Biology subjects

Narula, N.

Publications and source records attributed to Narula, N..

7 recordsLinked to original sources

bioRxiv2026

Gut inflammation promotes adverse food reactions by disrupting the microbial metabolism of food triggers

Background & AimsFood-related adverse reactions are frequently reported by patients with inflammatory bowel disease (IBD), but the underlying mechanisms are poorly understood. We investigated how intestinal inflammation and the microbiota contribute to the development of adverse food reactions. MethodsWe sensitized mice to different foods (dairy and gluten) after intestinal inflammation (chemically- and hapten-induced models), and then re-exposure to the sensitized foods through diet enrichment. To study whether inflamed microbiota facilitates adverse food reactions, we employed gnotobiotic models and bacterial supplementation experiments. We assessed markers of intestinal inflammation and sensitization, clinical responses, RNA transcripts, and microbiota composition and function. In a translational approach, we recruited IBD patients in remission and healthy controls, recorded self-reported food intolerances and clinical responses to triggering foods, and feces for gut microbiota analyses were collected. ResultsIntestinal inflammation facilitates food sensitization by disrupting microbial antigen metabolism, recruiting mast cells to the colon, and promoting mucosal IgE production. In gnotobiotic models, inflammation-driven depletion of colonic bacteria involved in food digestion contributed to food sensitization. Upon re-exposure to triggering foods, sensitized mice experienced visceral pain and low-grade inflammation through mast-cell mediated mechanisms, which also worsened experimental colitis. Supplementation with depleted bacteria or treatment with mast cell stabilizers attenuated food-driven responses. In IBD patients, self-reported food intolerances were common and associated with microbial disruption and depletion of food-metabolizing bacteria. ConclusionMicrobial metabolism of foods is disrupted after intestinal inflammation. This facilitates food sensitization, through colonic mast cell-mediated immune responses, which may explain the high number of adverse food reactions reported by IBD patients. WHAT YOU NEED TO KNOWO_ST_ABSBackground and contextC_ST_ABSPatients with inflammatory bowel disease (IBD) frequently report adverse food reactions, but the underlying mechanisms are not well understood. New findingsIntestinal inflammation promotes food sensitization by depleting bacteria that degrade food triggers. IBD patients in remission with food intolerances show reduced microbial diversity and loss of bacteria involved in digesting food triggers. LimitationsWe used chemically- and hapten-induced mouse models in this study due to the importance of monitoring inflammation onset. Food-driven immune reactions in the mucosa of IBD patients were not performed. Clinical research relevanceImpaired microbial food metabolism is linked to adverse food reactions in IBD. Microbiome-based therapies, such as probiotics capable of degrading dairy or gluten, should be considered for IBD patients with food intolerances. Basic research relevanceWe identified a novel mechanism in which microbial disruption caused by intestinal inflammation leads to adverse food reactions and worsened colitis in preclinical models. Restoring the microbial capacity to digest trigger foods reverses these effects. Lay AbstractIntestinal inflammation facilitates sensitization to gluten and dairy proteins by depleting microbes that digest them, contributing to the increase in adverse food reactions among IBD patients.

microbiology↗

bioRxiv2025

Uncovering genetic architecture of the heart via genetic association studies of unsupervised deep learning derived endophenotypes

Recent genome-wide association studies (GWAS) have effectively linked genetic variants to quantitative traits derived from time-series cardiac magnetic resonance imaging, revealing insights into cardiac morphology and function. Deep learning approach generally requires extensive supervised training on manually annotated data. In this study, we developed a novel framework using a 3D U-architecture autoencoder (cineMAE) to learn deep image phenotypes from cardiac magnetic resonance (CMR) imaging for genetic discovery, focusing on long-axis two-chamber and four-chamber views. We trained a masked autoencoder to develop Unsupervised Derived Image Phenotypes for heart (Heart-UDIPs). These representations were found to be informative to indicate various heart-specific phenotypes (e.g., left ventricular hypertrophy) and diseases (e.g., hypertrophic cardiomyopathy). GWAS on Heart UDIP identified 323 lead SNP and 628 SNP-prioritized genes, which exceeded previous methods. The genes identified by method described herein, exhibited significant associations with cardiac function and showed substantial enrichment in pathways related to cardiac disorders. These results underscore the utility of our Heart-UDIP approach in enhancing the discovery potential for genetic associations, without the need for clinically defined phenotypes or manual annotations.

bioinformatics↗

bioRxiv2023

SARS-CoV-2 infection triggers pro-atherogenic inflammatory 1 responses in human coronary vessels

COVID-19 patients present higher risk for myocardial infarction (MI), acute coronary syndrome, and stroke for up to 1 year after SARS-CoV-2 infection. While the systemic inflammatory response to SARS-CoV-2 infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques to locally promote inflammation remains unknown. Here, we report that SARS-CoV-2 viral RNA (vRNA) is detectable and replicates in coronary atherosclerotic lesions taken at autopsy from patients with severe COVID-19. SARS-CoV-2 localizes to plaque macrophages and shows a stronger tropism for arterial lesions compared to corresponding perivascular fat, correlating with the degree of macrophage infiltration. In vitro infection of human primary macrophages highlights that SARS-CoV-2 entry is increased in cholesterol-loaded macrophages (foam cells) and is dependent, in part, on neuropilin-1 (NRP-1). Furthermore, although viral replication is abortive, SARS-CoV-2 induces a robust inflammatory response that includes interleukins IL-6 and IL-1{beta}, key cytokines known to trigger ischemic cardiovascular events. SARS-CoV-2 infection of human atherosclerotic vascular explants recapitulates the immune response seen in cultured macrophages, including pro-atherogenic cytokine secretion. Collectively, our data establish that SARS-CoV-2 infects macrophages in coronary atherosclerotic lesions, resulting in plaque inflammation that may promote acute CV complications and long-term risk for CV events.

immunology↗

bioRxiv2023

Integrative Multi-omic Profiling of Two Human Decedents Receiving Pig Heart Xenografts Reveals Strong Perturbations in Early Immune-Cell and Cellular Metabolism Responses.

BackgroundRecent advances in xenotransplantation in living and decedent humans using pig xenografts have laid promising groundwork towards future emergency use and first in human trials. Major obstacles remain though, including a lack of knowledge of the genetic incompatibilities between pig donors and human recipients which may led to harmful immune responses against the xenograft or dysregulation of normal physiology. In 2022 two pig heart xenografts were transplanted into two brain-dead human decedents with a minimized immunosuppression regime, primarily to evaluate onset of hyper-acute antibody mediated rejection and sustained xenograft function over 3 days. MethodsWe performed multi-omic profiling to assess the dynamic interactions between the pig and human genomes in the first two pig heart-xenografts transplants into human decedents. To assess global and specific biological changes that may correlate with immune-related outcomes and xenograft function, we generated transcriptomic, lipidomic, proteomic and metabolomics datasets, across blood and tissue samples collected every 6 hours over the 3-day procedures. ResultsSingle-cell datasets in the 3-day pig xenograft-decedent models show dynamic immune activation processes. We observe specific scRNA-seq, snRNA-seq and geospatial transcriptomic changes of early immune-activation leading to pronounced downstream T-cell activity and hallmarks of early antibody mediated rejection (AbMR) and/or ischemia reperfusion injury (IRI) in the first xenograft recipient. Using longitudinal multiomic integrative analyses from blood in addition to antigen presentation pathway enrichment, we also observe in the first xeno-heart recipient significant cellular metabolism and liver damage pathway changes that correlate with profound physiological dysfunction whereas, these signals are not present in the other xenograft recipient. ConclusionsSingle-cell and multiomics approaches reveal fundamental insights into early molecular immune responses indicative of IRI and/or early AbMR in the first human decedent, which was not evident in the conventional histological evaluations.

systems biology↗

bioRxiv2022

Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma

Early-stage lung adenocarcinoma is typically treated by surgical resection of the tumor. While in the majority of cases surgery can lead to cure, approximately 30% of patients progress. Despite intense efforts to map the genetic landscape of early-stage lung tumors, there has been limited success in discovering accurate biomarkers that can predict clinical outcomes. Meanwhile, the role of the tumor-adjacent tissue in cancer progression has been largely ignored. To test whether tumor-adjacent tissue can be informative of progression-free survival and to probe the underlying molecular pathways involved, we designed a multi-omic study in both tumor and matched tumor-adjacent histologically normal lung tissue from the same patient. Our study includes 143 treatment naive stage I cases with long-term patient follow-up and is, to our knowledge, the largest such study with the longest follow-up. We performed a comprehensive histologic characterization of all tumors, mapped the mutational landscape and probed the transcriptome of both tumor and adjacent normal tissue. We evaluated the predictive power of each data modality and showed that the transcriptome of tumor-adjacent histologically normal lung tissue is the only reliable predictor of clinical outcome. Unbiased discovery of co-expressed gene modules revealed that inflammatory pathways are upregulated in the tumor-adjacent tissue of patients at high risk for disease progression. Furthermore, single-cell transcriptome analysis in the tumor-adjacent lung demonstrated that progression-associated inflammatory signatures were broadly expressed by both immune and non-immune cells including mesothelial cells, alveolar type 2 cells and fibroblasts, CD1 dendritic cells and MAST cells. Collectively, our studies suggest that molecular profiling of tumor-adjacent tissue can identify patients that are at high risk for disease progression.

bioinformatics↗

bioRxiv2022

Type I interferon and MAVS signaling restricts chikungunya virus heart infection and cardiac tissue damage

Chikungunya virus (CHIKV) infection has been associated with severe cardiac manifestations, yet, how CHIKV infection leads to heart disease remains unknown. Here, we leveraged both mouse models and human primary cells to define the mechanisms of CHIKV heart infection. We found that CHIKV actively replicates in cardiac fibroblasts and is cleared without significant tissue damage through the induction of a local type-I interferon response from both infected and non-infected cardiac cells. Importantly, signaling through the mitochondrial antiviral-signaling protein (MAVS) is required for viral clearance from the heart. In the absence of MAVS, persistent infection leads to focal myocarditis and major vessel vasculitis persisting for up to 60 days post-infection, suggesting CHIKV can lead to vascular inflammation and potential long-lasting cardiovascular complications. This study provides a model of CHIKV cardiac infection and mechanistic insight into CHIKV-induced heart disease, underscoring the importance of monitoring cardiac function in patients with CHIKV infections.

microbiology↗

bioRxiv2018

Evolution of the latitudinal diversity gradient in the hyperdiverse ant genus Pheidole

AimThe latitudinal diversity gradient is the dominant pattern of life on Earth, but a consensus understanding of its origins has remained elusive. The analysis of recently diverged, hyper-rich invertebrate groups provides an opportunity to investigate latitudinal patterns with the statistical power of large trees while minimizing potentially confounding variation in ecology and history. Here, we synthesize global phylogenetic and macroecological data on a hyperdiverse (>1100 species) ant radiation, Pheidole, and evaluate the roles of three general explanations for the latitudinal gradient: variation in diversification rate, tropical conservatism, and ecological regulation.\n\nLocationGlobal.\n\nTime PeriodThe past 35 million years.\n\nMajor taxa studiedThe hyperdiverse ant genus Pheidole Westwood.\n\nMethodsWe assembled geographic data for 1499 species and morphospecies, and inferred a dated phylogeny of Pheidole of 449 species, including 150 species newly sequenced for this study. We tested correlations between diversification rate and latitude with BAMM, HiSSE, GeoSSE, and FiSSE, and examined patterns of diversification as Pheidole spread around the globe.\n\nResultsWe found that Pheidole diversification occurred in series of bursts when new continents were colonized, followed by a slowdown in each region. There was no evidence of systematic variation of net diversification rates with latitude across any of the methods. Additionally, we found latitudinal affinity is moderately conserved with a Neotropical ancestor and phylogenetic inertia alone is sufficient to produce the gradient pattern.\n\nMain ConclusionsOverall our results are consistent with tropical conservatism explaining the diversity gradient, while providing no evidence that diversification rate varies systematically with latitude. There is evidence of ecological regulation on continental scales through the pattern of diversification after colonization. These results shed light on the mechanisms underlying the diversity gradient, while contributing toward a much-needed invertebrate perspective on global biodiversity dynamics.

evolutionary biology↗