Effects of Different Routes and Forms of Vitamin D Administration on Mesenteric Lymph Node CD4+ T Cell Polarization and Intestinal Injury in Obese Mice Complicated with Polymicrobial Sepsis

This study compared the efficacies of enteral cholecalciferol and/or intravenous (IV) calcitriol administration on mesenteric lymph node (MLN) cluster-of-differentiation-4-positive (CD4+) T cell distribution and intestinal barrier damage in obese mice complicated with sepsis. Mice were fed a high-fat diet for 16 weeks and then sepsis was induced by cecal ligation and puncture (CLP). Mice were divided into the following sepsis groups: without vitamin D (VD) (S); with oral cholecalciferol 1 day before CLP (G); with IV calcitriol 1 h after CLP (V); and with both cholecalciferol before and IV calcitriol after CLP (GV). All mice were sacrificed at 12 or 24 h after CLP. The findings show that the S group had a higher T helper (Th)17 percentage than the VD-treated groups at 12 h after CLP. The V group exhibited a higher Th1 percentage and Th1/Th2 ratio than the other groups at 24 h, whereas the V and GV groups had a lower Th17/regulatory T (Treg) ratio 12 h post-CLP in MLNs. In ileum tissues, the VD-treated groups had higher tight junction protein and cathelicidin levels, and higher mucin gene expression than the S group at 24 h post-CLP. Also, aryl hydrocarbon receptor (AhR) and its associated cytochrome P450 1A1 and interleukin 22 gene expressions were upregulated. In contrast, levels of lipid peroxides and inflammatory mediators in ileum tissues were lower in the groups with VD treatment after CLP. These results suggest that IV calcitriol seemed to have a more-pronounced effect on modulating the homeostasis of Th/Treg subsets in MLNs. Both oral cholecalciferol before and IV calcitriol after CLP promoted cathelicidin secretion, alleviated intestinal inflammation, and ameliorated the epithelial integrity in obese mice complicated with sepsis possibly via VD receptor and AhR signaling pathways.

[1]  A. Slominski,et al.  Molecular and structural basis of interactions of vitamin D3 hydroxyderivatives with aryl hydrocarbon receptor (AhR): An integrated experimental and computational study. , 2022, International journal of biological macromolecules.

[2]  Godfraind Catherine,et al.  AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms , 2022, Gut microbes.

[3]  Ming-Tsan Lin,et al.  Intravenous calcitriol administration modulates mesenteric lymph node CD4+ T-cell polarization and attenuates intestinal inflammation in obese mice complicated with polymicrobial sepsis. , 2021, JPEN - Journal of Parenteral and Enteral Nutrition.

[4]  A. Rosenwald,et al.  Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract , 2021, Frontiers in Immunology.

[5]  Kuen-Yuan Chen,et al.  Intravenous calcitriol administration regulates the renin-angiotensin system and attenuates acute lung injury in obese mice complicated with polymicrobial sepsis. , 2021, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[6]  M. Haussler,et al.  Introduction: Special Issue on Vitamin D Dedicated to the Memory of Anthony W Norman , 2020, JBMR Plus.

[7]  M. Holick,et al.  Immunologic Effects of Vitamin D on Human Health and Disease , 2020, Nutrients.

[8]  M. Henríquez,et al.  Cholecalciferol or Calcifediol in the Management of Vitamin D Deficiency , 2020, Nutrients.

[9]  S. Karras,et al.  Vitamin D and intestinal homeostasis: Barrier, microbiota, and immune modulation , 2020, The Journal of Steroid Biochemistry and Molecular Biology.

[10]  Jun Yu,et al.  Cathelicidin preserves intestinal barrier function in polymicrobial sepsis , 2020, Critical care.

[11]  J. Windsor,et al.  Gastrointestinal Dysfunction in Critical Illness: A Review of Scoring Tools. , 2020, JPEN. Journal of parenteral and enteral nutrition.

[12]  Xiaojie Gan,et al.  Vitamin D alleviates acute graft-versus-host disease through promoting the generation of Foxp3+ T cells. , 2019, Annals of translational medicine.

[13]  M. Kamboh,et al.  Vitamin D as a Principal Factor in Mediating Rheumatoid Arthritis-Derived Immune Response , 2019, BioMed research international.

[14]  P. Pelosi,et al.  Obesity in the critically ill: a narrative review , 2019, Intensive Care Medicine.

[15]  L. Rejnmark,et al.  Managing vitamin D deficiency in inflammatory bowel disease , 2019, Frontline Gastroenterology.

[16]  C. Tamone,et al.  Vitamin D: Nutrient, Hormone, and Immunomodulator , 2018, Nutrients.

[17]  Yousheng Li,et al.  Vitamin D Improves Intestinal Barrier Function in Cirrhosis Rats by Upregulating Heme Oxygenase-1 Expression , 2018, Biomolecules & therapeutics.

[18]  Hua Yang,et al.  6-Formylindolo(3,2-b)carbazole induced aryl hydrocarbon receptor activation prevents intestinal barrier dysfunction through regulation of claudin-2 expression. , 2018, Chemico-biological interactions.

[19]  R. Kumar,et al.  The Use of Vitamin D Metabolites and Analogues in the Treatment of Chronic Kidney Disease. , 2017, Endocrinology and metabolism clinics of North America.

[20]  D. Heyland,et al.  Vitamin D supplementation in the critically ill: A systematic review and meta-analysis. , 2017, Clinical nutrition.

[21]  D. Tsikas Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges. , 2017, Analytical biochemistry.

[22]  Seong-Min Lee,et al.  The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights. , 2017, The Journal of clinical investigation.

[23]  A. Cavani,et al.  IL‐17 and IL‐22 in immunity: Driving protection and pathology , 2017, European journal of immunology.

[24]  S. Bhoi,et al.  Coexistence of Th1/Th2 and Th17/Treg imbalances in patients with post traumatic sepsis. , 2016, Cytokine.

[25]  D. Aretha,et al.  The Role of Obesity in Sepsis Outcome among Critically Ill Patients: A Retrospective Cohort Analysis , 2016, BioMed research international.

[26]  C. Coopersmith,et al.  Mechanisms of Intestinal Barrier Dysfunction in Sepsis , 2016, Shock.

[27]  G. Martin,et al.  High dose vitamin D administration in ventilated intensive care unit patients: A pilot double blind randomized controlled trial , 2016, Journal of clinical & translational endocrinology.

[28]  A. Ananthakrishnan Editorial: Vitamin D and IBD: Can We Get Over the “Causation” Hump? , 2016, The American Journal of Gastroenterology.

[29]  I. Nagaoka,et al.  Antimicrobial cathelicidin peptide LL-37 inhibits the pyroptosis of macrophages and improves the survival of polybacterial septic mice. , 2016, International immunology.

[30]  Shery Jacob,et al.  A simple practice guide for dose conversion between animals and human , 2016, Journal of basic and clinical pharmacy.

[31]  Christopher W Seymour,et al.  Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). , 2016, JAMA.

[32]  L. Maggio-Price,et al.  Protective links between vitamin D, inflammatory bowel disease and colon cancer. , 2016, World journal of gastroenterology.

[33]  C. Camargo,et al.  Effect of Cholecalciferol Supplementation on Vitamin D Status and Cathelicidin Levels in Sepsis: A Randomized, Placebo-Controlled Trial , 2015, Critical care medicine.

[34]  S. Upala,et al.  Significant association between vitamin D deficiency and sepsis: a systematic review and meta-analysis , 2015, BMC Anesthesiology.

[35]  M. Cantorna,et al.  Vitamin D and 1,25(OH)2D Regulation of T cells , 2015, Nutrients.

[36]  H. D. de Geus,et al.  Vitamin D deficiency as a risk factor for infection, sepsis and mortality in the critically ill: systematic review and meta-analysis , 2014, Critical Care.

[37]  V. Badovinac,et al.  Impact of sepsis on CD4 T cell immunity , 2014, Journal of leukocyte biology.

[38]  D. Leaf,et al.  Randomized controlled trial of calcitriol in severe sepsis. , 2014, American journal of respiratory and critical care medicine.

[39]  W. Grady,et al.  Increased dietary vitamin D suppresses MAPK signaling, colitis, and colon cancer. , 2014, Cancer research.

[40]  D. Deb,et al.  1,25-Dihydroxyvitamin D Promotes Negative Feedback Regulation of TLR Signaling via Targeting MicroRNA-155–SOCS1 in Macrophages , 2013, The Journal of Immunology.

[41]  S. Peltier,et al.  Vitamin D metabolism, functions and needs: from science to health claims , 2013, European Journal of Nutrition.

[42]  Jun Sun,et al.  Vitamin D, vitamin D receptor and tissue barriers , 2013, Tissue barriers.

[43]  Qiurong Li,et al.  Lipopolysaccharide-Induced Bacterial Translocation Is Intestine Site-Specific and Associates with Intestinal Mucosal Inflammation , 2012, Inflammation.

[44]  P. Webb,et al.  Occludin is required for apoptosis when claudin–claudin interactions are disrupted , 2012, Cell Death and Disease.

[45]  C. Garlanda,et al.  AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch , 2011, Nature Immunology.

[46]  M. Jenkins,et al.  Origins of CD4+ effector and central memory T cells , 2011, Nature Immunology.

[47]  T. Pieber,et al.  Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double-blind, placebo-controlled pilot study , 2011, Critical care.

[48]  D. Ye,et al.  Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention , 2011, Molecular and Cellular Biochemistry.

[49]  David A Hildeman,et al.  T CELLS ARE POTENT EARLY MEDIATORS OF THE HOST RESPONSE TO SEPSIS , 2010, Shock.

[50]  Jerrold R. Turner,et al.  Intestinal mucosal barrier function in health and disease , 2009, Nature Reviews Immunology.

[51]  H. Mukhtar,et al.  Aryl hydrocarbon receptor is an ozone sensor in human skin. , 2009, The Journal of investigative dermatology.

[52]  S. Amini,et al.  Monocyte chemoattractant protein-1 (MCP-1): an overview. , 2009, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[53]  Jie-shou Li,et al.  Disruption of tight junctions during polymicrobial sepsis in vivo , 2009, The Journal of pathology.

[54]  V. Kuchroo,et al.  Induction and effector functions of TH17 cells , 2008, Nature.

[55]  T. Nomura,et al.  Regulatory T Cells and Immune Tolerance , 2008, Cell.

[56]  J. Turner,et al.  Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application. , 2006, The American journal of pathology.

[57]  M. Falagas,et al.  Obesity and infection. , 2006, The Lancet. Infectious diseases.

[58]  John H. White,et al.  Cutting Edge: 1,25-Dihydroxyvitamin D3 Is a Direct Inducer of Antimicrobial Peptide Gene Expression1 , 2004, The Journal of Immunology.

[59]  D. Taupin,et al.  Trefoil factors: initiators of mucosal healing , 2003, Nature Reviews Molecular Cell Biology.

[60]  M. Uskoković,et al.  A 1α,25-Dihydroxyvitamin D3 Analog Enhances Regulatory T-Cells and Arrests Autoimmune Diabetes in NOD Mice , 2002 .

[61]  M. Cantorna,et al.  1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. , 2000, The Journal of nutrition.

[62]  C. Probert,et al.  Mucins and inflammatory bowel disease , 2000, Postgraduate medical journal.

[63]  I. Chaudry,et al.  Immune suppression in polymicrobial sepsis: differential regulation of Th1 and Th2 responses by p38 MAPK. , 2000, The Journal of surgical research.

[64]  J. Macfie,et al.  Microbiology of bacterial translocation in humans , 1998, Gut.

[65]  J. Dipiro Cytokine Networks with Infection: Mycobacterial Infections, Leishmaniasis, Human Immunodeficiency Virus Infection, and Sepsis , 1997, Pharmacotherapy.

[66]  J. Hassett,et al.  The Gut Origin Septic States in Blunt Multiple Trauma (ISS = 40) in the ICU , 1987, Annals of surgery.

[67]  R. Berg,et al.  Bacterial translocation from the gastrointestinal tract of athymic (nu/nu) mice , 1980, Infection and immunity.

[68]  C. Elmets,et al.  The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers. , 2020, Advances in experimental medicine and biology.

[69]  M. Fernández,et al.  Impact of Obesity and Metabolic Syndrome on Immunity. , 2016, Advances in nutrition.

[70]  J. Macfie Current status of bacterial translocation as a cause of surgical sepsis. , 2004, British medical bulletin.

[71]  M. Uskoković,et al.  A 1alpha,25-dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. , 2002, Diabetes.

[72]  N. Webster,et al.  T helper cell subset ratios in patients with severe sepsis , 1999, Intensive Care Medicine.