Biology subjects

Lim, J. J.

Publications and source records attributed to Lim, J. J..

11 recordsLinked to original sources

bioRxiv2026

Triple-Omics Analysis Unveiled the Neuroprotective Mechanisms of Akkermansia muciniphila in an Environmental Exposure-Linked Mouse Model of Alzheimer's Disease

Cadmium (Cd) is an emerging environmental risk factor for cognitive decline and Alzheimer's disease, and few interventions limit its effects on the brain. Akkermansia muciniphila, a human gut commensal, is neuroprotective through mechanisms that remain unclear. Building on our finding that A. muciniphila prevented Cd-induced memory deficits without reducing brain Cd burden (Wang et al., 2026a), we tested whether it reprograms Cd-disrupted hippocampal RNA regulation. Male C57BL/6J mice received A. muciniphila (1x10^9 CFU, oral gavage, 5 days/week) before and throughout 9 weeks of 3 mg/L CdCl2 exposure; hippocampi were analyzed by RNA-seq, m6A epitranscriptomic profiling, and rMATS-based alternative-splicing analysis. Cd disrupted hippocampal neuropeptide signaling, neuronal excitability, and synaptic plasticity. Co-exposure with A. muciniphila reversed signatures enriched for Nrf2-centered cytoprotective signaling and opposed m6A and splicing changes across more than a thousand genes, largely without changes in total mRNA abundance. Restored events converged on machinery governing local translation, calcium-dependent plasticity, and synaptic transmission. Projected onto predicted protein structures, most introduced a premature termination codon predicted to trigger nonsense-mediated decay or edited short loop and linker segments rather than rebuilding folded domains, regulation largely invisible to gene-level expression analysis. Among these, paired events amplifying semaphorin-plexin signaling, an axis linked to oligodendrocyte injury and memory consolidation, were reversed. These findings identify restoration of hippocampal transcript fate and splice-isoform selection as a mechanism potentially underlying A. muciniphila-mediated protection against Cd neurotoxicity, and establish post-transcriptional RNA regulation as a gut-brain target for mitigating environmentally driven neurotoxicity.

pharmacology and toxicology↗

bioRxiv2026

Akkermansia muciniphila prevents cadmium-induced cognitive impairment through gut microbiome mediated mechanisms

Akkermansia muciniphila has emerged as a promising next-generation probiotic with beneficial effects on learning and memory, but whether and how it can protect against environmental toxicant-induced cognitive impairment remains unknown. Cadmium (Cd) is a widespread environmental neurotoxicant that disrupts the gut-brain axis and impairs hippocampus-dependent learning and memory, yet effective preventive interventions are lacking. In this study, we discovered that oral supplementation with human fecal microbiome-derived A. muciniphila prevented Cd-induced cognitive impairment in mice throughout 9 weeks of oral Cd exposure at a human body burden-relevant concentration. Notably, brain Cd concentrations were not affected by A. muciniphila supplementation, indicating that cognitive protection was mediated through gut-brain signaling rather than affecting metal accumulation in the brain. Multi-omics characterization identified coordinated gut-brain pathways underlying this protective effect. A. muciniphila preserved Cd-suppressed Lactobacillus taxa (L. crispatus, L. intestinalis, L. taiwanensis), which positively correlated with cognitive performance, and restored intestinal tight-junction integrity across multiple intestinal sections, particularly the ileum. A. muciniphila also normalized Cd-induced cytokine dysregulation in the serum. In addition, colonic branched-chain fatty acids (BCFAs) emerged as candidate gut-brain mediators, with 2-methylpentanoic acid showing a robust negative correlation with cognitive performance. These A. muciniphila-mediated changes across gut microbiome, intestinal barrier, systemic cytokines, and microbial metabolites coincided with reversal of Cd-induced hippocampal transcriptional alterations regulating synaptic and vascular signaling. Together, this study identified A. muciniphila as a preventive microbiome-based strategy against environmental Cd neurotoxicity in mice, demonstrated that the gut microbial homeostasis can confer cognitive resilience independently of brain toxicant burden, and revealed distinct BCFAs as potential gut-brain mediators of heavy-metal-induced cognitive decline.

pharmacology and toxicology↗

bioRxiv2026

Unconventional presentation of an immunodominant HLA-DR15-restricted nephritogenic proteinase 3 epitope implicated in vasculitis

Proteinase 3 (PR3) anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is associated with HLA-DR15, implicating HLA-DR15-restricted CD4 T cell autoimmunity in the disease. However, the PR3 epitopes presented by HLA-DR15 and the autoreactive CD4 T cell responses they elicit are undefined. Using humanized hPR3.DR15+ mice, we identified PR3216-231 as an immunodominant human PR3-derived CD4 T cell epitope presented by HLA-DR15. Immunopeptidomic profiling confirmed the natural processing and HLA-DR15-restricted presentation of PR3216-231. Structural analyses of HLA-DR15-PR3216-231 complexes revealed an unconventional mode of HLA class II antigen presentation, in which a 10 amino acid peptide core occupies the 9 amino acid binding groove, causing a central kink in the bound peptide. PR3216-231-specific CD4 T cells from both hPR3.DR15+ mice and patients with PR3-ANCA-associated vasculitis exhibited convergent T cell receptor features, and patients with active vasculitis displayed a clonally expanded, PR3216-231-specific CD4 TCR repertoire. Immunization of hPR3.DR15 mice with PR3216-231 induced cell-mediated glomerulonephritis characterized by increased renal infiltration of CD4 T cells and macrophages together with segmental glomerular necrosis. These findings identify a nephritogenic PR3-derived CD4 T cell epitope presented by HLA-DR15 in ANCA-associated vasculitis and define a new extended core binding pattern, broadening our understanding of HLA class II peptide presentation.

immunology↗

bioRxiv2025

Single-cell transcriptomics showed that maternal PCB exposure dysregulated ER stress-mediated cell type-specific responses in the liver of female offspring

Polychlorinated biphenyls (PCBs) are persistent environmental toxicants that bioaccumulate in the food chain and readily cross the placenta, raising concerns for developmental toxicity. While PCB exposure has been associated with metabolic and neurodevelopmental disorders, its cell type-specific effects on liver development remain poorly understood. This study aimed to investigate how maternal exposure to an environmentally relevant Fox River PCB mixture affects liver development in female offspring at single-cell resolution. We hypothesized that early-life PCB exposure disrupts hepatic metabolic and immune function in a cell type-specific manner. Using single-cell RNA sequencing (scRNA-seq) on liver tissue from postnatal day 28 female mice perinatally exposed to PCBs, we identified major hepatic and immune cell populations and assessed cell-specific transcriptional responses. PCB exposure significantly altered the proportions of endothelial cells and Kupffer cells and reduced neutrophil abundance. Transcriptomic analysis revealed that PCBs dysregulated key pathways in hepatocytes and non-parenchymal cells, including ER stress responses, drug metabolism, and glucose/insulin signaling. Notably, hepatocytes exhibited upregulation of phase-I drug-metabolizing enzymes and uptake transporters, but downregulation of phase-II enzymes and efflux transporters. Kupffer cells and endothelial cells had altered immune and metabolic gene expression, and intercellular communication analysis predicted disrupted fibronectin, collagen, and chemokine signaling due to PCB exposure. RT-qPCR validation confirmed increased hepatic ER stress marker expression. Together these findings demonstrate that perinatal PCB exposure induces persistent, cell type-specific transcriptomic reprogramming in the liver, impairing metabolic and immune functions. This study highlights the utility of single-cell transcriptomics for revealing toxicant effects with cellular precision during critical windows of development.

systems biology↗

bioRxiv2025

Cadmium-induced gut dysbiosis precedes the onset of hippocampus-dependent learning and memory deficits in mice

BackgroundCadmium (Cd) is a heavy metal recognized as a neurotoxicant. However, the mechanisms underlying its neurotoxicity remain poorly understood. The gut-brain axis, a bidirectional communication pathway between the central nervous system and the gut microbiome, has been linked to various neurological disorders. Because the gut microbiome is a known target of Cd, it is important to investigate whether the gut-brain axis mechanistically contributes to the Cd-induced neurotoxicity. ObjectiveIn our initial exploration of the role of the gut-brain axis in modulating Cd neurotoxicity on cognition, we investigated whether Cd exposure induces gut dysbiosis before the onset of cognitive deficits and explored the potential link between gut microbiome alterations and Cd-induced cognitive deficits. MethodsAdult male mice were exposed to 3 mg/L Cd via drinking water for nine weeks. Behavioral assessments were conducted throughout the exposure period to evaluate cognitive function. Fresh fecal pellets were collected weekly to monitor changes in the gut microbiome composition. The effects of Cd on the hippocampus and intestine were analyzed using transcriptomics and mass spectrometry (MS)-based metabolomics. ResultsCd exposure resulted in hippocampus-dependent learning and memory deficits, first observed at four weeks into exposure. RNA sequencing of the hippocampus at the terminal time point revealed reduced expression of genes involved in cognition and neuroinflammation in Cd exposed mice. Metagenomic shotgun sequencing showed that Cd-induced gut dysbiosis preceded the onset of cognitive impairments, with specific bacterial species associated with Cd-induced cognitive deficits. Furthermore, Cd exposure reduced the expression of genes involved in intestinal barrier integrity, increased inflammatory cytokines levels, and altered the levels of neuroactive microbial metabolites. ConclusionOur study is the first to show that Cd exposure triggers gut microbial shifts before the onset of cognitive deficits, accompanied by increased intestinal permeability and elevated proinflammatory biomarkers in both the intestine and brain at the terminal time point. These findings suggest a potential critical role of gut-brain axis in modulating Cd neurotoxicity and underscore the need for future research to elucidate the mechanistic involvement of gut microbiome as a potential target for mitigating Cd-induced cognitive decline.

systems biology↗

bioRxiv2024

Oral Exposure to Benzalkonium Chlorides in Male and Female Mice Reveals Sex-Dependent Alteration of the Gut Microbiome and Bile Acid Profile

Benzalkonium chlorides (BACs) are commonly used disinfectants in a variety of consumer and food-processing settings, and the COVID-19 pandemic has led to increased usage of BACs. The prevalence of BACs raises the concern that BAC exposure could disrupt the gastrointestinal microbiota, thus interfering with the beneficial functions of the microbes. We hypothesize that BAC exposure can alter the gut microbiome diversity and composition, which will disrupt bile acid homeostasis along the gut-liver axis. In this study, male and female mice were exposed orally to d7-C12- and d7-C16-BACs at 120 {micro}g/g/day for one week. UPLC-MS/MS analysis of liver, blood, and fecal samples of BAC-treated mice demonstrated the absorption and metabolism of BACs. Both parent BACs and their metabolites were detected in all exposed samples. Additionally, 16S rRNA sequencing was carried out on the bacterial DNA isolated from the cecum intestinal content. For female mice, and to a lesser extent in males, we found that treatment with either d7-C12- or d7-C16-BAC led to decreased alpha diversity and differential composition of gut bacteria with notably decreased actinobacteria phylum. Lastly, through a targeted bile acid quantitation analysis, we observed decreases in secondary bile acids in BAC-treated mice, which was more pronounced in the female mice. This finding is supported by decreases in bacteria known to metabolize primary bile acids into secondary bile acids, such as the families of Ruminococcaceae and Lachnospiraceae. Together, these data signify the potential impact of BACs on human health through disturbance of the gut microbiome and gut-liver interactions.

pharmacology and toxicology↗

bioRxiv2023

Genome-scale metabolic model predicts mechanistic differences in metabolic gradient of spatially resolved small intestine villi

Studying the spatial metabolic gradient provides significant opportunities for understanding the spatial division of labor within the tissue microenvironment. Enterocytes have the capacity to perform serial oxidation and conjugation reactions for detoxification, making the small intestine important as one of the first-pass metabolic organs. Recently, the enterocyte metabolic gradient was found to exhibit differential metabolic preferences depending on its location in the villus. However, it remains unclear how metabolism mechanistically differs in enterocyte microenvironments. To bridge this knowledge gap, we leveraged spatial transcriptomics data to (1) reconstruct genome-scale metabolic networks (GSMMs) that are location-specific, and (2) identify metabolic genes that may explain the differential susceptibility of different villus sections to diseases, diet, and other factors. We found that enterocytes at the bottom of the villus are enriched in genes related to intermediary metabolism, phase-I and -II metabolism, bile acid metabolism, and transporters. Comparing enterocyte GSMMs between the top and bottom of villi, we show that enterocytes at the top produce NAD and threonine more robustly compared to bottom enterocytes. Conversely, bottom enterocytes produce guanosine monophosphate (GMP) more readily than enterocytes at the top of the villus. These metabolic differences may have implications for differential villi susceptibility to diseases such as neuroendocrine tumors, acute graft-versus-host disease, and nutritional perturbations such as high-fat diets. Taken together, our findings demonstrate in a mechanistic manner the metabolic differences of enterocytes in the small intestine, providing information that can be applied to additional disease states and inform therapeutics development. AUTHOR SUMMARYSignificant metabolic gradients exist across different locations in a cell. Currently, bulk expression experiments, used in most animal studies and clinical trials, fail to describe this spatial variation due to the averaging effect in the tissue of interest. Recently, single-cell RNA sequencing technologies revealed heterogeneity within tissues. However, the underlying differences and mechanisms for the spatial metabolic variations remain understudied. In this research, we focus on the small intestine, which plays a critical role in nutrient absorption, distribution, and drug metabolism. The walls of the small intestine are composed of finger-like projections, called villi, that are composed of enterocytes. To investigate the potential mechanism underlying metabolic differences of enterocytes along the villi, we built and compared networks formed by gene-protein reaction relationships from spatially resolved bulk and scRNA-seq data. We found that enterocytes at the villus top more robustly produced key components in cell metabolism, such as nicotinamide adenine dinucleotide (nad) and threonine, whereas enterocytes at the villus bottom more robustly produced the nucleotide guanosine monophosphate (GMP). Our approach can be extended to the study of metabolic differences in other organs and diseases and to research the metabolism of specific compounds.

bioinformatics↗

bioRxiv2023

Single cell transcriptomics unveiled that early life BDE-99 exposure reprogrammed the gut-liver axis to promote a pro-inflammatory metabolic signature in male mice at late adulthood

Polybrominated diphenyl ethers (PBDEs) are a class of legacy flame retardants that bioaccumulate in the environment, raising global health concerns. The gut microbiome is an important regulator of liver including xenobiotic biotransformation, nutrient homeostasis, and immune regulation. Using bulk RNA-Seq, we recently showed that neonatal exposure to BDE-99, a human breast milk-enriched PBDE congener, up-regulated pro-inflammation- and down-regulated drug metabolism-related genes predominantly in males in young adulthood. However, it remains unknown whether such dysregulation persists into late adulthood, how various cell types in the liver contribute to the hepatotoxicity, and to what extent gut microbiome is involved in BDE-99 mediated developmental reprogramming of the liver. To address these knowledge gaps, male C57BL/6 mouse pups were orally exposed to corn oil (10 ml/kg) or BDE-99 (57 mg/kg) once daily from postnatal days 2-4. At 15 months of age, single cell transcriptomics (scRNA-seq) in liver showed that neonatal BDE-99 exposure down-regulated key xenobiotic- and fatty acid metabolizing enzymes and up-regulated genes involved in microbial influx in hepatocytes. Neonatal BDE-99 exposure also led to a persistent increase in the hepatic proportion of neutrophils, a predicted increase of macrophage migration inhibitory factor (MIF) signaling, which activates macrophage populations, as well as histopathological abnormalities of the liver in 15 months of age. The BDE-99 mediated hepatic reprogramming is associated with decreased intestinal tight junction protein (Tjp) transcripts, persistent dysbiosis of the gut microbiome, and dysregulation of inflammation-related fatty acid metabolites. ScRNA-seq in germ-free (GF) mice demonstrated the necessity of a normal gut microbiome in maintaining hepatic immunotolerance. Fecal microbiome transplant to GF mice using large intestinal microbiome from adults that were neonatally exposed to BDE-99 down-regulated Tjp transcripts and up-regulated several cytokines in the large intestine. In conclusion, neonatal BDE-99 exposure reprogrammed the cell type-specific gene expression and cell-cell communication networks in liver towards a pro-inflammation with compromised metabolic functions at late adulthood. Importantly, gut microbiome is necessary in promoting immunotolerance in the liver, and BDE-99-mediated pro-inflammatory signaling may be partly due to the dysregulated gut environment.

pharmacology and toxicology↗

bioRxiv2022

Growth phase estimation for abundant bacterial populations sampled longitudinally from human stool metagenomes.

Longitudinal sampling of the stool has yielded important insights into the ecological dynamics of the human gut microbiome. However, due to practical limitations, the most densely sampled time series from the human gut are collected at a frequency of about once per day, while the population doubling times for gut commensals are on the order of minutes-to-hours. Despite this, much of the prior work on human gut microbiome time series modeling has, implicitly or explicitly, assumed that day-to-day fluctuations in taxon abundances are related to population growth or death rates, which is likely not the case. Here, we propose an alternative model of the human gut as a flow-through ecosystem at a dynamical steady state, where population dynamics occur internally and the bacterial population sizes measured in a bolus of stool represent an endpoint of these internal dynamics. We formalize this idea as stochastic logistic growth of a population in a system held at a semi-constant flow rate. We show how this model provides a path toward estimating the growth phases of gut bacterial populations in situ. We validate our model predictions using an in vitro Escherichia coli growth experiment. Finally, we show how this method can be applied to densely-sampled human stool metagenomic time series data. Consistent with our model, stool donors with slower defecation rates tended to harbor a larger proportion of taxa in later growth phases, while faster defecation rates were associated with more taxa in earlier growth phases. We discuss how these growth phase estimates may be used to better inform metabolic modeling in flow-through ecosystems, like animal guts or industrial bioreactors.

ecology↗

bioRxiv2021

Arg-tRNA synthetase links inflammatory metabolism to RNA splicing via nuclear condensates

Cells respond to perturbations like inflammation by sensing changes in metabolite levels. Especially prominent is arginine, which has known connections to the inflammatory response. Here, we found that depletion of arginine during inflammation decreased levels of a nuclear form of arginyl-tRNA synthetase (ArgRS). Surprisingly, we found that nuclear ArgRS interacts with serine/arginine repetitive matrix protein 2 (SRRM2), a spliceosomal protein and nuclear speckle component and that arginine depletion impacted both condensate-like nuclear trafficking of SRRM2 and splice-site usage in certain genes. These splice-site usage changes cumulated in synthesis of different protein isoforms that altered cellular metabolism and peptide presentation to immune cells. Our findings uncover a novel mechanism whereby a tRNA synthetase cognate to a key amino acid that is metabolically controlled during inflammation modulates the splicing machinery.

molecular biology↗

bioRxiv2021

Bacteria.guru: comparative transcriptomics and co-expression database for bacterial pathogens

SummaryThe bacterial kingdom comprises unicellular prokaryotes able to establish symbioses from mutualism to parasitism. To combat bacterial pathogenicity, we need an enhanced understanding of gene function and regulation, which will mediate the development of novel antimicrobials. Gene expression can predict gene function, but there lacks a database enabling expansive inter- and intraspecific exploration of gene expression profiles and co-expression networks for bacteria. To address this, we integrated the genomic and transcriptomic data of the 17 most notorious and studied bacterial pathogens, creating bacteria.guru, an interactive database that can identify, visualize, and compare gene expression profiles, co-expression networks, functionally enriched clusters, and gene families across species. Through illustrating antibiotic resistance mechanisms in P. aeruginosa, we demonstrate that bacteria.guru could potentially aid the discovery of multi-faceted antibiotic targets. Hence, we believe bacteria.guru will facilitate future bacterial research. AvailabilityThe database and co-expression networks are freely available from https://bacteria.guru/. The sample annotations are found in the supplemental data.

bioinformatics↗