Publications

Associate Professor of Medicine (Gastroenterology and Hepatology); Associate Dean, Academic Affairs, School of Medicine

Publications

  • Novel circulating and tissue monocytes as well as macrophages in pancreatitis and recovery. Gastroenterology Manohar, M., Jones, E. K., Rubin, S. J., Subrahmanyam, P. B., Swaminathan, G., Mikhail, D., Bai, L., Singh, G., Wei, Y., Sharma, V., Siebert, J. C., Maecker, H. T., Husain, S. Z., Park, W. G., Pandol, S. J., Habtezion, A. 2021

    Abstract

    BACKGROUND AND AIMS: Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality. Uncovering inflammatory pathways that lead to progression and recovery will inform ways to monitor and/or develop effective therapies.METHODS: We performed single-cell mass cytometry (CyTOF) analysis to identify pancreatic and systemic inflammatory signals during mild (referred as AP), severe AP (SAP) and recovery using two independent experimental models and blood from AP and recurrent AP (RAP) patients. Flowcytometric validation of monocytes subsets identified by CyTOF analysis was performed independently.RESULTS: Ly6C+ inflammatory monocytes were most altered cells in the pancreas during experimental AP, recovery, and SAP. Deep profiling uncovered heterogeneity among pancreatic and blood monocytes and identified seven novel subsets during AP and recovery, and six monocyte subsets during SAP. Notably, a dynamic shift in pancreatic CD206+ macrophage population was observed during AP and recovery. Deeper profiling of the CD206+ macrophage identified seven novel subsets during AP, recovery and SAP. DE analysis of these novel monocyte and CD206+ macrophage subsets revealed significantly altered surface (CD44, CD54, CD115, CD140a, CD196, PDPN) and functional markers (IFN-gamma, IL-4, IL-22, LAP-TGF-beta, TNF-alpha, T-bet, RoRgammat) that were associated with recovery and SAP. Moreover, a targeted functional analysis further revealed distinct expression of pro- and anti-inflammatory cytokines by pancreatic CD206+ macrophage subsets as the disease either progressed or resolved. Similarly, we identified heterogeneity among circulating classical inflammatory monocytes (CD14+CD16-) and novel subsets in patients with AP and RAP.CONCLUSION: We identified several novel monocyte/macrophage subsets with unique phenotype and functional characteristics that are associated with AP, recovery, and SAP. Our findings highlight differential innate immune responses during AP progression and recovery that can be leveraged for future disease monitoring and targeting.

    View details for DOI 10.1053/j.gastro.2021.08.033

    View details for PubMedID 34450180

  • PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies: Rationale and Study Design for PROCEED From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas Yadav, D. n., Park, W. G., Fogel, E. L., Li, L. n., Chari, S. T., Feng, Z. n., Fisher, W. E., Forsmark, C. E., Jeon, C. Y., Habtezion, A. n., Hart, P. A., Hughes, S. J., Othman, M. O., Rinaudo, J. A., Pandol, S. J., Tirkes, T. n., Serrano, J. n., Srivastava, S. n., Van Den Eeden, S. K., Whitcomb, D. C., Topazian, M. n., Conwell, D. L. ; 47 (10): 1229–38

    Abstract

    Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) is the first prospective, observational cohort study of chronic pancreatitis (CP) in the United States. The primary goals of PROCEED are to define disease progression, test the predictive capability of candidate biomarkers, and develop a platform to conduct translational and mechanistic studies in CP. Using objective and consensus-driven criteria, PROCEED will enroll adults at different stages of CP-controls, suspected CP, and definite CP. In addition to collecting detailed information using structured case report forms and protocol-mandated evaluations at baseline and during follow-up, PROCEED will establish a linked biorepository of blood, urine, saliva, stool, pancreatic fluid, and pancreatic tissue. Enrollment for PROCEED began in June 2017. As of July 1, 2018, nine clinical centers of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer are enrolling, and 350 subjects have completed baseline evaluation. In conclusion, PROCEED will provide the most accurate and reliable estimates to date on progression of CP. The established cohort and biorepository will facilitate numerous analyses, leading to new strategies for diagnosis, methods to monitor disease progression, and treatment of CP.

    View details for PubMedID 30325862

  • Protective Effect of Saffron in Mouse Colitis Models Through Immune Modulation. Digestive diseases and sciences Singh, G., Haileselassie, Y., Ji, A. R., Maecker, H. T., Sinha, S. R., Brim, H., Habtezion, A., Ashktorab, H. 2021

    Abstract

    BACKGROUND: People with inflammatory bowel disease (IBD) including ulcerative colitis are at risk for colorectal cancer. Despite available effective drugs used to treat IBD, many patients fail or lose response over time with some displaying drug-induced adverse events. Saffron (Crocus sativus) has been reported to have anti-inflammatory properties. Its protective role in IBD has not been explored extensively.AIM: To establish whether saffron treatment alleviates inflammation in experimental colitis.METHODS: Colitis was induced in C57BL/6 mice with 3% DSS and treated with either saffron doses (7.5, 15, 20, 25mg/kg body weight) or vehicle through daily gavage. On day 11, mice were euthanized and analyzed for gross and microscopic inflammation. Distal colon segments were collected for mRNA and protein expression of HO-1 protein and GPX2, (the downstream targets of NRF-2). Nrf-2 translocation from cytosol to nucleus was confirmed by immunofluorescence, and further Nrf-2 protein expression in nuclear and cytosolic fraction of colon was analyzed by immunoblot. Immune cells were isolated from the lamina propria of mouse colon for flow cytometry-based immunophenotyping. Colitis was also induced in C57BL/6 Ahr knockout and wild type mice to explore the involvement of Ahr-dependent pathways in saffron's protective effect(s). The therapeutic effect of saffron was further validated in another TNBS model of colitis.RESULTS: Saffron 20mg/kg body weightshowed improved colon gross and histology features and led to better body weight, colon length, histology score, and reduced disease activity index (DAI). Saffron significantly decreased pro-inflammatory macrophages (M1), while increasing anti-inflammatory macrophages (M2) and IL10+dendritic cells. Saffron treatment also enhanced CD3+T and CD3+CD8+T cells followed by increase in different CD3+CD4+T cells subsets like CD25+T cells, FoxP3+CD25+regulatory T cells, and CD4+FOXP3+CD25-regulatory T cells. Immunoblot analysis showed a significant increase in HO-1/GPX2 protein expression. With saffron treatment, Nrf-2 translocation into nucleus from cytosol also supports the involvement of Nrf-2 and its downstream targets in the protective effect of saffron. Further, we demonstrated that saffron in part exert anti-inflammatory effect through activation of aryl hydrocarbon receptor (AhR)-nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways.CONCLUSION: These data demonstrate saffron's therapeutic potential and its protective role in part via Ahr/Nrf-2 pathways and regulatory innate and adaptive immune cells.

    View details for DOI 10.1007/s10620-021-07163-3

    View details for PubMedID 34275090

  • CYTOKINE PROFILE ELEVATIONS ON ADMISSION CAN DETERMINE RISKS OF SEVERE ACUTE PANCREATITIS IN CHILDREN. The Journal of pediatrics Farrell, P. R., Jones, E. K., Hornung, L., Thompson, T., Patel, J., Lin, T. K., Nathan, J. D., Vitale, D. S., Habtezion, A., Abu-El-Haija, M. 2021

    Abstract

    OBJECTIVES: To utilize a Luminex platform to examine multiple cytokines simultaneously as well as clinical laboratory testing in order to identify markers that predict acute pancreatitis (AP) severity in the pediatric population on admission.STUDY DESIGN: Patients (<19 years) prospectively enrolled over a 4-year period in a single institution AP database were included in separate derivation and validation cohorts. Plasma samples were obtained within 48 hours of admission and stored for analysis. Samples from mild AP and SAP (moderately severe and severe combined) were analyzed using Luminex panels and C-Reactive Protein (CRP) testing.RESULTS: The derivation cohort examined 62 cytokines in 66 subject samples (20 control, 36 mild AP, 10 SAP) and identified interleukin 6 (IL-6) [P = .02] and monocyte chemotactic protein-1 (MCP-1) [p=0.02] as cytokines that were differentially expressed between mild and SAP. Our validation cohort analyzed 76 cytokines between 10 controls, 19 mild AP and 6 SAP subjects. IL-6 (p=0.02) and MCP-1 (p=0.007) were again found to differentiate mild AP from SAP. CRP values were obtained from 53 of the subjects, revealing a strong association between elevated CRP values and progression to severe disease (P<0.0001).CONCLUSION: This study identified and validated IL-6 and MCP-1 as predictors of SAP using 2 distinct cohorts, and showed that CRP elevation is a marker of progression to SAP. These biomarkers have not been extensively studied in the pediatric AP population. Our data allows for risk-stratification of AP patients, and represent novel insight into the immunologic response in SAP.

    View details for DOI 10.1016/j.jpeds.2021.07.015

    View details for PubMedID 34273357

  • Preventive effects of saffron in a colitis mouse model. Banskota, S., Khan, W., Singh, G., Habtezion, A., Brim, H., Ashktorab, H. AMER ASSOC CANCER RESEARCH. 2021