Biology subjects

Popovich, P. G.

Publications and source records attributed to Popovich, P. G..

9 recordsLinked to original sources

bioRxiv2026

Oral Bacterial Translocation Promotes Lung Dysbiosis and Infection Risk after Spinal Cord Injury

Spinal cord injury (SCI) causes systemic pathophysiology that extends beyond the injured spinal cord. Respiratory infections remain a leading cause of death after SCI and can impair neurological recovery, yet the microbial source of these infections remains poorly defined. This study defined the onset and origin of pulmonary dysbiosis after SCI by testing whether commensal bacteria move to the lung from the gut or oral cavity. In a murine model, bacterial culture, 16S rRNA sequencing and source-tracking analyses showed that SCI rapidly increased lung bacterial burden and shifted the pulmonary microbiome toward an oral-like community. Gut-associated bacteria did not measurably reach the lung through lymphatic or vascular routes. Systemic antibiotics commonly used to treat infection failed to reliably reduce post-SCI lung bacterial burden. In contrast, oral and lung-directed antibiotic delivery reduced bacteria linked to post-injury dysbiosis more effectively. These findings identify the oral cavity as a proximal source of lung dysbiosis after SCI, and support route-specific strategies to prevent respiratory infection after SCI.

neuroscience↗

bioRxiv2025

Transcriptional and epigenetic repression of hematopoietic stem cells underlies bone marrow failure after spinal cord injury

Spinal cord injury (SCI) triggers systemic pathology beyond the nervous system, including bone marrow failure that can worsen infection risk, anemia, and motor recovery. Here we identify a neuroendocrine mechanism that rapidly imprints long-lasting dysfunction in hematopoietic stem cells (HSCs), which sustain lifelong production of immune cells, red blood cells, and platelets. Rather than mounting a canonical stress-hematopoietic response, SCI HSCs enter a broadly repressed state marked by chromatin closure and suppression of programs required for cell-cycle entry, genome maintenance, and redox defense. This maladaptive state leads to persistent DNA damage, impaired oxidative stress resolution, pancytopenia, and loss of long-term HSC regenerative capacity. Mechanistically, SCI-induced glucocorticoid surges drive glucocorticoid receptor-dependent repression of DNA repair genes, including Lig1 and Fen1. Acute glucocorticoid receptor blockade after SCI restores durable hematopoiesis, revealing an early therapeutic window to preserve hematopoietic integrity after neurotrauma. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/680535v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1627bb3org.highwire.dtl.DTLVardef@a73e19org.highwire.dtl.DTLVardef@1ddf85dorg.highwire.dtl.DTLVardef@1dcd8fe_HPS_FORMAT_FIGEXP M_FIG C_FIG Key FindingsO_LIAcute SCI prevents induction of normal stress-induced repair programs in HSCs. C_LIO_LISCI HSPCs exhibit increased chromatin compaction. C_LIO_LISCI compromises HSC genome-maintenance and redox capabilities. C_LIO_LISCI HSCs have defects in normal cell cycle regulation, are hypersensitive to genotoxic stress, and are deficient in long-term reconstitution. C_LIO_LIEarly glucocorticoid receptor (GR) blockade restores long-term hematopoiesis, supporting a GR-dependent but reversible repression mechanism. C_LI

cell biology↗

bioRxiv2025

Precision Prediction of Microbial Ecosystem Impact on Host Metabolism Using Genome-Resolved Metagenomics

Microorganisms often drive ecosystem function, yet precision disturbance response and ecosystem impact predictions remain challenging due to poorly captured ecological and metabolic interconnectedness and functional redundancy. For example, while mammalian gut dysbiosis is recognized to influence host metabolism, key microbiota and mechanisms governing their effects remain poorly understood. Here we developed a genome-resolved eco-systems biology workflow to predict how gut microbial metabolism affects mammalian health, and we applied it to a spinal cord-gut axis dataset. By scaling and integrating temporally resolved network analytics and consensus statistical approaches, we identified largely previously uncharacterized microbial species that best predict host physiology following neurological impairment. In silico validation through "complete" pathway-centric and comparative genomic analyses revealed that among these species, the major encoded microbial metabolic changes were in pathways directly linked to host nitrogen balance, and they varied by host sex and microbial ecotype/species. Moreover, we identified the exact bacterial species (and their draft genome sequences) driving urease-dependent versus amino acid-dependent nitrogen gut metabolism - findings that explain previously mechanistically-ambiguous, but clinically relevant, ammonia-driven host nitrogen imbalance. More broadly, these ecology- and community-aware approaches provide a framework to study dynamic, interconnected microbiomes that advances from enrichment-based single-taxon and single-gene correlations towards building microbe(s)-driven mechanistic insights that integrate community context and whole pathways.

microbiology↗

bioRxiv2025

The Spinal Cord-Gut Axis Regulates Gut Microbial Homeostasis: Insights from a New Murine Metagenomic Catalog

The spinal cord, a nexus for brain-body crosstalk, controls gut physiology and microbial homeostasis, but the underlying mechanisms remain unclear. Using genome-resolved longitudinal metagenomics in male and female C57BL/6 mice before and up to 6 months after disrupting the spinal cord-gut axis, we reconstructed over 6,500 microbial draft genomes. This "Mouse B6 Gut Catalog" improved or doubled species- and strain-level representation in other published catalogs. Impaired spinal cord-gut crosstalk induced persistent, sex-, time- and lesion-specific alterations in community composition, marked by a consistent loss of Lactobacillus johnsonii. Feeding this key bacterium to mice with a clinically relevant spinal cord injury improved host health. Genome-resolved, community-contextualized metabolic profiling revealed that shifts in carbohydrate- mediated microbe-microbe interactions explain the reduction of L. johnsonii. These findings identify carbohydrate metabolism as a keystone mechanism shaping gut microbiota and emphasize that mammalian health and gut ecosystem function depend on a functional spinal cord-gut axis. Additionally, these data improve murine microbiome catalogs and demonstrate that metagenome-informed microbial interventions can improve host health and likely mitigate long-term dysbiosis.

microbiology↗

bioRxiv2025

Regulation of hematopoietic stem cell (HSC) proliferation by Epithelial Growth Factor Like-7 (EGFL7)

Understanding the pathways regulating normal and malignant hematopoietic stem cell (HSC) biology is important for improving outcomes for patients with hematologic disorders. Epithelial Growth Factor Like-7 (EGFL7) is [~]30 kDa secreted protein that is highly expressed in adult HSCs. Using Egfl7 genetic knock-out (Egfl7 KO) mice and recombinant EGFL7 (rEGFL7) protein, we examined the role of Egfl7 in regulating normal hematopoiesis. We found that Egfl7 KO mice had decreases in overall BM cellularity resulting in significant reduction in the number of hematopoietic stem and progenitor cells (HSPCs), which was due to dysregulation of normal cell-cycle progression along with a corresponding increase in quiescence. rEGFL7 treatment rescued our observed hematopoietic defects of Egfl7 KO mice and enhanced HSC expansion after genotoxic stress such as 5-FU and irradiation. Furthermore, treatment of WT mice with recombinant EGFL7 (rEGFL7) protein expands functional HSCs evidenced by an increase in transplantation potential. Overall, our data demonstrates a role for EGFL7 in HSC expansion and survival and represents a potential strategy for improving transplant engraftment or recovering bone marrow function after stress.

cell biology↗

bioRxiv2023

Targeting the Microbiome to Improve Gut Health and Breathing Function After Spinal Cord Injury

Spinal cord injury (SCI) is a devastating condition characterized by impaired motor and sensory function, as well as internal organ pathology and dysfunction. This internal organ dysfunction, particularly gastrointestinal (GI) complications, and neurogenic bowel, can reduce the quality of life of individuals with an SCI and potentially hinder their recovery. The gut microbiome impacts various central nervous system functions and has been linked to a number of health and disease states. An imbalance of the gut microbiome, i.e., gut dysbiosis, contributes to neurological disease and may influence recovery and repair processes after SCI. Here we examine the impact of high cervical SCI on the gut microbiome and find that transient gut dysbiosis with persistent gut pathology develops after SCI. Importantly, probiotic treatment improves gut health and respiratory motor function measured through whole-body plethysmography. Concurrent with these improvements was a systemic decrease in the cytokine tumor necrosis factor-alpha and an increase in neurite sprouting and regenerative potential of neurons. Collectively, these data reveal the gut microbiome as an important therapeutic target to improve visceral organ health and respiratory motor recovery after SCI. Research HighlightsO_LICervical spinal cord injury (SCI) causes transient gut dysbiosis and persistent gastrointestinal (GI) pathology. C_LIO_LITreatment with probiotics after SCI leads to a healthier GI tract and improved respiratory motor recovery. C_LIO_LIProbiotic treatment decreases systemic tumor necrosis factor-alpha and increases the potential for sprouting and regeneration of neurons after SCI. C_LIO_LIThe gut microbiome is a valid target to improve motor function and secondary visceral health after SCI. C_LI

neuroscience↗

bioRxiv2020

Liver inflammation before spinal cord injury worsens neuropathology, hepatic injury, metabolic syndrome and locomotor deficits

Liver inflammation can enhance acute leukocyte recruitment to sites of central nervous system (CNS) injury. The consequences of hepatic inflammation on recovery after injury, however, are unknown. Here, we hypothesize that liver inflammation at the time of spinal cord injury (SCI) will exacerbate spinal cord pathology and impair recovery. Rats receiving SCI with concomitant liver inflammation had worse intraspinal pathology and greater locomotor deficits than rats with baseline liver inflammation. Hepatic inflammation also potentiated SCI-induced non-alcoholic steatohepatitis (NASH), endotoxemia, insulin resistance and adiposity. Circulating and cerebrospinal levels of Fetuin-A were higher in SCI rats with liver inflammation. When microinjected into intact spinal cords, Fetuin-A caused robust macrophage activation, iron accumulation and neuron loss. These studies verify that outcomes from CNS injury are worse if the liver is concomitantly inflamed and implicate Fetuin-A as a potential neuropathological mediator. These novel data suggest hepatic inflammation is a potential clinical target for improving recovery from SCI.

neuroscience↗

bioRxiv2019

Human immune cells infiltrate the lesioned spinal cord and impair recovery after spinal cord injury in humanized mice

Summary PointsO_LIImmune compromised mice require ~4 months of engraftment with human umbilical cord blood CD34+ stem cells to develop a full and functional human immune system\nC_LIO_LIThe human neuroinflammatory response elicited after spinal cord injury in humanized mice is limited at 2 months post-engraftment but matures by 4 months\nC_LIO_LIIntraspinal neuroinflammation consists of a florid human T cell and macrophage response, and human T cells co-localize with human macrophages\nC_LIO_LIA human intraspinal neuroinflammatory response exacerbates lesion pathology and impairs functional recovery\nC_LI\n\nAbstractHumanized mice are a useful tool to help better understand how the human immune system responds to central nervous system (CNS) injury. However, the optimal parameters for using humanized mice in preclinical CNS injury models have not been established. Here, we show that it takes 3-4 months after engraftment of neonatal immune compromised mice with human umbilical cord stem cells to generate a robust human immune system. Indeed, sub-optimal human immune cell responses occurred when humanized mice received spinal contusion injuries at 2 months vs. 4 months post-engraftment. Human T cells directly contact human macrophages within the spinal cord lesion of these mice and the development of a mature human immune system was associated with worse lesion pathology and neurological recovery. Together, data in this report establish an optimal experimental framework for using humanized mice to help translate promising preclinical therapies for CNS injury.

neuroscience↗

bioRxiv2018

Microglia limit lesion expansion and promote functional recovery after spinal cord injury in mice

Traumatic spinal cord injury (SCI) elicits a robust intraspinal inflammatory reaction that is dominated by at least two major subpopulations of macrophages, i.e., those derived from resident microglia and another from monocytes that infiltrate the injury site from the circulation. Previously, we implicated monocyte-derived macrophages (MDMs) as effectors of acute post-injury pathology after SCI; however, it is still unclear whether microglia also contribute to lesion pathology. Assigning distinct functional roles to microglia and MDMs in vivo has been difficult because these CNS macrophage subsets are morphologically and phenotypically similar. Here, to characterize the role that microglia play in experimental models of thoracic spinal contusion or lumbar crush injury, mice were fed vehicle chow or chow laced with a CSF1R receptor antagonist, PLX5622. Feeding PLX5622 depletes microglia. In both groups, spontaneous recovery of hindlimb motor function was evaluated for up to 8 weeks post-SCI using open-field and horizontal ladder tests. Histopathological assessment of intraspinal pathology was assessed in 8 week post-injury tissues. In both SCI models, microglia depletion exacerbated lesion pathology and impaired spontaneous recovery of hind limb function. Notably, the loss of microglia prevented astroglial encapsulation of the lesion core, which was associated with larger lesions, enhanced demyelination and neuron loss and a larger inflammatory response that was dominated by monocyte-derived macrophages. The neuroprotective and healing properties of microglia become obvious in the subacute phases of recovery; microglia depletion up to 7 days post-injury (dpi) had no apparent effect on recovery while delayed depletion from 8-28dpi exacerbated lesion pathology and significantly impaired functional recovery. These data suggest that microglia have essential tissue repair functions after SCI. Selective enhancement of microglial activities may be a novel strategy to preserve tissue and promote recovery of function after neurotrauma.

neuroscience↗