Danielle Kim

All Publications

• Calorie restriction and pravastatin administration during pregnancy in obese rhesus macaques modulates maternal and infant metabolism and infant brain and behavioral development. Frontiers in nutrition Hasegawa, Y., Kim, D. H., Zhang, Z., Taha, A. Y., Capitanio, J. P., Hogrefe, C. E., Bauman, M. D., Golub, M. S., Van de Water, J., VandeVoort, C. A., Walker, C. K., Slupsky, C. M. 2023; 10: 1146804

  Abstract

  Maternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development.A total of 19 obese mothers were assigned to either one of the two intervention groups (n = 5 for calorie restriction; n = 7 for pravastatin) or an obese control group (n = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers (n = 6) using metabolomics methods.Gestational calorie restriction normalized one-carbon metabolism dysregulation in obese mothers, but altered energy metabolism in her offspring. Although administration of pravastatin during pregnancy tended to normalize blood cholesterol in the mothers, it potentially impacted the gut microbiome and kidney function of their offspring. In the offspring, both calorie restriction and pravastatin administration during pregnancy tended to normalize the activity of AMPK in the brain at 6 months, and while results of the Visual Paired-Comparison test, which measures infant recognition memory, was not significantly impacted by either of the interventions, gestational pravastatin administration, but not calorie restriction, tended to normalize anxiety assessed by the Human Intruder test.Although the two interventions tested in a non-human primate model led to some improvements in metabolism and/or infant brain development, negative impacts were also found in both mothers and infants. Our study emphasizes the importance of assessing gestational interventions for maternal obesity on both maternal and offspring long-term outcomes.

  View details for DOI 10.3389/fnut.2023.1146804

  View details for PubMedID 37255938

  View details for PubMedCentralID PMC10225656

• Neonatal immune signatures differ by sex regardless of neurodevelopmental disorder status: Macrophage migration inhibitory factor (MIF) alone reveals a sex by diagnosis interaction effect BRAIN BEHAVIOR AND IMMUNITY Kim, D. J., Iosif, A., Ramirez-Celis, A., Ashwood, P., Ames, J. L., Lyall, K., Berger, K., Croen, L. A., Van de Water, J. 2023; 111: 328-333

  Abstract

  Immune dysregulation, including aberrant peripheral cytokine/chemokine levels, is implicated in neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD). While the diagnosis of ASD is more common in males compared to females, sex effects in immune dysregulation related to neurodevelopment remain understudied. The aim of this exploratory study was to determine whether there are sex-specific effects in neonatal immune dysregulation with respect to an ASD or delayed development (DD) diagnosis. We utilized the data from the Early Markers for Autism study, a population based case-control study of prenatal and neonatal biomarkers of ASD. The immune profile of newborns later diagnosed with ASD (n = 482, 91 females), DD (n = 140, 61 females) and sex-matched general population controls (GP; n = 378, 67 females) were analyzed using neonatal bloodspots (NBS) via 42-plex multiplex assay. Multiple linear regression analysis was performed to identify whether sex was associated with differences in cytokine/chemokine levels of children with ASD, DD, and GP. A sex by diagnosis interaction effect was observed only for the chemokine macrophage migration inhibitory factor (MIF), with males displaying higher levels of NBS MIF than females in the GP control group (p = 0.02), but not in ASD (p = 0.52) or DD (p = 0.29) groups. We found that regardless of child diagnosis, newborn bloodspot eluates from females had a significantly higher concentration than males with the same diagnosis of the chemokines granulocyte chemotactic protein 2 (GCP-2; p < 0.0001), macrophage inflammatory protein 2-alpha (GROβ; p = 0.002), interferon-inducible t-cell alpha chemoattractant (I-TAC; p < 0.0001), stromal cell-derived factor 1 alpha and beta (SDF-1α-β; p = 0.03), innate inflammatory chemokines interferon-gamma induced protein 10 (IP-10; p = 0.02), macrophage inflammatory protein 1-alpha (MIP-1α; p = 0.02), and Th1-related pro-inflammatory cytokine interleukin-12 active heterodimer (IL-12p70; p = 0.002). In contrast, males had a higher concentration than females of secondary lymphoid-tissue chemokine (6CKINE; p = 0.02), monocyte chemotactic protein 1 (MCP-1; p = 0.005) and myeloid progenitor inhibitory factor 1 (MPIF-1; p = 0.03). Results were similar when analyses were restricted to NBS from DD and ASD further classified as ASD with intellectual disability (ID), ASD without ID, and DD (GCP-2, p = 0.007; I-TAC, p = 0.001; IP-10, p = 0.005; IL-12p70, p = 0.03 higher in females; MPIF-1, p = 0.03 higher in male). This study is the first to examine sex differences in neonatal cytokine/chemokine concentrations, and whether these differences are associated with neurodevelopmental outcomes. Results highlight the importance of considering sex as a critical factor in understanding the immune system as it relates to child development.

  View details for DOI 10.1016/j.bbi.2023.05.002

  View details for Web of Science ID 001001255900001

  View details for PubMedID 37164311

• Maternal Immune Dysregulation and Autism-Understanding the Role of Cytokines, Chemokines and Autoantibodies FRONTIERS IN PSYCHIATRY McLellan, J., Kim, D. J., Bruce, M., Ramirez-Celis, A., van de Water, J. 2022; 13: 834910

  Abstract

  Autism spectrum disorder (ASD) is acknowledged as a highly heterogeneous, behaviorally defined neurodevelopmental disorder with multiple etiologies. In addition to its high heritability, we have come to recognize a role for maternal immune system dysregulation as a prominent risk factor for the development of ASD in the child. Examples of these risk factors include altered cytokine/chemokine activity and the presence of autoantibodies in mothers that are reactive to proteins in the developing brain. In addition to large clinical studies, the development of pre-clinical models enables the ability to evaluate the cellular and molecular underpinnings of immune-related pathology. For example, the novel animal models of maternal autoantibody-related (MAR) ASD described herein will serve as a preclinical platform for the future testing of targeted therapeutics for one 'type' of ASD. Identification of the cellular targets will advance precision medicine efforts toward tailored therapeutics and prevention. This minireview highlights emerging evidence for the role of maternal immune dysregulation as a potential biomarker, as well as a pathologically relevant mechanism for the development of ASD in offspring. Further, we will discuss the current limitations of these models as well as potential avenues for future research.

  View details for DOI 10.3389/fpsyt.2022.834910

  View details for Web of Science ID 000811997700001

  View details for PubMedID 35722542

  View details for PubMedCentralID PMC9201050

• Maternal Immune Dysregulation and Autism Spectrum Disorder Neural Engineering Techniques for Autism Spectrum Disorder, Volume 2: Diagnosis and Clinical Analysis, Kim, D. H., Ramirez-Celis, A., Van de Water, J. Elsevier. 2022
• Neonatal chemokine markers predict subsequent diagnosis of autism spectrum disorder and delayed development BRAIN BEHAVIOR AND IMMUNITY Kim, D. J., Krakowiak, P., Meltzer, A., Hertz-Picciotto, I., Water, J. 2022; 100: 121-133

  Abstract

  Immune dysregulation has been found to be related to a diagnosis of autism spectrum disorder (ASD). However, investigations in very early childhood examining immunological abnormalities such as altered neonatal cytokine/chemokine profiles in association with an aberrant developmental trajectory, are sparse. We assessed neonatal blood spots from 398 children, including 171 with ASD, which were subdivided according to severity (121 severe, 50 mild/moderate) and cognitive/adaptive levels (144 low-functioning, 27 typical to high-functioning). The remainder were 69 children with developmental delay (DD), and 158 with typical development (TD), who served as controls in the Childhood Autism Risks from Genetics and the Environment (CHARGE) study. Exploratory analysis suggested that, in comparisons with TD and DD, CTACK (CCL27) and MPIF-1 (CCL23), respectively, were independently associated with ASD. Higher neonatal levels of CTACK were associated with decreased odds of ASD compared to TD (odds ratio [OR] = 0.40, 95% confidence interval [Cl] 0.21, 0.77), whereas higher levels of MPIF-1 were associated with increased odds of ASD (OR = 2.38, 95% Cl 1.42, 3.98) compared to DD but not to TD. MPIF-1 was positively associated with better scores in several developmental domains. Dysregulation of chemokine levels in early life can impede normal immune and neurobehavioral development, which can lead to diagnosis of ASD or DD. This study collectively suggests that certain peripheral chemokines at birth are associated with ASD progression during childhood and that children with ASD and DD have distinct neonatal chemokine profiles that can differentiate their diagnoses.

  View details for DOI 10.1016/j.bbi.2021.11.009

  View details for Web of Science ID 000744050900013

  View details for PubMedID 34808292

• Development of the Microbiota-Gut-Brain Axis in Early Life Gut-Brain Connection, Myth or Reality? The Role of Microbiome in Health and Diseases Kim, D. H., Rude, K. M., Gareau, M. G. World Scientific Publishing Co. 2021
• Myelin as a regulator of development of the microbiota-gut-brain axis. Brain, behavior, and immunity Keogh, C. E., Kim, D. H., Pusceddu, M. M., Knotts, T. A., Rabasa, G., Sladek, J. A., Hsieh, M. T., Honeycutt, M., Brust-Mascher, I., Barboza, M., Gareau, M. G. 2021; 91: 437-450

  Abstract

  Myelination in the peripheral and central nervous systems is critical in regulating motor, sensory, and cognitive functions. As myelination occurs rapidly during early life, neonatal gut dysbiosis during early colonization can potentially alter proper myelination by dysregulating immune responses and neuronal differentiation. Despite common usage of antibiotics (Abx) in children, the impact of neonatal Abx-induced dysbiosis on the development of microbiota, gut, brain (MGB) axis, including myelination and behavior, is unknown. We hypothesized that neonatal Abx-induced dysbiosis dysregulates host-microbe interactions, impairing myelination in the brain, and altering the MGB axis. Neonatal C57BL/6 mice were orally gavaged daily with an Abx cocktail (neomycin, vancomycin, ampicillin) or water (vehicle) from postnatal day 7 (P7) until weaning (P23) to induce gut dysbiosis. Behavior (cognition; anxiety-like behavior), microbiota sequencing, and qPCR (ileum, colon, hippocampus and pre-frontal cortex [PFC]) were performed in adult mice (6-8 weeks). Neonatal Abx administration led to intestinal dysbiosis in adulthood, impaired intestinal physiology, coupled with perturbations of bacterial metabolites and behavioral alterations (cognitive deficits and anxiolytic behavior). Expression of myelin-related genes (Mag, Mog, Mbp, Mobp, Plp) and transcription factors (Sox10, Myrf) important for oligodendrocytes were significantly increased in the PFC region of Abx-treated mice. Increased myelination was confirmed by immunofluorescence imaging and western blot analysis, demonstrating increased expression of MBP, SOX10 and MYRF in neonatally Abx-treated mice compared to sham controls in adulthood. Finally, administration of the short chain fatty acid butyrate following completion of the Abx treatment restored intestinal physiology, behavior, and myelination impairments, suggesting a critical role for the gut microbiota in mediating these effects. Taken together, we identified a long-lasting impact of neonatal Abx administration on the MGB axis, specifically on myelin regulation in the PFC region, potentially contributing to impaired cognitive function and bacterial metabolites are effective in reversing this altered phenotype.

  View details for DOI 10.1016/j.bbi.2020.11.001

  View details for PubMedID 33157256

  View details for PubMedCentralID PMC7749851

• Nod-like receptors are critical for gut-brain axis signalling in mice JOURNAL OF PHYSIOLOGY-LONDON Pusceddu, M. M., Barboza, M., Keogh, C. E., Schneider, M., Stokes, P., Sladek, J. A., Kim, H. D., Torres-Fuentes, C., Goldfild, L. R., Gillis, S. E., Brust-Mascher, I., Rabasa, G., Wong, K. A., Lebrilla, C., Byndloss, M. X., Maisonneuve, C., Baumler, A. J., Philpott, D. J., Ferrero, R. L., Barrett, K. E., Reardon, C., Gareau, M. G. 2019; 597 (24): 5777-5797

  Abstract

  •Nucleotide binding oligomerization domain (Nod)-like receptors regulate cognition, anxiety and hypothalamic-pituitary-adrenal axis activation. •Nod-like receptors regulate central and peripheral serotonergic biology. •Nod-like receptors are important for maintenance of gastrointestinal physiology. •Intestinal epithelial cell expression of Nod1 receptors regulate behaviour.Gut-brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre+ Nod1f/f ), but not Nod2, increased susceptibility to stress-induced anxiety-like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.

  View details for DOI 10.1113/JP278640

  View details for Web of Science ID 000501169700001

  View details for PubMedID 31652348

  View details for PubMedCentralID PMC6911019

• Prognostic Impact of <i>Fusobacterium nucleatum</i> Depends on Combined Tumor Location and Microsatellite Instability Status in Stage II/III Colorectal Cancers Treated with Adjuvant Chemotherapy JOURNAL OF PATHOLOGY AND TRANSLATIONAL MEDICINE Oh, H., Kim, J., Bae, J., Kim, H., Cho, N., Kang, G. 2019; 53 (1): 40-+

  Abstract

  This study aimed to investigate the prognostic impact of intratumoral Fusobacterium nucleatum in colorectal cancer (CRC) treated with adjuvant chemotherapy.F. nucleatumDNA was quantitatively measured in a total of 593 CRC tissues retrospectively collectedfrom surgically resected specimens of stage III or high-risk stage II CRC patients who had receivedcurative surgery and subsequent oxaliplatin-based adjuvant chemotherapy (either FOLFOXor CAPOX). Each case was classified into one of the three categories: F. nucleatum-high, -low, or -negative.No significant differences in survival were observed between the F.nucleatum-high and -low/negative groups in the 593 CRCs (p = .671). Subgroup analyses accordingto tumor location demonstrated that disease-free survival was significantly better in F.nucleatum-high than in -low/negative patients with non-sigmoid colon cancer (including cecal,ascending, transverse, and descending colon cancers; n = 219; log-rank p = .026). In multivariateanalysis, F. nucleatum was determined to be an independent prognostic factor in non-sigmoidcolon cancers (hazard ratio, 0.42; 95% confidence interval, 0.18 to 0.97; p = .043). Furthermore,the favorable prognostic effect of F. nucleatum-high was observed only in a non-microsatellite instability-high (non-MSI-high) subset of non-sigmoid colon cancers (log-rank p = 0.014), but not ina MSI-high subset (log-rank p = 0.844), suggesting that the combined status of tumor locationand MSI may be a critical factor for different prognostic impacts of F. nucleatum in CRCs treatedwith adjuvant chemotherapy.Intratumoral F. nucleatum load is a potential prognosticfactor in a non-MSI-high/non-sigmoid/non-rectal cancer subset of stage II/III CRCs treatedwith oxaliplatin-based adjuvant chemotherapy.

  View details for DOI 10.4132/jptm.2018.11.29

  View details for Web of Science ID 000455821700005

  View details for PubMedID 30586952

  View details for PubMedCentralID PMC6344805

• Modulation of calcium carbonate precipitation by exopolysaccharide in <i>Bacillus</i> sp JH7 APPLIED MICROBIOLOGY AND BIOTECHNOLOGY Kim, H., Shin, B., Lee, Y., Park, W. 2017; 101 (16): 6551-6561

  Abstract

  Extracellular polymeric substance (EPS) is proposed to facilitate calcium ion supersaturation through its nucleation effect during the microbially induced calcium carbonate precipitation (MICP) process. However, the supersaturation effect of Ca2+ via EPS in MICP has not been clearly demonstrated. Enhanced exopolysaccharide production of the alkali- and halotolerant MICP-capable bacteria, Bacillus sp. JH7, was achieved through glycerol addition. This was demonstrated by measuring cellular precipitation and Congo red binding. Interestingly, field emission scanning electron microscopy and energy-dispersive X-ray spectrometry analysis demonstrated that there was no MICP under glycerol-amended conditions. Although glycerol promoted exopolysaccharide capture of Ca2+ ions, Ca2+ embedded onto EPS did not participate in MICP formation. The pH was reduced in glycerol-added media, which led us to analyze high acetate production under our test conditions. Purified glycerol-induced exopolysaccharide showed a higher capacity of Ca2+ capture than the control. Quantitative RT-PCR analysis showed that three genes involved in exopolysaccharide production were highly upregulated by glycerol. The amounts of three detected monosaccharides (arabinose, glucose, and mannose) were altered by glycerol. Cell hydrophobicity measurements indicated that glycerol could confer more hydrophilic characteristics to cells, which might enhance Ca2+ binding onto EPS. Unexpectedly, our data demonstrated, for the first time, that glycerol could promote exopolysaccharide and acetate production under our test condition, which could inhibit MICP by reducing the availability of free Ca2+.

  View details for DOI 10.1007/s00253-017-8372-8

  View details for Web of Science ID 000407077400023

  View details for PubMedID 28639010

• Non-ureolytic calcium carbonate precipitation by <i>Lysinibacillus</i> sp YS11 isolated from the rhizosphere of <i>Miscanthus sacchariflorus</i> JOURNAL OF MICROBIOLOGY Lee, Y., Kim, H., Park, W. 2017; 55 (6): 440-447

  Abstract

  Although microbially induced calcium carbonate precipitation (MICP) through ureolysis has been widely studied in environmental engineering fields, urea utilization might cause environmental problems as a result of ammonia and nitrate production. In this study, many non-ureolytic calcium carbonate-precipitating bacteria that induced an alkaline environment were isolated from the rhizosphere of Miscanthus sacchariflorus near an artificial stream and their ability to precipitate calcium carbonate minerals with the absence of urea was investigated. MICP was observed using a phase-contrast microscope and ion-selective electrode. Only Lysinibacillus sp. YS11 showed MICP in aerobic conditions. Energy dispersive X-ray spectrometry and X-ray diffraction confirmed the presence of calcium carbonate. Field emission scanning electron microscopy analysis indicated the formation of morphologically distinct minerals around cells under these conditions. Monitoring of bacterial growth, pH changes, and Ca2+ concentrations under aerobic, hypoxia, and anaerobic conditions suggested that strain YS11 could induce alkaline conditions up to a pH of 8.9 and utilize 95% of free Ca2+ only under aerobic conditions. Unusual Ca2+ binding and its release from cells were observed under hypoxia conditions. Biofilm and extracellular polymeric substances (EPS) formation were enhanced during MICP. Strain YS11 has resistance at high pH and in high salt concentrations, as well as its spore-forming ability, which supports its potential application for self-healing concrete.

  View details for DOI 10.1007/s12275-017-7086-z

  View details for Web of Science ID 000402151800006

  View details for PubMedID 28551875

• Draft Genome Sequences of Two Ureolytic Bacteria Isolated from Concrete Block Waste GENOME ANNOUNCEMENTS Park, H., Park, B., Kim, H., Park, W., Choi, I. 2016; 4 (4)

  Abstract

  We sequenced genomes of two ureolytic bacteria, Bacillus sp. JH7 and Sporosarcina sp. HYO08, which were isolated from concrete waste and have a potential for biocementation applications.

  View details for DOI 10.1128/genomeA.00762-16

  View details for Web of Science ID 000460662700132

  View details for PubMedID 27491992

  View details for PubMedCentralID PMC4974313

• Calcium Carbonate Precipitation by <i>Bacillus</i> and <i>Sporosarcina</i> Strains Isolated from Concrete and Analysis of the Bacterial Community of Concrete JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY Kim, H., Eom, H., Park, C., Jung, J., Shin, B., Kim, W., Chung, N., Choi, I., Park, W. 2016; 26 (3): 540-548

  Abstract

  Microbially induced calcium carbonate precipitation (CCP) is a long-standing but re-emerging environmental engineering process for production of self-healing concrete, bioremediation, and long-term storage of CO2. CCP-capable bacteria, two Bacillus strains (JH3 and JH7) and one Sporosarcina strain (HYO08), were isolated from two samples of concrete and characterized phylogenetically. Calcium carbonate crystals precipitated by the three strains were morphologically distinct according to field emission scanning electron microscopy. Energy dispersive X-ray spectrometry mapping confirmed biomineralization via extracellular calcium carbonate production. The three strains differed in their physiological characteristics: growth at alkali pH and high NaCl concentrations, and urease activity. Sporosarcina sp. HYO08 and Bacillus sp. JH7 were more alkali- and halotolerant, respectively. Analysis of the community from the same concrete samples using barcoded pyrosequencing revealed that the relative abundance of Bacillus and Sporosarcina species was low, which indicated low culturability of other dominant bacteria. This study suggests that calcium carbonate crystals with different properties can be produced by various CCP-capable strains, and other novel isolates await discovery.

  View details for DOI 10.4014/jmb.1511.11008

  View details for Web of Science ID 000372876600014

  View details for PubMedID 26699752