Biology subjects

Kiebish, M. A.

Publications and source records attributed to Kiebish, M. A..

9 recordsLinked to original sources

bioRxiv2026

Maternal diet and genetics shape the human milk metabolome

Human milk contains a diverse array of metabolites that contribute to infant nutrition, immune development, and microbial colonization. The maternal factors shaping the milk metabolome, and the relative contribution of genetics or diet vs. other factors, remain poorly understood. Here, we profiled 458 milk metabolites in 349 one-month postpartum human milk samples and integrated metabolomic data with maternal diet, clinical, transcriptomic, and genomic measurements. Maternal diet was broadly associated with milk metabolite composition, with significant correlations identified between dietary features and 323 metabolites. Coffee consumption strongly predicted milk quinic acid and 1,3-dimethyluric acid abundance, while high-fiber dietary patterns were associated with metabolites including proline-betaine and N-acetylornithine. Integration of milk transcriptomic and metabolomic data via machine learning identified biologically plausible gene-metabolite pairs, including associations between QPRT expression and quinolinic acid, and DPEP1 and cysteine-glycine dipeptide. Genome-wide association analyses identified nine study-wide significant metabolite quantitative trait loci, including novel milk-specific associations near PDE6A affecting purine metabolites and near GNE affecting free sialic acid. Comparison with plasma metabolite studies demonstrated both shared and milk-specific genetic regulation of metabolites. Finally, we found that of all tested maternal features, diet explained the largest proportion of variation in the milk metabolome. Together, these findings demonstrate that the human milk metabolome reflects both maternal exposures and mammary gland-specific biology. This work establishes a framework for understanding how genetic and environmental factors shape milk composition.

genomics↗

bioRxiv2024

Ascitic fluid protects against ferroptosis and enables the peritoneal spread of ovarian cancer

One of the most common sites of metastasis in ovarian cancer (OVCA) is the peritoneum. Often, this spread is accompanied by the accumulation of a fluid called ascites in the peritoneal cavity. Despite its common occurrence in metastatic OVCA patients, ascites and its influence on the peritoneal spread of OVCA are poorly understood. Interestingly, OVCA cells are vulnerable to ferroptosis, a type of cell death caused by lipid peroxidation. Hence, how these ferroptosis-sensitive OVCA cells persist in their spread to the peritoneum remains unknown. Here, we show that ascites robustly protects OVCA cells and patient-derived organoids against ferroptosis and enhances the peritoneal spread of OVCA cells in mice. Mechanistically, ascites downregulates the mitochondrial enzyme, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), which contributes to an increase in lipid droplets. Additionally, upon ferroptosis induction, ascites represses the upregulation of the transferrin receptor, TFRC, thereby decreasing cellular labile iron levels. Furthermore, we show that lipid-lowering fibrates reverse cellular changes induced by ascites, and they attenuate the peritoneal spread of OVCA cells in mice. Our findings implicate the importance of ascites in ferroptosis protection and the peritoneal spread of OVCA, and they suggest that targeting the ferroptosis protection by ascites may present a novel therapeutic approach to limit OVCA metastasis.

cancer biology↗

bioRxiv2023

ScreenDMT reveals linoleic acid diols replicably associate with BMI and stimulate adipocyte calcium fluxes

Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from a cohort of 83 people and test which lipids association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME both replicably inversely associate with BMI and mechanistically activate calcium fluxes in mouse brown and white adipocytes in vitro, which implicates this pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.

bioinformatics↗

bioRxiv2023

Ketogenic diet as a metabolic vehicle for enhancing the therapeutic efficacy of mebendazole and devimistat in preclinical pediatric glioma

Invasion of high-grade glioma (HGG) cells through the brain and spinal cord is a leading cause of cancer death in children. Despite advances in treatment, survivors often suffer from lifelong adverse effects of the current toxic therapies used for management. This study investigated the influence of nutritional ketosis on the therapeutic action of mebendazole (MBZ) and devimistat (CPI-613) against the highly invasive VM-M3 and non-invasive CT-2A glioblastoma cells grown orthotopically in juvenile syngeneic mice. Additionally, both drugs were tested in the human pediatric GBM cell line SF-188. DON (6-Diazo-5-oxo-L-norleucine) was used as a positive drug control for glutamine targeting. Cerebral implantation of the VM-M3 cells, which are mesenchymal origin, invaded throughout the brain and the spinal column similar to that seen in children with HGG. Neither the CT-2A nor the VM-NM1 glioblastoma stem cell tumors showed distal invasion in syngeneic juvenile mouse brains. The maximum therapeutic benefit of MBZ and CPI-613 on tumor invasion, growth, and mouse survival occurred only when the drugs were administered together with a ketogenic diet (KD). MBZ treatment inhibited both the glutaminolysis and the glycolysis pathways in VM-M3 cells grown either in vivo or in vitro. Both MBZ and CPI-613 significantly reduced the in vitro growth and viability of the SF-188 cells. Moreover, drug administration together with the KD allowed for lower dosing thus minimizing toxicity while improving overall survival of the mice. This preclinical study in two different HGGs, grown in syngeneic juvenile mice, highlights the potential importance of diet/drug therapeutic strategies for managing childhood brain cancer.

cancer biology↗

bioRxiv2022

Residual Complex I activity supports glutamate catabolism and mtSLP via canonical Krebs cycle activity during acute anoxia without OXPHOS

Anoxia halts oxidative phosphorylation (OXPHOS) causing an accumulation of reduced compounds in mitochondrial matrix which impedes dehydrogenases. By simultaneously measuring oxygen concentration, NADH autofluorescence, mitochondrial membrane potential and ubiquinone reduction extent in organello in real-time, we show that Complex I utilized endogenous quinones to oxidize NADH under acute anoxia. Untargeted or [U-13C]glutamate-targeted metabolomic analysis of matrix and effluxed metabolites extracted during anoxia in the presence or absence of site-specific inhibitors of the electron transfer system inferred that NAD+ regenerated by Complex I is reduced by the 2-oxoglutarate dehydrogenase complex yielding succinyl-CoA supporting mitochondrial substrate-level phosphorylation (mtSLP), releasing succinate. Yet, targeted metabolomic analysis using [U-13C]malate also revealed concomitant succinate dehydrogenase reversal during anoxia yielding succinate by reducing fumarate, albeit to a small extent. Our results highlight the importance of quinone availability to Complex I oxidizing NADH, thus maintaining glutamate catabolism and mtSLP in the absence of OXPHOS.

biochemistry↗

bioRxiv2022

Serum metabolomic analysis of men on a low-carbohydrate diet for biochemically recurrent prostate cancer reveal the potential role of ketogenesis to slow tumor growth: A secondary analysis of the CAPS2 diet trial

BackgroundSystemic treatments for prostate cancer (PC) have significant side effects. Thus, newer alternatives with fewer side effects are urgently needed. Animal and human studies suggest the therapeutic potential of low carbohydrate diet (LCD) for PC. To test this possibility, Carbohydrate and Prostate Study 2 (CAPS2) trial was conducted in PC patients with biochemical recurrence (BCR) after local treatment to determine the effect of a 6-month LCD intervention vs. usual care control on PC growth as measured by PSA doubling time (PSADT). We previously reported the LCD intervention led to significant weight loss, higher HDL, and lower triglycerides and HbA1c with a suggested longer PSADT. However, the metabolic basis of these effects are unknown. MethodsTo identify the potential metabolic basis of effects of LCD on PSADT, serum metabolomic analysis was performed using baseline, month 3, and month 6 banked sera to identify the metabolites significantly altered by LCD and that correlated with varying PSADT. ResultsLCD increased the serum levels of ketone bodies, glycine and hydroxyisocaproic acid. Reciprocally, LCD reduced the serum levels of alanine, cytidine, asymmetric dimethylarginine (ADMA) and 2-oxobutanoate. As high ADMA level is shown to inhibit nitric oxide (NO) signaling and contribute to various cardiovascular diseases, the ADMA repression under LCD may contribute to the LCD-associated health benefit. Regression analysis of the PSADT revealed a correlation between longer PSADT with higher level of 2-hydroxybutyric acids, ketone bodies, citrate and malate. Longer PSADT was also associated with LCD reduced nicotinamide, fructose-1, 6-biphosphate (FBP) and 2-oxobutanoate. ConclusionThese results suggest a potential association of ketogenesis and TCA metabolites with slower PC growth and conversely glycolysis with faster PC growth. The link of high ketone bodies with longer PSADT supports future studies of ketogenic diets to slow PC growth.

cancer biology↗

bioRxiv2021

Identification and Validation of N-Acetylputrescine in Combination With Non-Canonical Clinical Features As a Parkinsons Disease Biomarker Panel

Parkinsons disease is a progressive neurodegenerative disorder in which loss of dopaminergic neurons in the substantia nigra results in a clinically heterogeneous group with variable motor and non-motor symptoms with a degree of misdiagnosis. Only 3-5% of sporadic Parkinsons patients present with genetic abnormalities, thus environmental, metabolic, and other unknown causes contribute to the pathogenesis of Parkinsons disease, which highlights the critical need for biomarkers. There could be a significant clinical benefit to treating Parkinsons disease at the earliest stage and identify at-risk populations once disease-modifying treatments are available. In the present study, we prospectively collected and analyzed plasma samples from 201 Parkinsons disease patients and 199 age-matched non-diseased controls. Multiomic and Bayesian artificial intelligence analysis of molecular and clinical data identified the diagnostic utility of N-acetyl putrescine (NAP) in combination with smell (B-SIT), depression/anxiety (HADS), and acting out dreams (RBD1Q) clinical measurements. The clinical and biomarker panel demonstrated an area under the curve, AUC = 0.9, positive predictive value, PPV = 0.91, and negative predictive value, NPV = 0.66 utilizing all four variables. The assessed diagnostic panel demonstrates combinatorial utility in diagnosing Parkinsons disease, allowing for an integrated interpretation of disease pathophysiology and highlighting the use of multi-tiered panels in neurological disease diagnosis.

neuroscience↗

bioRxiv2020

Children Developing Celiac Disease Have a Distinct and Proinflammatory Gut Microbiota in the First 5 Years of Life

Celiac disease (CD) is an autoimmune disorder triggered by gluten consumption. To identify the role of gut microbes in CD onset, we performed a longitudinal study focusing on two important phases of gut microbiota development at ages 2.5 and 5 (n=16). We obtained samples from children who developed CD during or after the study (CD progressors) and age, sex, and HLA-matched healthy controls. CD progressors had a distinct gut microbiota composition and IgA-sequencing identified unique IgA targets in the gut. Three cytokines, one chemokine, and 19 plasma metabolites were significantly altered in CD progressors at age 5. Feeding C57BL/6J mice with taurodeoxycholic acid (TDCA), a 2-fold increased microbiota-derived metabolite in CD progressors, caused villous atrophy, increased intraepithelial lymphocytes (IELs), CD4+ T-cells, Natural Killer cells, and Qa-1 expression on T-cells while decreasing T-regulatory cells in IELs. Thus, TDCA drives inflammation in the small intestines that potentially contribute to the CD onset. HighlightsO_LICD progressors have a distinct gut microbiome composition compared to healthy controls in two important phases of gut microbiota development (age 2.5 and 5 years) C_LIO_LICD progressors have more IgA-coated bacteria in their gut at age 5 compared to healthy controls. Further, IgA-sequencing identified unique bacterial targets in CD progressors. C_LIO_LIThree plasma proinflammatory cytokines and a chemokine were increased in CD progressors years before diagnosis, indicating an early inflammatory response. C_LIO_LIWe identified 19 metabolites that are significantly altered in CD progress at age 5 and microbiota-derived TDCA increased two-fold. C_LIO_LITDCA treatment in B6 mice increased CD4+ cells and NK cells while decreasing CD8+ T-regulatory (Treg) cells. It also increased Qa-1 expression on immune cells. C_LI

microbiology↗

bioRxiv2018

Multi-OMIC analysis of brain and serum from chronically-stressed mice reveals network disruptions in purine metabolism, fatty acid beta-oxidation, and antioxidant activity that are reversed by antidepressant treatment

Major depressive disorder (MDD) is a complex condition with unclear pathophysiology. Molecular disruptions within the periphery and limbic brain regions contribute to depression symptomatology. Here, we utilized a mouse chronic stress model of MDD and performed metabolomic, lipidomic, and proteomic profiling on serum plus several brain regions (ventral hippocampus, nucleus accumbens, and prefrontal cortex) of susceptible, resilient, and unstressed control mice. Proteomic analysis identified three serum proteins reduced in susceptible animals; lipidomic analysis detected differences in lipid species between resilient and susceptible animals in serum and brain; and metabolomic analysis revealed pathway dysfunctions of purine metabolism, beta oxidation, and antioxidants, which were differentially associated with stress susceptibility vs resilience by brain region. Antidepressant treatment ameliorated MDD-like behaviors and affected key metabolites within outlined networks, most dramatically in the ventral hippocampus. This work presents a resource for chronic stress-induced, tissue-specific changes in proteins, lipids, and metabolites and illuminates how molecular dysfunctions contribute to individual differences in stress sensitivity.

neuroscience↗