Tobacco Alkaloid Assessment in a DSS-Induced Colitis Mouse Model with a Fully Humanized Immune System

Inflammatory bowel disease (IBD) refers to chronic intestinal immune-mediated diseases including two main disease manifestations: ulcerative colitis (UC) and Crohn’s disease (CD). Epidemiological, clinical, and preclinical evidence has highlighted the potential anti-inflammatory properties of naturally occurring alkaloids. In the present study, we investigated the potential anti-inflammatory activities of the tobacco alkaloids nicotine and anatabine in a dextran sulfate sodium (DSS)-induced UC mouse model with a fully humanized immune system. Our results show that nicotine significantly reduced all acute colitis symptoms and improved colitis-specific endpoints, including histopathologically assessed colon inflammation, tissue damage, and mononuclear cell infiltration. The tobacco alkaloid anatabine showed similar effectiveness trends, although they were generally weaker or not significant. Gene expression analysis in the context of biological network models of IBD further pinpointed a possible mechanism by which nicotine attenuated DSS-induced colitis in humanized mice. The current study enables further investigation of possible molecular mechanisms by which tobacco alkaloids attenuate UC symptoms.

[1]  Dimitris E. Messinis,et al.  Systems biology reveals anatabine to be an NRF2 activator , 2022, Frontiers in Pharmacology.

[2]  M. Peitsch,et al.  Causal Biological Network Model for Inflammasome Signaling Applied for Interpreting Transcriptomic Changes in Various Inflammatory States , 2022, International journal of inflammation.

[3]  A. H. Paz,et al.  Cholinergic immunomodulation in inflammatory bowel diseases , 2021, Brain, behavior, & immunity - health.

[4]  Y. Hwang,et al.  Inhibiting TLR7 Expression in the Retinal Pigment Epithelium Suppresses Experimental Autoimmune Uveitis , 2022, Frontiers in Immunology.

[5]  M. Peitsch,et al.  Systems biology approach highlights mechanistic differences between Crohn’s disease and ulcerative colitis , 2021, Scientific Reports.

[6]  M. Peitsch,et al.  Development of an Advanced Multicellular Intestinal Model for Assessing Immunomodulatory Properties of Anti-Inflammatory Compounds , 2021, Frontiers in Pharmacology.

[7]  M. Peitsch,et al.  In Vivo Profiling of a Natural Alkaloid, Anatabine, in Rodents: Pharmacokinetics and Anti-Inflammatory Efficacy. , 2021, Journal of Natural Products.

[8]  Rémi H. J. Dulize,et al.  Anatabine ameliorates intestinal inflammation and reduces the production of pro-inflammatory factors in a dextran sulfate sodium mouse model of colitis , 2020, Journal of Inflammation.

[9]  D. Hinds,et al.  Anti-IL-13Rα2 therapy promotes recovery in a murine model of inflammatory bowel disease , 2019, Mucosal Immunology.

[10]  Jiao Peng,et al.  Plant-Derived Alkaloids: The Promising Disease-Modifying Agents for Inflammatory Bowel Disease , 2019, Front. Pharmacol..

[11]  G. Kaplan,et al.  Past and Future Burden of Inflammatory Bowel Diseases Based on Modeling of Population-Based Data. , 2019, Gastroenterology.

[12]  S. A. Kristian,et al.  Topical nicotinic receptor activation improves wound bacterial infection outcomes and TLR2‐mediated inflammation in diabetic mouse wounds , 2018, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[13]  K. Tomita,et al.  Nicotine treatment ameliorates DSS‐induced colitis by suppressing MAdCAM‐1 expression and leukocyte recruitment , 2018, Journal of leukocyte biology.

[14]  P. Andrade,et al.  Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety , 2018, International journal of molecular sciences.

[15]  S. Bueno,et al.  Impact of Cigarette Smoking on the Gastrointestinal Tract Inflammation: Opposing Effects in Crohn’s Disease and Ulcerative Colitis , 2018, Front. Immunol..

[16]  Nima Hamidi,et al.  Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies , 2017, The Lancet.

[17]  Hong Yang,et al.  Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics , 2017, Front. Physiol..

[18]  L. Peyrin-Biroulet,et al.  Ulcerative colitis , 2017, The Lancet.

[19]  L. Peyrin-Biroulet,et al.  Crohn's disease , 2017, The Lancet.

[20]  Yili Yang,et al.  Nicotine protects against DSS colitis through regulating microRNA-124 and STAT3 , 2017, Journal of Molecular Medicine.

[21]  Eugene Y. Kim,et al.  Enteric Viruses Ameliorate Gut Inflammation via Toll-like Receptor 3 and Toll-like Receptor 7-Mediated Interferon-β Production. , 2016, Immunity.

[22]  A. Ford,et al.  Systematic review with meta‐analysis: the adverse effects of tobacco smoking on the natural history of Crohn's disease , 2016, Alimentary pharmacology & therapeutics.

[23]  V. Maslyakov,et al.  Effect of α7n-Acetylcholine Receptor Activation and Antibodies to TNF-α on Mortality of Mice and Concentration of Proinflammatory Cytokines During Early Stage of Sepsis , 2015, Bulletin of experimental biology and medicine.

[24]  Jie Du,et al.  1,25-Dihydroxyvitamin D Protects Intestinal Epithelial Barrier by Regulating the Myosin Light Chain Kinase Signaling Pathway , 2015, Inflammatory bowel diseases.

[25]  Katherine A. Radek,et al.  Keratinocyte nicotinic acetylcholine receptor activation modulates early TLR2-mediated wound healing responses. , 2015, International immunopharmacology.

[26]  Rena Li,et al.  Chronic Anatabine Treatment Reduces Alzheimer’s Disease (AD)-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD , 2015, PloS one.

[27]  E. Latorre,et al.  Antibiotic-Induced Depletion of Murine Microbiota Induces Mild Inflammation and Changes in Toll-Like Receptor Patterns and Intestinal Motility , 2015, Microbial Ecology.

[28]  Jennifer Park,et al.  Causal biological network database: a comprehensive platform of causal biological network models focused on the pulmonary and vascular systems , 2015, Database J. Biol. Databases Curation.

[29]  R. Flavell,et al.  Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome , 2015, Nature Communications.

[30]  G. Barreto,et al.  Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease , 2015, Front. Aging Neurosci..

[31]  Manuel C. Peitsch,et al.  Computational Systems Toxicology , 2015, Methods in Pharmacology and Toxicology.

[32]  Y. Ishii,et al.  Nicotine suppresses acute colitis and colonic tumorigenesis associated with chronic colitis in mice. , 2014, American journal of physiology. Gastrointestinal and liver physiology.

[33]  K. Tracey,et al.  α7 Nicotinic Acetylcholine Receptor Signaling Inhibits Inflammasome Activation by Preventing Mitochondrial DNA Release , 2014, Molecular medicine.

[34]  Yang Xiang,et al.  Quantification of biological network perturbations for mechanistic insight and diagnostics using two-layer causal models , 2014, BMC Bioinformatics.

[35]  E. Podack,et al.  Humanized mice: novel model for studying mechanisms of human immune-based therapies , 2013, Immunologic Research.

[36]  Jiahua Xie,et al.  Molecular genetics of alkaloid biosynthesis in Nicotiana tabacum. , 2013, Phytochemistry.

[37]  C. Weaver,et al.  Linking Vitamin D Deficiency to Inflammatory Bowel Disease , 2013, Inflammatory bowel diseases.

[38]  Jian-guo Li,et al.  Vagus Nerve Stimulation Attenuates Intestinal Epithelial Tight Junctions Disruption in Endotoxemic Mice Through &agr;7 Nicotinic Acetylcholine Receptors , 2013, Shock.

[39]  I. Nookaew,et al.  Enriching the gene set analysis of genome-wide data by incorporating directionality of gene expression and combining statistical hypotheses and methods , 2013, Nucleic acids research.

[40]  V. Mathura,et al.  Amelioration of Experimental Autoimmune Encephalomyelitis by Anatabine , 2013, PloS one.

[41]  M. Verma,et al.  Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation. , 2013, European journal of pharmacology.

[42]  A. Lichtman,et al.  Novel Insights on the Effect of Nicotine in a Murine Colitis Model , 2013, The Journal of Pharmacology and Experimental Therapeutics.

[43]  R. Leong,et al.  Review article: ulcerative colitis, smoking and nicotine therapy , 2012, Alimentary pharmacology & therapeutics.

[44]  M. Krzyżaniak,et al.  Targeting -7 Nicotinic Acetylcholine Receptor in the Enteric Nervous System A Cholinergic Agonist Prevents Gut Barrier Failure after Severe Burn Injury , 2012 .

[45]  Manuel C. Peitsch,et al.  Assessment of network perturbation amplitudes by applying high-throughput data to causal biological networks , 2012, BMC Systems Biology.

[46]  V. Mathura,et al.  Anatabine lowers Alzheimer's Aβ production in vitro and in vivo. , 2011, European journal of pharmacology.

[47]  R. Edwards,et al.  Cytokine-Induced Alterations of α7 Nicotinic Receptor in Colonic CD4 T Cells Mediate Dichotomous Response to Nicotine in Murine Models of Th1/Th17- versus Th2-Mediated Colitis , 2011, The Journal of Immunology.

[48]  Qi Li,et al.  Nicotine Reduces TNF-α Expression Through a α7 nAChR/MyD88/NF-ĸB Pathway in HBE16 Airway Epithelial Cells , 2011, Cellular Physiology and Biochemistry.

[49]  D. Greiner,et al.  Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rgamma(null) mutation. , 2010, Clinical immunology.

[50]  S. Gerber,et al.  Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/gammac-/-, Balb/c-Rag1-/-gammac-/-, and C.B-17-scid/bg immunodeficient mice. , 2009, Human immunology.

[51]  M. El-Mas,et al.  EXACERBATION BY NICOTINE OF THE CYCLOSPORINE A‐INDUCED IMPAIRMENT OF β‐ADRENOCEPTOR‐MEDIATED RENAL VASODILATION IN RATS , 2008, Clinical and experimental pharmacology & physiology.

[52]  S. Melgar,et al.  Validation of murine dextran sulfate sodium-induced colitis using four therapeutic agents for human inflammatory bowel disease. , 2008, International immunopharmacology.

[53]  S. Diebold,et al.  Recognition of viral single-stranded RNA by Toll-like receptors. , 2008, Advanced drug delivery reviews.

[54]  N. Lu,et al.  The Effect of the Cholinergic Anti‐Inflammatory Pathway on Experimental Colitis , 2007, Scandinavian journal of immunology.

[55]  A. Levine,et al.  Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease , 2007, Gut.

[56]  L. Ulloa,et al.  The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation , 2007, British journal of pharmacology.

[57]  W. Wu,et al.  Nicotine promotes colon tumor growth and angiogenesis through beta-adrenergic activation. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[58]  S. Galandiuk,et al.  Smoking and inflammatory bowel disease: a meta-analysis. , 2006, Mayo Clinic proceedings.

[59]  J. Shupe,et al.  Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. , 2006, Immunity.

[60]  R. Newcombe,et al.  A randomized trial of nicotine enemas for active ulcerative colitis. , 2005, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[61]  H. Berthoud,et al.  Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway , 2005, Nature Immunology.

[62]  R. Dummer,et al.  Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors. , 2004, Archives of dermatology.

[63]  J. Macdonald,et al.  Transdermal nicotine for induction of remission in ulcerative colitis. , 2004, The Cochrane database of systematic reviews.

[64]  P. Malfertheiner,et al.  Inhibition of p38 MAP kinase‐and RICK/NF‐κB‐signaling suppresses inflammatory bowel disease , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[65]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[66]  Kevin J. Tracey,et al.  Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation , 2002, Nature.

[67]  Philip Rosenstiel,et al.  p38 Mitogen-Activated Protein Kinase Is Activated and Linked to TNF-α Signaling in Inflammatory Bowel Disease1 , 2002, The Journal of Immunology.

[68]  P. Testoni,et al.  Distal ulcerative colitis refractory to rectal mesalamine: role of transdermal nicotine versus oral mesalamine. , 2002, Canadian journal of gastroenterology = Journal canadien de gastroenterologie.

[69]  Koichi Ito,et al.  Nicotine inhibits the production of inflammatory mediators in U937 cells through modulation of nuclear factor-kappaB activation. , 1998, Biochemical and biophysical research communications.

[70]  S. Rogers,et al.  Nicotine blocks TNF-alpha-mediated neuroprotection to NMDA by an alpha-bungarotoxin-sensitive pathway. , 1998, Journal of neurobiology.

[71]  K. Batts,et al.  Nicotine tartrate liquid enemas for mildly to moderately active left‐sided ulcerative colitis unresponsive to first‐line therapy: a pilot study , 1997, Alimentary pharmacology & therapeutics.

[72]  K. Batts,et al.  Transdermal Nicotine for Mildly to Moderately Active Ulcerative Colitis , 1997, Annals of Internal Medicine.

[73]  R. Newcombe,et al.  Transdermal nicotine compared with oral prednisolone therapy for active ulcerative colitis. , 1996, European journal of gastroenterology & hepatology.

[74]  R G Newcombe,et al.  Transdermal nicotine for active ulcerative colitis. , 1994, The New England journal of medicine.