Biology subjects

Park, J.

Publications and source records attributed to Park, J..

At least 91 records · Page 5Linked to original sources

bioRxiv2026

Programmable domestication of thermophilic bacteria through removal of non-canonical defense systems

Thermophilic bacteria offer major advantages for industrial biotechnology, yet most remain genetically intractable because cellular defense systems block efficient DNA acquisition. Here, we present a programmable domestication strategy that converts wild Geobacillus strains into genetically tractable thermophilic hosts. We developed the Domestication of Non-Model Bacteria (DNMB) Suite, a multi- omics-guided computational framework that systematically identifies genetic barriers to transformation. DNMB analysis revealed that non-canonical nuclease-based defense systems, including Wadjet II, constitute dominant barriers to DNA uptake in previously intractable Geobacillus strains. Targeted deletion of these loci increased transformation efficiency by up to six orders of magnitude. We further established a hierarchical thermophilic engineering toolkit that integrates plasmid artificial modification, conjugation-assisted DNA delivery, and genome editing using an endogenous CRISPR-Cas9 system. The resulting domesticated strains support stable heterologous expression and tunable genetic control at elevated temperatures. Together, these results establish a generalizable framework for transforming genetically intractable thermophiles into programmable industrial chassis.

bioengineering↗

bioRxiv2026

Diverse high-fat diets drive multi-omic reprogramming that persists after dietary reversal

Dietary fat composition modulates host physiology and the gut microbiome, but the long-term effects of specific fat sources and the extent to which these changes resolve after dietary reversal remain incompletely defined. Here, we present a longitudinal multi-omic resource of mice maintained for one year on a purified control diet, seven high-fat diets differing in predominant fat source, or reversal regimens in which animals were switched from high-fat to control diet after 4 or 9 months. We further incorporated two cohorts with distinct pre-existing microbiome configurations to determine how baseline community structure shapes diet-induced remodeling of the gut microbiome ecosystem. By integrating longitudinal phenotyping, fecal metagenomics, fecal metabolomics, plasma metabolomics and lipidomics, and intestinal single-cell RNA sequencing, we defined the shared and dietary fat-specific responses across host and microbiome compartments. Baseline microbiome composition strongly influenced microbial responses to diet, indicating that pre-existing community structure is a major determinant of dietary ecosystem remodeling. Although many altered features shifted toward baseline after dietary reversal, only approximately half of diet-associated microbial changes recovered within the study window. A subset of taxa exhibited persistent alterations, including sustained depletion of Lactobacillus johnsonii and Bifidobacterium pseudolongum and sustained enrichment of Alistipes finegoldii, consistent with a "microbiome memory" of prior high-fat diet exposure. This memory effect is mirrored in the host, by sustained suppression of major histocompatibility complex class II (MHC-II) gene expression in intestinal epithelial cells after dietary reversal. These findings indicate that dietary fats leave a lasting imprint on the host-microbiome interactome that survives dietary intervention. Together, these data establish a resource for defining how dietary fat source, baseline microbiome composition, and dietary history shape host-microbiome states. The entire resource is available online as an RShiny app.

systems biology↗

bioRxiv2026

Systemic delivery of drug-free polymeric nanoparticles reprograms innate immunity in a sex-dependent manner after spinal cord injury

Sex differences influence distinct inflammatory responses after spinal cord injury (SCI), yet their impact on immune-modulating nanotherapeutics remains unclear. Here, we investigated the sex-dependent effects of drug-free poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) following SCI. Systemic NP administration enhanced locomotor recovery in both sexes and eliminated the functional gap observed in controls. Mechanistically, NPs engaged distinct immune pathways between sexes. Females accumulated more NPs in the spleen, leading to reduced monocyte-derived macrophage infiltration, whereas males showed greater NP accumulation at the lesion and attenuated microglial activation. Transcriptomic analysis showed preferential modulation of eicosanoid-related pathways in females and NF-{kappa}B-linked signaling in males. These sex-specific, yet convergent NPs-induced immunomodulatory effects reduced fibrotic scarring and enhanced remyelination, with females showing greater Schwann cell-mediated repair and males exhibiting marked suppression of microglial activation. Collectively, these findings demonstrate that NPs promote comparable functional recovery in both sexes through distinct, sex-influenced immune mechanisms and establish a translational framework for sex-informed immune targeting and nanotherapeutic design in SCI and other inflammation-mediated diseases. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/709912v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@5af2ecorg.highwire.dtl.DTLVardef@1027071org.highwire.dtl.DTLVardef@12449ceorg.highwire.dtl.DTLVardef@169a327_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2026

Lung endothelial niche signaling governs self-renewal and fate transitions of human alveolar stem cells

Chronic lung diseases such as pulmonary fibrosis are characterized by the irreversible loss of alveolar type 1 (AT1) cells, yet the mechanisms governing human alveolar stem cell self-renewal and differentiation remain poorly defined. Here, we identify a lung endothelial niche that sustains the self-renewal of human alveolar type 2 (AT2) stem cells through MAPK signaling, enabling robust long-term expansion while preserving stem cell fate. Although YAP activation initiates AT1 transcriptional programs, it is insufficient to complete lineage maturation. We show that MAPK inhibition together with LATS inhibition promotes nuclear translocation of YAP, enhancing AT1 differentiation. Expanded human AT2 stem cells engraft in fibrotic lungs and contribute to alveolar regeneration while undergoing directed differentiation within diseased human lung tissue. Together, our findings define a niche-controlled signaling mechanism governing human alveolar stem cell fate and advance our understanding of alveolar regeneration.

cell biology↗

bioRxiv2026

Evolutionarily conserved neural dynamics across mice, monkeys, and humans

On evolutionary timescales, brain circuits adapt to support survival in each species ecological niche. While some anatomical aspects of neural circuitry are conserved across species with distant evolutionary origins, each species also exhibits specific circuit adaptations that enable its behavioral repertoire. It remains unclear whether homologous brain regions leverage analogous neural computations as different species perform common behaviors such as reaching and manipulating objects. Here, we directly assessed conservation of neural computations using intracortical recordings from mouse, monkey, and human motor cortex--a homologous region across many mammals--during motor behaviors crucial for survival. We hypothesized that, despite their phylogenetic distance, rodents and primates produce movements through conserved neural computations implemented by motor cortical population dynamics. Remarkably, we found that movement-related neural dynamics were highly conserved across species, while variations in behavioral output were uniquely captured in neural trajectory geometries. Strikingly, neural dynamics during movement across species were more conserved than those across brain regions in the same human and between motor preparation and execution in the same monkeys. Lastly, through manipulation of neural network models trained to perform reaching movements, we reinforce that conservation of neural dynamics across species likely stems from shared circuit constraints. We thus assert that evolution maintains neural computations across phylogeny even as behavioral repertoires expand.

neuroscience↗

bioRxiv2026

EvoStructCLIP: A Mutation-Centered Multimodal Embedding Model for CAGI7 Variant Effect Prediction

AO_SCPLOWBSTRACTC_SCPLOWWe present EvoStructCLIP, a mutation-centered multimodal embedding model that integrates local 3D structural windows and evolutionary constraints to predict missense variant effects. EvoStructCLIP combines two encoders: a structure voxel encoder derived from AlphaFold residue neighborhoods and an MSA-based evolutionary encoder. It aligns the modalities through CLIP-style contrastive learning, with FuseMix regularization and an auxiliary pathogenicity loss trained on 153,787 ClinVar variants. Evaluations using lightweight regressors demonstrate that EvoStructCLIP embeddings capture highly transferable predictive signals across diverse phenotypes, including gene-specific functional readouts of BRCA1, KCNQ4, and PTEN/TPMT. This transferability is further supported in the CAGI7 blind competition setting, where models generalized to predicting different gene-specific readouts for BARD1, FGFR, and TSC2 without target-specific retraining and achieved competitive performance across heterogeneous biological tasks.

bioinformatics↗

bioRxiv2026

Genome wide transcriptional changes underlie gradual and recurrent adaptation to protein malnutrition in zebrafish

Lysosome-rich enterocytes (LREs) are a specialized population of intestinal cells that mediate the uptake and absorption of dietary proteins in fish and neonatal mammals. Loss of LRE function causes inhibited growth and poor survival due to protein malnutrition. Previously, we reported that in zebrafish loss of Plasmolipin (pllp), an endosomal membrane protein highly expressed in LREs, impairs LRE differentiation and dietary protein absorption, resulting in marked reduction in survival rates. Raising pllp homozygous mutants surviving to adulthood and in-crossing them for multiple generations resulted in their adaptation to malnutrition, with adapted pllp mutants showing no survival deficits. To uncover mechanisms underlying this phenomenon, we compared the older adapted pllp allele with genetically related wild type (WT) fish and a newly generated pllp mutant allele. Using transcriptome profiling and quantitative protein absorption assays, we found that adapted pllp mutants exhibit upregulation of LRE endocytic components, resulting in a capacity for protein absorption that exceeds that of WT. This hyperactivation of LRE endocytic and absorptive activity is aided by a fine-tuned transcriptional regulation of immune genes that may contribute to the enhanced survival of pllp mutants in the face of increased exposure to environmental antigens. Genetic analyses indicate that these adaptations emerge gradually and are recurrent as shown experimentally by the adaptation of a mutant allele upon inbreeding and natural selection. Overall, our study illustrates that genome wide transcriptional changes underly adaptation mechanisms that enhance intestinal function and organismal survival in response to protein malnutrition. Author SummaryIn this study, we investigated how zebrafish adapt to protein malnutrition when the function of specialized intestinal protein-absorbing enterocytes, also found in newborn mammals, is impaired. We observed that fish carrying a mutation that severely disrupts intestinal protein absorption gradually recovered their ability to survive over multiple generations of inbreeding, even though the underlying mutation remained intact. By comparing gene activity in these adapted fish with that of newly generated mutants, we found that adaptation involves a coordinated rewiring of two systems: the enterocytes themselves became hyperactivated, absorbing more protein than even wildtype fish, while the immune system was simultaneously recalibrated to dampen inflammation. We further showed that this adaptive process is recurrent by using a second, independently generated mutant line that underwent a strikingly similar recovery trajectory over successive generations. Together, our findings reveal that animals can overcome a severe, heritable nutritional deficit through a gradual, genome-wide transcriptional response that fundamentally reshapes intestinal function across generations.

developmental biology↗

bioRxiv2026

Representational invariance of numerosity via divisive normalization in coarse and fine visual channels

Robust evidence now suggests that numerosity perception emerges from the early visual cortex. However, such empirical findings pose a theoretical challenge for explaining how a low-level perceptual system represents discrete values from continuous input independently of other magnitude dimensions. Among proposals for this representational invariance, two computational accounts with ties to neural data have garnered attention: divisive normalization and Fourier decomposition. Here, we test these hypotheses using an integrated neural, behavioral, and computational approach and show that: (1) The visual cortex remains sensitive to numerosity even when the input images are equalized for their Fourier power, inconsistent with the Fourier decomposition account. (2) The divisive normalization model explains this neural phenomenon through the selective disruption of fine but not coarse visual channels when encoding normalized local contrast. (3) Backward masking that disrupts fine processing in a psychophysical experiment degrades the acuity of intact dot arrays to the level of Fourier-power equalized dot arrays, which validates the unique prediction of the divisive normalization model. These findings provide converging evidence for the proposal that normalized local contrast enables representational invariance of numerosity in the visual cortex.

neuroscience↗

bioRxiv2026

Existence of Causation without Correlation in Transcriptional Networks

It is commonly assumed that lack of correlation is evidence for lack of causal relationship. Here, however we show that in transcriptional networks, causal linkages can exist in the absence of correlation. We find that a substantial proportion of transcribed genes in yeast and in mouse, show evidence of state-dependent (nonlinear) and temporally coordinated dynamics in their expression patterns (65-77%). Using a test that accommodates this fact, we uncover strong causal relationships that are invisible to correlation-based analyses for both yeast and mouse models. Specifically, for yeast we detect uncorrelated causal relationships for the transcriptional regulators WHI5 and YHP1, and can verify these relationships experimentally. These genes reside at important checkpoints in the cell cycle where multiple signals are integrated at single nodes, giving rise to causal relationships, that despite being uncorrelated, can be accurately detected (71-78%) using a nonlinear causality test.

systems biology↗

bioRxiv2026

Accurate somatic variant detection from formalin fixed, paraffin embedded tissue (FFPE) derived WES and WGS by DeepOmicsFFPE-PLUS, a sequence context-based transformer

Formalin-fixed paraffin-embedded (FFPE) tissues represent a vast archival resource for genomic studies, yet their utility remains constrained by fixation-induced DNA damage and subsequent sequencing artifacts. To comprehensively characterize and address this challenge, we analyzed matched FFPE and fresh-frozen tumor samples from two institutions, spanning different storage durations, DNA qualities, sequencing platforms (WES and WGS), exome capture kits, and somatic variant callers. We found that FFPE-induced artifacts exhibit strong batch- and age-specific patterns, with a predominance of C:G>T:A substitutions, which particularly complicate the accurate identification of low allele frequency true variants. Enzymatic repair methods partially alleviated these artifacts but remained insufficient. To overcome these limitations, we developed DeepOmicsFFPE-PLUS(https://github.com/Theragen-Bio/DeepOmicsFFPE-PLUS), an advanced AI-based tool to accurately distinguish true somatic variants from FFPE-specific artifacts. DeepOmicsFFPE-PLUS demonstrated consistently superior performance across diverse conditions, achieving high sensitivity and specificity--even for low-frequency variants--outperforming existing tools. Application of our model to WGS data further enabled recovery of biologically relevant mutational signatures, including restoration of microsatellite instability (MSI)-associated signatures initially obscured by FFPE artifacts. Our findings underscore the necessity of artifact-aware variant calling in FFPE genomics and establish DeepOmicsFFPE-PLUS as a robust tool for artifact removal, enabling high-fidelity downstream analyses and personalized therapeutic target discovery.

cancer biology↗

bioRxiv2026

Repeated experience drives multiscale engram reorganization to shape memory strength and precision

How memories are shaped by repeated experiences remains unclear. Reorganization of memory engram could underlie memory transformation. Here, by combining c-Fos-based engram cell tagging with optogenetics, spine imaging, and reactivation analyses in the dentate gyrus (DG) and medial prefrontal cortex (mPFC), we discovered a distinct system-wide engram reorganization following repeated learning; that is, a reshuffling of engram cells in the DG, as well as the rapid maturation of mPFC engram cells, forming a dual engram distributed within the hippocampal-mPFC network. These mPFC engram cells were crucial for relearning-dependent enhancement of memory precision. In addition, we found that reactivation of DG engram cells during retraining is critical for engram reorganization-dependent memory strengthening. These findings establish a causal link between engram reorganization and memory transformation by relearning.

neuroscience↗

bioRxiv2026

Maternal-fetal immune conflict contributes to male-specific impairments in a mouse model of neurodevelopmental disorders

Autism spectrum disorder (ASD) arises from genetic and environmental risk factors. One environmental factor, maternal immune activation (MIA)--in which pathogenic infection during pregnancy increases ASD risk in offspring--disproportionately affects males. However, the basis for this male-specific vulnerability, and the mechanisms by which inflammatory signals cross the maternal-fetal interface to affect the male embryo, remain largely unknown. Using the poly(I:C) mouse model of neurodevelopmental disorders, we characterize fetal, placental, and amniotic changes occurring within twenty-four hours of MIA. We find that 30% of embryos exhibit large-scale teratogenic abnormalities--ranging from decreased fetal weight to altered sensory organ development--while 70% develop normally. These abnormalities occur exclusively in a subset of males, never in females. Single-nucleus transcriptomics revealed robust induction of pro-inflammatory gene programs in the placentas of affected males across a broad range of cell types, and most prominently in spongiotrophoblasts--fetally derived cells that partly form the maternal-fetal border. These cells simultaneously down-regulate extracellular matrix and hormone biosynthesis pathways, coinciding with a breakdown in placental structural integrity and the accumulation of immune cells and cytokines in the amniotic fluid. One such cytokine, IL-6, is required for MIA-evoked developmental abnormalities to emerge. Our data indicate that MIA drives a rapid shift from an immunosuppressive to a pro-inflammatory maternal-fetal interface in a vulnerable subset of male embryos, producing acute, sex-restricted developmental deficits. We propose that male embryos may express unique proteins capable of triggering this inflammatory response, which--combined with MIA-induced loss of maternal immunosuppression--selectively derails male embryonic development.

developmental biology↗

bioRxiv2026

Injury-transduced SerpinOLs modulate neuroinflammation and glial activation in the diseased and non-diseased CNS

Oligodendroglial dysfunction is common in CNS diseases and injuries, but the molecular and functional responses of oligodendroglia to CNS pathologies remain poorly defined. Here, we report that oligodendrocytes (OLs) respond to demyelinating diseases by dysregulating serine protease inhibitor clade A member 3N (SERPINA3N). Homeostatic OLs transition to Serpina3n-expressing OLs (SerpinOLs) under other diseased conditions including stroke, endotoxicity, neurodegeneration, neurotrauma, and non-diseased healthy aging conditions. Mechanistically, general neuroinflammation or inflammatory mediators is insufficient for SerpinOL transition. Instead, oligodendrocyte damage/injury, even in the absence of neuroinflammation or glial activation, is sufficient for the transition. Phenotypically, SerpinOLs are characterized by molecular signatures of inflammatory and immune regulation and STAT3 signaling activation. Functionally, SerpinOLs exacerbate neuroinflammation and promote glial activation toward pro-inflammatory and neurodegenerative states. Together, our findings suggest SerpinOLs are a common population of injury-transduced OLs that amplify neuroinflammation and glial activation in the diseased and non-diseased CNS through SERPINA3N secretion. Our findings provide new insights into myelination-independent role of OLs in regulating CNS pathophysiology.

neuroscience↗

bioRxiv2026

Fail closed trust gated synthetic augmentation governs tail risk under subject shift in EEG

Synthetic augmentation can silently harm subject-disjoint EEG generalization. We propose trustgated augmentation (TGA), a control layer that scores synthetic windows with a teacher trained on real data for label consistency and confidence; only samples above a confidence quantile q are eligible. A fail-closed selector injects synthetic data only if validation AUROC exceeds real-only by a margin, otherwise reverting to real-only. In PainMunich chronic-pain EEG (n = 189) at 5% subject scarcity, ungated augmentation harmed 56% of paired runs ({Delta}AUROC< -0.01), whereas TGA at q = 0.99 reduced harm to 24% with comparable mean AUROC. In BCI IV-2a motor imagery (n = 9) at 25% scarcity, strict gating improved AUROC (0.679 vs 0.627) and reduced harm (0.16 vs 0.44). A covariance-manifold audit showed synthetic windows were strongly off-manifold (mean distance ratio 2.39 x 104), motivating explicit governance.

bioinformatics↗

bioRxiv2026

Label-free quantitative phenotyping of hepatic stellate cell activation using holotomography with AI-enabled subcellular segmentation

Hepatic stellate cell (HSC) activation is a central driver of liver fibrosis, yet its quantitative characterization in living cells remains limited by endpoint assays that rely on fixation and labeling. Here we introduce a label-free framework that combines three-dimensional holotomography (HT) with automated, AI-assisted analysis to study HSC activation dynamics in live cells. Using refractive index tomography, we non-invasively visualize hallmark structural features of HSC activation, including lipid droplet depletion, cytoskeletal remodeling, and changes in cellular morphology. Correlative fluorescence imaging validates the biological relevance of HT-derived features, while longitudinal imaging reveals continuous activation trajectories at single-cell resolution. Automated segmentation of whole cells and subcellular organelles enables scalable extraction of multi-parametric biophysical descriptors, defining a quantitative phenotypic fingerprint that distinguishes quiescent and activated states. Together, this work establishes holotomography-based quantitative phenotyping as a powerful approach for studying HSC activation and, more broadly, dynamic cell-state transitions in living systems.

cell biology↗

bioRxiv2026

Translesion DNA synthesis on pyrimidine dimers by Plant organellar DNA polymerases is metal-dependent

Ultraviolet (UV) radiation generates crosslinked DNA lesions--primarily cyclobutane pyrimidine dimers (CPDs) and [6-4] photoproducts ([6-4] PPs)--that block the progression of replicative DNA polymerases. In plants, these lesions are efficiently removed from nuclear DNA by dedicated repair pathways; however, comparable repair mechanisms are absent in plastids and mitochondria. Consequently, how plant organellar DNA polymerases (POPs) tolerate or bypass UV-induced damage has remained unclear. Here, we show that the two Arabidopsis thaliana organellar polymerases, AtPolIs, possess robust translesion synthesis (TLS) activity across CPDs. Although wild-type enzymes display only limited extension across [6-4] PPs, removal of their exonuclease function dramatically enhances bypass, yielding an efficiency of replication across the [6-4] PP that closely resembles that observed on an undamaged template. This establishes AtPolI as the first known replicative DNA polymerase capable of efficiently bypassing a [6-4] PP. We further demonstrate that TLS across UV photoproducts relies on three unique amino acid insertions within the AtPolI polymerase domain, as deletion of any single insertion abolishes TLS. Notably, Mn{superscript 2} can restore TLS activity in these variants, but only for CPD lesions. Together, these findings identify AtPolIs as the first plant organellar replicases with intrinsic [6-4] PP bypass capability and define the structural features that enable this function. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/701875v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@f497bcorg.highwire.dtl.DTLVardef@15ba2eorg.highwire.dtl.DTLVardef@724e29org.highwire.dtl.DTLVardef@697c8b_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Pol γ possesses separate metal binding sites for polymerase and strand displacement functions

Accurate replication of mitochondrial genome (mtDNA) integrity, which is essential for cellular metabolism and energy supply, relies primarily on DNA polymerase gamma (Pol {gamma}), Twinkle helicase, and mitochondrial single-stranded DNA binding protein (mtSSB). Twinkle alone exhibits little helicase activity while reports indicate that Pol {gamma} displays from modest to limited unwinding activity. This led us to dissect Pol {gamma} strand displacement activity using structural, biochemical and in silico approaches. Here, we show that human Pol {gamma} carries out robust strand displacement synthesis at physiological concentrations of divalent metal ions which reveals that distinct metal-binding sites can independently regulate DNA synthesis and unwinding activities. We further showed that Pol {gamma} can displace RNA/DNA hybrid with comparable efficiency as DNA/DNA duplex, representing a key implication on RNA primer removal to preserve mtDNA integrity. Our cryo-electron microscopy structures of Pol {gamma} complexed with a template containing downstream dsDNA and an incoming nucleotide revealed the structural mechanism for the strand displacement activity. We identified four conformational states that represent successive stages of DNA unwinding, accompanied by coordinated rearrangement of the downstream DNA and Pol {gamma} elements that mediate strand displacement. This work establishes biochemical and structural mechanisms of Pol {gamma} strand displacement activity, providing fundamental insight into human mitochondrial DNA replication and integrity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/701366v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1be1dborg.highwire.dtl.DTLVardef@8912c5org.highwire.dtl.DTLVardef@12f5e75org.highwire.dtl.DTLVardef@e25d2a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Neonatal Enteric Infection Disrupts the Microbiota-Gut-Brain Axis Through Pattern Recognition Receptors and Altered Neuroimmune Signaling

Early-life enteric infection can have long-lasting effects on the microbiota-gut-brain (MGB) axis. Using a neonatal Enteropathogenic Escherichia coli (EPEC) model, we show that intestinal epithelial cell (IEC) NOD1 signaling coordinates mucosal immunity, barrier repair, and neuroimmune outcomes throughout early development and into adulthood. Neonates infected at postnatal day (P) 7 exhibited ileal inflammation, as demonstrated by increased expression of inflammatory cytokines (Il1{beta}, Il6, Il12, Il22), chemokines/chemokine receptors (Ccl2, Cxcl1, Ccr2), and barrier-repair genes (Muc2, Slc26a3), with increased monocyte/macrophage infiltration and reduced epithelial proliferation in WT mice that was blunted in Nod1{Delta}IEC mice. Neonatal infection of WT mice induced persistent defects into adulthood (P56), including increased intestinal permeability, sustained inflammatory/repair signatures, hippocampal inflammation, altered neurogenesis, and impaired recognition memory, which were largely absent in Nod1{Delta}IEC mice, establishing a crucial role for IEC NOD1 as a determinant of long-term MGB remodeling. Microbially derived ligands of NOD2, muropeptides, isolated from probiotic Lactobacillus species attenuated EPEC-induced mucosal inflammation and chemokine induction without altering bacterial burden, demonstrating NOD2 host-directed immunomodulation. Together, these findings identify an important role for NOD-dependent signaling axis in the gastrointestinal tract that links early-life infection to enduring gut-brain dysfunction and reveals probiotic-derived muropeptides as candidate microbial therapeutics.

physiology↗