Browsing by Author "Heathers, Laura"

Now showing 1 - 7 of 7
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    Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease
    (Springer Nature, 2024-12-30) Li, Zhen; Gu, Min; Zaparte, Aline; Fu, Xiaoming; Mahen, Kala; Mrdjen, Marko; Li, Xinmin S.; Yang, Zhihong; Ma, Jing; Thoudam, Themis; Chandler, Kristina; Hesler, Maggie; Heathers, Laura; Gorse, Kiersten; Van, Thanh Trung; Wong, David; Gibson, Aaron M.; Wang, Zeneng; Taylor, Christopher M.; Quijada, Pearl; Makarewich, Catherine A.; Hazen, Stanley L.; Liangpunsakul, Suthat; Brown, J. Mark; Lefer, David J.; Welsh, David A.; Sharp, Thomas E., III; Medicine, School of Medicine
    The mechanism(s) underlying gut microbial metabolite (GMM) contribution towards alcohol-mediated cardiovascular disease (CVD) is unknown. Herein we observe elevation in circulating phenylacetylglutamine (PAGln), a known CVD-associated GMM, in individuals living with alcohol use disorder. In a male murine binge-on-chronic alcohol model, we confirm gut microbial reorganization, elevation in PAGln levels, and the presence of cardiovascular pathophysiology. Fecal microbiota transplantation from pair-/alcohol-fed mice into naïve male mice demonstrates the transmissibility of PAGln production and the CVD phenotype. Independent of alcohol exposure, pharmacological-mediated increases in PAGln elicits direct cardiac and vascular dysfunction. PAGln induced hypercontractility and altered calcium cycling in isolated cardiomyocytes providing evidence of improper relaxation which corresponds to elevated filling pressures observed in vivo. Furthermore, PAGln directly induces vascular endothelial cell activation through induction of oxidative stress leading to endothelial cell dysfunction. We thus reveal that the alcohol-induced microbial reorganization and resultant GMM elevation, specifically PAGln, directly contributes to CVD.
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    Levels of circulating follicular helper T cells, T helper 1 cells, and the prognostic significance of soluble form of CD40 ligand on survival in patients with alcoholic cirrhosis
    (KeAi Communications Co., 2018-03) Hollister, Kristin; Kusumanchi, Praveen; Ross, Ruth Ann; Chandler, Kristina; Oshodi, AdePeju; Heathers, Laura; Teagarden, Sean; Wang, Li; Dent, Alexander L.; Liangpunsakul, Suthat; Microbiology and Immunology, School of Medicine
    Background: Excessive drinkers (ED) and patients with alcoholic liver disease (ALD) are several times more susceptible to bacterial and viral infections and have a decrease in antibody responses to vaccinations. Follicular helper T (TFH) cells are essential to select B cells in the germinal center and to produce antibodies. TFH cells express both a membrane-associated and a soluble form of CD40 ligand (sCD40L); in which the latter form is released to circulation upon T cell activation. The effect of alcohol on TFH cells has not been studied. Objectives: The goals of this study are to determine the levels of TFH and T helper 1 (Th1) cells in ED and those with alcoholic cirrhosis (AC) when compared to healthy controls and to determine the prognostic significance of sCD40L in a cohort of patients with AC. Methods: Controls, ED, and those with AC were enrolled. Baseline demographic, laboratory tests, and peripheral blood mononuclear cells (PBMCs) were isolated and assessed via flow cytometry for TFH cells. In vitro study was performed to determine the ability of PBMCs to secrete interferon (IFN)-γ upon stimulation. Serum sCD40L were also determined and its prognostic significance was tested in a cohort of AC patients. Results: The levels of circulating TFH (cTFH) cells were significantly lower in peripheral blood of subjects with ED and AC compared to controls (P<0.05). IFN-γ secretion from PBMCs upon stimulation was also lower in ED and those with cirrhosis. Serum sCD40L was significantly lower in ED and AC when compared to that in controls (P<0.0005). Its level was an independent predictor of mortality. Conclusions: Patients with AC had significantly lower level of cTFH and sCD40L. The level of sCD40L was an independent predictor of mortality in these patients.
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    The Promise and Pitfalls of Facebook Advertising: a Genetic Counselor’s Perspective
    (Springer, 2018-04) Verbrugge, Jennifer; Rumbaugh, Malia; Cook, Lola; Schulze, Jeanine; Miller, Mandy; Heathers, Laura; Arnedo, Vanessa; Kuhl, Maggie McGuire; Foroud, Tatiana; Medical and Molecular Genetics, School of Medicine
    Facebook advertising is a powerful tool for increasing the outreach and recruitment of research participants. We describe our experience as genetic counselors within the context of an internet-based research study, recruiting subjects for a Parkinson disease (PD) biomarker study.
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    Serum metabolomic analysis reveals several novel metabolites in association with excessive alcohol use - an exploratory study
    (Elsevier, 2022) Liu, Danni; Yang, Zhihong; Chandler, Kristina; Oshodi, Adepeju; Zhang, Ting; Ma, Jing; Kusumanchi, Praveen; Huda, Nazmul; Heathers, Laura; Perez, Kristina; Tyler, Kelsey; Ross, Ruth Ann; Jiang, Yanchao; Zhang, Dabao; Zhang, Min; Liangpunsakul, Suthat; Medicine, School of Medicine
    Appropriate screening tool for excessive alcohol use (EAU) is clinically important as it may help providers encourage early intervention and prevent adverse outcomes. We hypothesized that patients with excessive alcohol use will have distinct serum metabolites when compared to healthy controls. Serum metabolic profiling of 22 healthy controls and 147 patients with a history of EAU was performed. We employed seemingly unrelated regression to identify the unique metabolites and found 67 metabolites (out of 556), which were differentially expressed in patients with EAU. Sixteen metabolites belong to the sphingolipid metabolism, 13 belong to phospholipid metabolism, and the remaining 38 were metabolites of 25 different pathways. We also found 93 serum metabolites that were significantly associated with the total quantity of alcohol consumption in the last 30 days. A total of 15 metabolites belong to the sphingolipid metabolism, 11 belong to phospholipid metabolism, and 7 metabolites belong to lysolipid. Using a Venn diagram approach, we found the top 10 metabolites with differentially expressed in EAU and significantly associated with the quantity of alcohol consumption, sphingomyelin (d18:2/18:1), sphingomyelin (d18:2/21:0,d16:2/23:0), guanosine, S-methylmethionine, 10-undecenoate (11:1n1), sphingomyelin (d18:1/20:1, d18:2/20:0), sphingomyelin (d18:1/17:0, d17:1/18:0, d19:1/16:0), N-acetylasparagine, sphingomyelin (d18:1/19:0, d19:1/18:0), and 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1). The diagnostic performance of the top 10 metabolites, using the area under the ROC curve, was significantly higher than that of commonly used markers. We have identified a unique metaboloic signature among patients with EAU. Future studies to validate and determine the kinetics of these markers as a function of alcohol consumption are needed.
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    Serum Metabolomic Profiling Identifies Key Metabolic Signatures Associated With Pathogenesis of Alcoholic Liver Disease in Humans
    (Wiley, 2019-02-20) Yang, Zhihong; Kusumanchi, Praveen; Ross, Ruth A.; Heathers, Laura; Chandler, Kristina; Oshodi, Adepeju; Thoudam, Themis; Li, Feng; Wang, Li; Liangpunsakul, Suthat; Medicine, School of Medicine
    Alcoholic liver disease (ALD) develops in a subset of heavy drinkers (HDs). The goals of our study were to (1) characterize the global serum metabolomic changes in well-characterized cohorts of controls (Cs), HDs, and those with alcoholic cirrhosis (AC); (2) identify metabolomic signatures as potential diagnostic markers, and (3) determine the trajectory of serum metabolites in response to alcohol abstinence. Serum metabolic profiling was performed in 22 Cs, 147 HDs, and 33 patients with AC using ultraperformance liquid chromatography-tandem mass spectrometry. Hepatic gene expression was conducted in Cs (n = 16) and those with AC (n = 32). We found progressive changes in the quantities of metabolites from heavy drinking to AC. Taurine-conjugated bile acids (taurocholic acid [TCA], 127-fold; taurochenodeoxycholic acid [TCDCA], 131-fold; and tauroursodeoxycholic acid, 56-fold) showed more striking elevations than glycine-conjugated forms (glycocholic acid [GCA], 22-fold; glycochenodeoxycholic acid [GCDCA], 22-fold; and glycoursodeoxycholic acid [GUDCA], 11-fold). This was associated with increased liver cytochrome P450, family 7, subfamily B, member 1 and taurine content (more substrates); the latter was due to dysregulation of homocysteine metabolism. Increased levels of GCDCA, TCDCA, GCA, and TCA positively correlated with disease progression from Child-Pugh A to C and Model for End-Stage Liver Disease scores, whereas GCDCA, GCA, and GUDCA were better predictors of alcohol abstinence. The levels of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor (FGF) 21 but not FGF19 were increased in HDs, and all three were further increased in those with AC. Conclusion: Serum taurine/glycine-conjugated bile acids could serve as noninvasive markers to predict the severity of AC, whereas GLP-1 and FGF21 may indicate a progression from heavy drinking to AC.
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    Staged Screening Identifies People with Biomarkers Related to Neuronal Alpha-Synuclein Disease
    (Wiley, 2025) Brown, Ethan G.; Chahine, Lana M.; Siderowf, Andrew; Gochanour, Caroline; Kurth, Ryan; Marshall, Micah J.; Caspell-Garcia, Chelsea; Brumm, Michael C.; Stanley, Craig E., Jr.; Korell, Monica; McMahon, Bridget; Kuhl, Maggie; Fabrizio, Kimberly; Heathers, Laura; Concha-Marambio, Luis; Soto, Claudio; Chowdhury, Sohini; Coffey, Christopher S.; Foroud, Tatiana M.; Simuni, Tanya; Marek, Kenneth; Tanner, Caroline M.; Parkinson Progression Marker Initiative; Medical and Molecular Genetics, School of Medicine
    Objective: Remote identification of individuals with severe hyposmia may enable scalable recruitment of participants with underlying alpha-synuclein aggregation. We evaluated the performance of a staged screening paradigm using remote smell testing to enrich for abnormal dopamine transporter single-photon emission computed tomography imaging (DAT-SPECT) and alpha-synuclein aggregation. Methods: The Parkinson's Progression Markers Initiative (PPMI) recruited participants for the prodromal cohort who were 60-years and older without a Parkinson's disease diagnosis. Participants were invited to complete a University of Pennsylvania Smell Identification Test (UPSIT) independently through an online portal. Hyposmic participants were invited to complete DAT-SPECT, which determined eligibility for enrollment in longitudinal assessments and further biomarker evaluation including cerebrospinal fluid alpha-synuclein seed amplification assay (aSynSAA). Results: As of January 29, 2024, 49,843 participants were sent an UPSIT and 31,293 (63%) completed it. Of UPSIT completers, 8,301 (27%) scored <15th percentile. Of 1,546 who completed DAT-SPECT, 1,060 (69%) had DAT-SPECT binding <100% expected for age and sex. Participants with an UPSIT <10th percentile (n = 1,221) had greater likelihood of low DAT-SPECT binding compared to participants with an UPSIT in the 10th to 15th percentile (odds ratio, 3.01; 95% confidence interval, 1.85-4.91). Overall, 55% (198/363) of cases with UPSIT <15th percentile and DAT-SPECT <100% had positive aSynSAA, which increased to 70% (182/260) when selecting for more severe hyposmia (UPSIT <10th percentile). Interpretation: Remote screening for hyposmia and reduced DAT-SPECT binding identifies participants with a high proportion positive aSynSAA. Longitudinal data will be essential to define progression patterns in these individuals to ultimately inform recruitment into disease modification clinical trials.
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    The utility of commonly used laboratory tests to screen for excessive alcohol use in clinical practice
    (Wiley, 2015-08) Gough, Gina; Heathers, Laura; Puckett, Deonna; Westerhold, Chi; Ren, Xiaowei; Yu, Zhangsheng; Crabb, David W.; Liangpunsakul, Suthat; Department of Medicine, IU School of Medicine
    BACKGROUND: This current study was undertaken to carefully assess the accuracy of routinely used laboratory tests in detecting excessive/recent alcohol use. We also determined the kinetics of these markers in subjects who underwent an intensive alcohol rehabilitation program. METHODS: The study cohort consisted of 210 nonexcessive drinkers, 272 excessive drinkers, and 76 with alcoholic cirrhosis. To determine the kinetics of these markers during alcohol abstinence, we followed 45 subjects with history of excessive alcohol use for 12 weeks during the intensive alcohol treatment program. RESULTS: Percentage of carbohydrate deficient transferrin (%CDT) provided the highest diagnostic performance (area under the curve [AUC] 0.77) followed by gamma-glutamyl transferase (GGT) (AUC 0.68) to detect excessive drinkers. The percentage of excessive drinkers with aspartate aminotransferase:alanine aminotransferase (AST:ALT) > 2 was only 2%, whereas 51% of subjects with alcoholic cirrhosis had AST:ALT > 2. In the multivariate analysis, the levels of GGT and %CDT were associated with the level of alcohol consumed during the past 30 days. The levels of GGT, mean corpuscular volume (MCV), and %CDT were significantly lower compared to those at baseline before alcohol rehabilitation, whereas the AST, ALT, and AST:ALT ratio were unchanged. The percent reduction was ~2.7% (for MCV), 19% (for GGT), and 43% (for %CDT) at the end of the 12-week follow-up compared to the baseline. CONCLUSIONS: %CDT are useful markers to screen for excessive alcohol use and for follow-up of abstinence. Most subjects with excessive alcohol use do not have a high AST:ALT ratio. Rather, the AST:ALT > 2 is suggestive of alcoholic cirrhosis. The performance of the %CDT to screen for heavy alcohol use is still not ideal. Further research to identify the noninvasive marker(s) (i.e., using proteomic or metabolomics approach) should be considered.