on paired SC and ORT implants of the CKP syngeneic gastric cancer model. Histopathological differences were minimal, but scRNA-seq revealed profound TME divergence. ORT tumors displayed robust stromal activation, coordinated fibroblast and endothelial signaling, and an immune compartment marked by higher T/NK cell activation and IgA-biased B cell plasma programs, reflecting a physiological mucosal environment. In contrast, SC tumors had higher overall T cell infiltration but showed markedly increased CD8+ T cell exhaustion and an enriched oxidative tumor program. Our findings provide critical guidance: SC models are optimal for high-throughput and exhaustion-focused assays, whereas ORT models are indispensable for studying organ-specific immune and stromal biology with translational fidelity.

cancer biology↗

bioRxiv2025

Effective imaging and treatment of Acute Myeloid Leukemia with radiotheranostics targeting the activated conformation of integrin-Beta2

There remains an unmet clinical need for improved treatment strategies in Acute Myeloid Leukemia (AML). Although radiopharmaceutical therapies targeting non-cancer-selective antigens have shown promise in AML, their clinical utility is often limited by prolonged bone marrow suppression. Using a unique proteomics-based strategy, we recently identified the active conformation of integrin-{beta}2 (aITGB2) as a novel, tumor-selective target for AML. Importantly, this conformational epitope is expressed widely on AML cells but minimally on normal marrow progenitors/healthy tissues. Here we first confirmed widespread aITGB2 expression on AML tumors that was largely independent of tumor genotype or prior therapeutic regimen. We developed diagnostic and therapeutic radiopharmaceuticals targeting aITGB2 utilizing a conformation-specific antibody (clone 7065). PET/CT imaging with 89Zr and 134Ce-labeled 7065 in AML models revealed high target-mediated uptake, greater than that compared to standard of care [18F]-FDG. PET/CT imaging with [89Zr]DFO*-7065 showed reduced binding to normal bone marrow and immune cells in humanized immune system mice compared to [89Zr]DFO*-anti-CD33. For therapy, we developed [225Ac]Macropa-PEG4-7065 using an optimized chelator-linker combination. Treatment with [225Ac]Macropa-PEG4-7065 in Nomo-1 and PDX AML disseminated models delayed tumor growth and improved overall survival compared to controls, including [225Ac]DOTA-anti-CD33, a clinical stage-radioimmunotherapy under evaluation in AML. Relapsed tumors demonstrated persistent aITGB2 expression, supporting continued development of fractionated dosing schemes, and proteomics analysis indicated activation of TCA cycle and carbon metabolism pathways, consistent with therapy-induced stress responses. These findings highlight [89Zr]DFO*-7065 and [225Ac]Macropa-7065 as a promising aITGB2-targeted theranostic pair with potential for imaging and treatment in future clinical translation. One Sentence SummaryThis study demonstrates promising preclinical efficacy of aITGB2-targeted radiotheranostics for selective imaging and therapy in AML.

cancer biology↗

bioRxiv2025

Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer

Liver cancer is a leading cause of cancer-related death world-wide in part due to the shortage of effective therapies, and MYC overexpression defines an aggressive and especially difficult to treat subset of patients. Given MYCs ability to reprogram cancer cell metabolism, and the livers role as a coordinator of systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate liver tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner to sustain their growth. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited MYC-driven liver tumorigenesis. In vivo isotope tracing studies uncovered a role for alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle, nucleotide production, and amino acid synthesis. Treating transgenic MYC-driven liver tumor mouse models with L-Cycloserine, a compound that inhibits GPT2, was sufficient to diminish the frequency of mouse tumor formation and attenuate growth of established human liver tumors. Thus, we identify a new targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.

cancer biology↗

bioRxiv2025

Novel mouse model of cerebral microbleeds created by Crispr/Cas9-mediated Col4a1 deletion in adult brain microvessels

Cerebral small vessel disease is a leading cause of cognitive decline and stroke in the elderly, with cerebral microbleeds (CMBs) as one of the key imaging biomarkers. Our understanding of its pathophysiology remains limited due to the lack of appropriate animal models. We report a novel mouse CMB model created by disrupting collagen IV, a core component of the vascular basement membrane (BM), specifically within brain microvessels. Targeted deletion of Col4a1 was achieved in adult mice using brain endothelial-specific AAV vectors with CRISPR/Cas9. MRI revealed numerous CMBs with distributions similar to those of human CMBs. CMB burden increased progressively over six months following Col4a1 deletion in a dose-dependent manner, accompanied by cognitive decline and motor incoordination. Histological examination revealed hemosiderin deposits corresponding to MRI-detected CMBs without evidence of macroscopic hemorrhage or white matter lesions, while ultrastructural analysis demonstrated significant BM thinning in Col4a1-depleted microvessels. Analysis of human MRI and genomic data identified significant associations between CMB susceptibility and genetic variants in TIMP2, an endogenous inhibitor of the matrix-degrading enzyme MMP2, underscoring the clinical relevance of our model. These findings establish a direct causal relationship between microvessel COL4A1 and CMB, suggesting that dysregulated collagen IV homeostasis in BM underlies CMB development.

neuroscience↗

bioRxiv2025

Mechanical environment afforded by engineered polymer hydrogel critically regulates survival of neural stem cells transplanted in the injured spinal cord via Piezo1-mediated mechanotransduction

Neural stem cell (NSC) transplantation is a promising therapeutic approach for spinal cord repair, but poor graft survival remains a critical challenge. Here, we demonstrate that the mechanical properties of the transplantation microenvironment play a crucial role in NSC survival in the injured spinal cord. While our previously engineered imidazole-poly(organophosphazene) (I-5) hydrogel effectively prevented cavity formation by promoting extracellular matrix remodeling, NSCs transplanted with 10% hydrogel exhibited poor survival. Remarkably, increasing the hydrogel concentration to 16%, which created a 5-fold stiffer matrix, significantly enhanced NSC graft survival and synaptic integration. Using in vitro models with controlled substrate stiffness, we found that NSCs on stiffer substrates displayed enhanced adhesion, complex morphology, and increased viability. Importantly, we identified the mechanosensitive ion channel Piezo1 as the key molecular mediator of these stiffness-dependent behaviors. CRISPR/Cas9-mediated Piezo1 gene editing in NSCs significantly reduced graft survival in vivo when transplanted with 16% hydrogel, confirming that Piezo1-mediated mechanotransduction is essential for NSC survival in the injured spinal cord. Our findings reveal a previously unrecognized mechanism governing graft survival in the injured spinal cord and suggest that optimizing the mechanical properties of biomaterial scaffolds or targeting Piezo1-dependent mechanotransduction could substantially improve outcomes of cell-based therapies for neurological disorders.

neuroscience↗

bioRxiv2025

Production of homozygous deletion mutants targeting fertilization regulator genes through multiplex genome editing

Producing the gene-knockout mutant is a critical strategy in reverse genetics for gene functional analyses. Plant science has applied various mutagenesis, including chemical mutagen, T-DNA insertion, and genome editing. The intact gene expression is completely disrupted, while the mutant retains the intact sequence region. Lately, effective whole open reading frame (ORF) deletion through the CRISPR/Cas9 system using multiplex guide RNAs was reported in Arabidopsis, targeting a gene expressed in somatic cells. Here we applied the scheme targeting the reproductive genes GENERATIVE CELL SPECIFIC 1(GCS1), GAMETE EXPRESSED 2 (GEX2), DUF679 DOMAIN MEMBRANE PROTEIN 8 (DMP8), and DMP9, which are fertilization regulators. Homozygous gene deletion lines were successfully obtained in the T1 generation, with acquisition rates ranging from 8.3% to 30.0%. The rates approximately correlated with the scores predicted by the DeepSpCas9. The analysis of the GCS1 deletion line ({Delta}gcs1) suggested that avoiding the first bolt removal is important for consistent phenotype of the developed inflorescences. Compared to the previously reported mutants, the GEX2 deletion line ({Delta}gex2) showed a difference in seed development phenotype, indicating that the remaining intact gene region in the mutant could unexpectedly influence the function. Simultaneous deletions of DMP8 and DMP9, which are in distinct chromosomes, were also succeeded in the T1 generation. The obtained results showed that all deletions were inheritable. The scheme challenged here demonstrated the effective production of homozygous mutants for the genes, even if the reproductive lethal or recessive.

plant biology↗

bioRxiv2024

Actin dysregulation induces immune evasion via oxidative stress-activated PD-L1 in gastric cancer

Diffuse gastric adenocarcinoma (DGAC) is an aggressive malignancy with limited therapeutic options, poor prognosis, and poorly understood biology. CRACD, an actin polymerization regulator, is often inactivated in gastric cancer, including DGAC. We found that genetic engineering of murine gastric organoids with Cracd ablation combined with Kras mutation and Trp53 loss induced aberrant cell plasticity, hyperproliferation, and hypermucinosis, the features that recapitulate DGAC transcriptional signatures. Notably, CRACD inactivation remodeled the immune landscape for immune evasion through PD-L1 enrichment in tumor cells. Mechanistically, CRACD loss disrupted actin dynamics, generating reactive oxygen species that activated HIF1, which transactivated PD-L1. Pharmacologic inhibition of HIF1 or PD-L1 restored immune surveillance and suppressed tumorigenesis. These findings reveal a novel role of actin homeostasis in limiting cell plasticity and immune evasion, position CRACD as a potential biomarker for stratifying patients with DGAC, and highlight HIF1 and PD-L1 as actionable therapeutic targets.

cancer biology↗

bioRxiv2024

Intravital imaging of pulmonary lymphatics in inflammation and metastatic cancer

Intravital microscopy has enabled the study of immune dynamics in the pulmonary microvasculature, but many key events remain unseen because they occur in deeper lung regions. We therefore developed a technique for stabilized intravital imaging of bronchovascular cuffs and collecting lymphatics surrounding pulmonary veins in mice. Intravital imaging of pulmonary lymphatics revealed ventilation-dependence of steady-state lung lymph flow and ventilation-independent lymph flow during inflammation. We imaged the rapid exodus of migratory dendritic cells through lung lymphatics following inflammation and measured effects of pharmacologic and genetic interventions targeting chemokine signaling. Intravital imaging also captured lymphatic immune surveillance of lung-metastatic cancers and lymphatic metastasis of cancer cells. To our knowledge, this is the first imaging of lymph flow and leukocyte migration through intact pulmonary lymphatics. This approach will enable studies of protective and maladaptive processes unfolding within the lungs and in other previously inaccessible locations. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/612619v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@66dd00org.highwire.dtl.DTLVardef@1373576org.highwire.dtl.DTLVardef@1970dfeorg.highwire.dtl.DTLVardef@17c15c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Detrimental Influence of Arginase-1 in Infiltrating Macrophages on Post-Stroke Functional Recovery and Inflammatory Milieu

Post-stroke inflammation critically influences functional outcomes following ischemic stroke. Arginase-1 (Arg1) is conventionally understood as a marker for anti-inflammatory macrophages, associated with the resolution of inflammation and promotion of tissue repair in various pathological conditions. However, its specific role in post-stroke recovery remains to be elucidated. This study investigates the functional impact of Arg1 expressed in macrophages on post-stroke recovery and inflammatory milieu. We observed a time-dependent increase in Arg1 expression, peaking at 7 days after photothrombotic stroke in mice. Cellular mapping analysis revealed that Arg1 was predominantly expressed in LysM-positive infiltrating macrophages. Using a conditional knockout (cKO) mouse model, we examined the role of Arg1 expressed in infiltrating macrophages. Contrary to its presumed beneficial effects, Arg1 cKO in LysM-positive macrophages significantly improved skilled forelimb motor function recovery after stroke. Mechanistically, Arg1 cKO attenuated fibrotic scar formation, enhanced peri-infarct remyelination, and increased synaptic density while reducing microglial synaptic elimination in the peri-infarct cortex. Gene expression analysis of FACS-sorted microglia revealed decreased TGF-{beta} signaling and pro-inflammatory cytokine activity in peri-infarct microglia from Arg1 cKO animals. In vitro co-culture experiments demonstrated that Arg1 activity in macrophages modulates microglial synaptic phagocytosis, providing evidence for macrophage-microglia interaction. These findings provide new insights into Arg1 function in CNS injury and highlight an interaction between infiltrating macrophages and resident microglia in shaping the post-stroke inflammatory milieu. Our study identifies Arg1 in macrophages as a potential therapeutic target for modulating post-stroke inflammation and improving functional recovery.

neuroscience↗

bioRxiv2024

Loss of neutrophil Shp1 produces hemorrhagic and lethal acute lung injury

The acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality and neutrophils are critical to its pathogenesis. Neutrophil activation is closely regulated by inhibitory tyrosine phosphatases including Src homology region 2 domain containing phosphatase-1 (Shp1). Here, we report that loss of neutrophil Shp1 in mice produced hyperinflammation and lethal pulmonary hemorrhage in sterile inflammation and pathogen-induced models of acute lung injury (ALI) through a Syk kinase-dependent mechanism. We observed large intravascular neutrophil clusters, perivascular inflammation, and excessive neutrophil extracellular traps in neutrophil-specific Shp1 knockout mice suggesting an underlying mechanism for the observed pulmonary hemorrhage. Targeted immunomodulation through the administration of a Shp1 activator (SC43) reduced agonist-induced reactive oxygen species in vitro and ameliorated ALI-induced alveolar neutrophilia and NETs in vivo. We propose that the pharmacologic activation of Shp1 has the potential to fine-tune neutrophil hyperinflammation that is central to the pathogenesis of ARDS.

immunology↗

bioRxiv2024

IgG hexamers initiate acute lung injury

Antibodies can initiate lung injury in a variety of disease states such as autoimmunity, transfusion reactions, or after organ transplantation, but the key factors determining in vivo pathogenicity of injury-inducing antibodies are unclear. A previously overlooked step in complement activation by IgG antibodies has been elucidated involving interactions between IgG Fc domains that enable assembly of IgG hexamers, which can optimally activate the complement cascade. Here, we tested the in vivo relevance of IgG hexamers in a complement-dependent alloantibody model of acute lung injury. We used three approaches to block alloantibody hexamerization (antibody carbamylation, the K439E Fc mutation, or treatment with domain B from Staphylococcal protein A), all of which reduced acute lung injury. Conversely, Fc mutations promoting spontaneous hexamerization made a harmful alloantibody into a more potent inducer of acute lung injury and rendered an innocuous alloantibody pathogenic. Treatment with a recombinant Fc hexamer decoy therapeutic protected mice from lung injury, including in a model with transgenic human FCGR2A expression that exacerbated pathology. These results indicate a direct in vivo role of IgG hexamerization in initiating acute lung injury and the potential for therapeutics that inhibit or mimic hexamerization to treat antibody-mediated diseases. Brief summaryIgG antibodies can form hexamers. This study shows that hexamer assembly is an important event determining the ability of IgG to trigger acute lung injury. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/577129v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@15b0346org.highwire.dtl.DTLVardef@33f39eorg.highwire.dtl.DTLVardef@bf0f4dorg.highwire.dtl.DTLVardef@185b5bf_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Glucose-fed microbiota alters intestinal epithelium and increases susceptibility to bacterial pathogens

Overconsumption of dietary sugar can lead to many negative health effects including the development of Type 2 diabetes, metabolic syndrome, cardiovascular disease, and neurodegenerative disorders. Recently, the human intestinal microbiota strongly associated with our overall health has also been known to be affected by diet. However, mechanistic insight into the importance of the human intestinal microbiota and the effects of chronic sugar ingestion has not been possible largely due to the complexity of the human microbiome which contains hundreds of types of organisms. Here, we use an interspecies C. elegans-E. coli system, where E. coli are subjected to high sugar, then consumed by the bacterivore host C. elegans to become the microbiota. This glucose-fed microbiota results in a significant lifespan reduction accompanied by reduced healthspan including locomotion, stress resistance, and changes in behavior and feeding. Lifespan reduction is also accompanied by two potential major contributors: increased intestinal bacterial density and increased reactive oxygen species. The glucose-fed microbiota accelerated the age-related development of intestinal cell permeability, intestinal distention, and dysregulation of immune effectors. Ultimately, the changes in the intestinal epithelium due to aging with the glucose fed microbiota results in increased susceptibility to multiple bacterial pathogens. Taken together, our data reveal that chronic ingestion of sugar such as a western diet has profound health effects on the host due to changes in the microbiota and may contribute to the current increased incidence of ailments including inflammatory bowel diseases as well as multiple age-related diseases.

physiology↗