Biology subjects

Dumlao, D.

Publications and source records attributed to Dumlao, D..

6 recordsLinked to original sources

bioRxiv2026

Adipose-driven complement-lipid reprogramming controls nociceptive vulnerability in obesity-associated osteoarthritis

Obesity amplifies osteoarthritis (OA) pain disproportionately to joint damage, creating a major unmet clinical need for non-opioid interventions that act beyond the joint. Using OA as a translational model, we integrated serum multi-omics in obese mice with surgically induced OA and genetic and adipose-reconstitution models of complement factor D (FD). In humans, we analyzed longitudinal metabolomics data from the IDEA weight-loss trial and conducted functional studies in dorsal root ganglion (DRG) neurons. Adipose-derived FD emerged as a regulator of systemic immunometabolic state: FD deficiency in obese mice worsened pain sensitivity whereas restoring circulating FD normalized pain and inflammatory markers without altering joint structure. Cross-species lipid profiling identified conserved shifts in linoleic acid versus arachidonic acid-derived lipids that were associated with pain phenotypes in mice and with pain improvement in humans. Defined lipid cocktails modulated excitability and TRPV1 sensitivity in human DRG neurons, and transcriptomics of knee-innervating DRGs revealed diet and FD-dependent activation of complement and neuronal excitability pathways. Together, these findings define an adipose-complement-lipid axis that regulates nociceptive vulnerability independent of joint damage and identify extra-articular targets for translational, non-opioid OA pain therapies. One Sentence SummaryWe identify an adipose-complement-lipid axis that systemically regulates sensory neuron sensitization, providing a mechanistic basis for pain-structure discordance in obesity-associated osteoarthritis.

physiology↗

bioRxiv2025

Complement factor D (adipsin) mediates pressure-pain hypersensitivity post destabilization of medial meniscus injury

BACKGROUNDAlthough osteoarthritis (OA) is the leading cause of pain and disability worldwide, there is a lack of models to probe the separable mechanism of OA structural damage and knee pain. We previously identified that deletion of complement factor D (FD) results in increased pressure-pain hyperalgesia despite cartilage protection after destabilization of the medial meniscus (DMM) surgery. However, how these discordant OA phenotypes manifest is not understood. We employed a novel targeted lipidomics approach to elucidate the role of eicosanoids in FD-mediated pain. We hypothesize that the absence of Cfd (FD-/-) will protect cartilage but cause increased pressure-pain hyperalgesia and eicosanoid dysregulation that persists throughout OA development. METHODSMale and female FD-/- and wild-type (WT) mice were challenged with DMM or remained naive (n=5-11/group) at 16 weeks old. Pressure-pain hyperalgesia was measured bi-weekly for 8 weeks post-DMM. A second cohort was evaluated at 2 weeks post-DMM (n=6-10/group) to investigate DMM injury response. Structural damage was scored using the Modified Mankin system. To determine changes in eicosanoid profiles, serum and synovial fluid samples were analyzed via liquid chromatography-mass spectrometry (LC-MS). Statistical analysis was performed with unpaired t-test, two-way, or three-way ANOVA with Sidaks posthoc test. Statistical significance is defined as p<0.05. RESULTSIn contrast to WT mice, FD-/- showed no significant differences in Modified Mankin scores 8 weeks post-DMM. As expected, FD-/- hyperalgesia levels persisted until 8 weeks post DMM, similar to WT. Changes in eicosanoid profiles of pain-associated factors in FD-/-when compared to WT were found in the synovial fluid at 2 weeks and the serum at 8 weeks post-DMM. CONCLUSIONThe absence of Cfd drives knee hyperalgesia in male and female mice at 2 weeks-post DMM and persists through an 8-week observation period despite observing cartilage protection. Changes of eicosanoid profiles at both time points suggest that FD drives pain acutely, and the hyperalgesia phenotype emerges early in response to DMM injury, elucidating the role of the alternative complement in mediating OA pain and structural damage.

physiology↗

bioRxiv2024

Expansion of a bacterial operon during cancer treatment ameliorates drug toxicity

Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Herein, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal study of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. 16S rRNA gene sequencing revealed significant shifts in gut microbial community structure during oral fluoropyrimidine treatment across multiple patient cohorts, in mouse small and large intestinal contents, and in patient-derived ex vivo communities. Metagenomic sequencing revealed marked shifts in pyrimidine-related gene abundance during oral fluoropyrimidine treatment, including enrichment of the preTA operon, which is sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU). preTA+ bacteria depleted 5-FU in gut microbiota grown ex vivo and the mouse distal gut. Germ-free and antibiotic-treated mice experienced increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota, preTA+ E. coli, or preTA-high CRC patient stool. Finally, preTA abundance was negatively associated with fluoropyrimidine toxicity in patients. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach is generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease. One Sentence Summary: Gut microbial enzymes can be used to predict and prevent anticancer drug toxicity.

systems biology↗

bioRxiv2023

A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity

Diet can protect from autoimmune disease; however, whether diet acts via the host and/or microbiome remains unclear. Here, we use a ketogenic diet (KD) as a model to dissect these complex interactions. A KD rescued the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis in a microbiota-dependent fashion. Dietary supplementation with a single KD-dependent host metabolite ({beta}-hydroxybutyrate, {beta}HB) rescued EAE whereas transgenic mice unable to produce {beta}HB in the intestine developed more severe disease. Transplantation of the {beta}HB-shaped gut microbiota was protective. Lactobacillus sequence variants were associated with decreased T helper 17 (Th17) cell activation in vitro. Finally, we isolated a L. murinus strain that protected from EAE, which was phenocopied by the Lactobacillus metabolite indole lactic acid. Thus, diet alters the immunomodulatory potential of the gut microbiota by shifting host metabolism, emphasizing the utility of taking a more integrative approach to study diet-host-microbiome interactions.

microbiology↗

bioRxiv2019

Integrated Metabolomic and Transcriptomic Profiling Reveals Novel Activation-Induced Metabolic Networks in Human T cells

The targeting of metabolic pathways is emerging as an exciting new approach for modulating immune cell function and polarization states. In this study, carbon tracing and systems biology approaches integrating metabolomic and transcriptomic profiling data were used to identify adaptations in human T cell metabolism important for fueling pro-inflammatory T cell function. Results of this study demonstrate that T cell receptor (TCR) stimulation leads to a significant increase in glucose and amino acid metabolism that trigger downstream biosynthetic processes. Specifically, increased expression of several enzymes such as CTPS1, IL4I1, and ASL results in the reprogramming of amino acid metabolism. Additionally, the strength of TCR signaling resulted in different metabolic enzymes utilized by T cells to facilitate similar biochemical endpoints. Furthermore, this study shows that cyclosporine represses the pathways involved in amino acid and glucose metabolism, providing novel insights on the immunosuppressive mechanisms of this drug. To explore the implications of the findings of this study in clinical settings, conventional immunosuppressants were tested in combination with drugs that target metabolic pathways. Results showed that such combinations increased efficacy of conventional immunosuppressants. Overall, the results of this study provide a comprehensive resource for identifying metabolic targets for novel combinatorial regimens in the treatment of intractable immune diseases.

immunology↗

bioRxiv2019

Structural basis for the transport mechanism of the human glutamine transporter SLC1A5 (ASCT2)

Alanine-serine-cysteine transporter 2 (ASCT2, SLC1A5) is the primary transporter of glutamine in cancer cells and regulates the mTORC1 signaling pathway. The SLC1A5 function involves finely tuned orchestration of two domain movements that include the substrate-binding transport domain and the scaffold domain. Here, we present cryo-EM structures of human SLC1A5 and its complex with the substrate, L-glutamine in an outward-facing conformation. These structures reveal insights into the conformation of the critical ECL2a loop which connects the two domains, thus allowing rigid body movement of the transport domain throughout the transport cycle. Furthermore, the structures provide new insights into substrate recognition, which involves conformational changes in the HP2 loop. A putative cholesterol binding site was observed near the domain interface in the outward-facing state. Comparison with the previously determined inward-facing structure of SCL1A5 provides a basis for a more integrated understanding of substrate recognition and transport mechanism in the SLC1 family. Our structures are likely to aid the development of potent and selective SLC1A5 inhibitors for the treatment of cancer and autoimmune disorders.

biophysics↗