Berberine ameliorates aGVHD by gut microbiota remodelling, TLR4 signalling suppression and colonic barrier repairment for NLRP3 inflammasome inhibition

Berberine (BBR), an isoquinoline alkaloid, is used to treat gastrointestinal disorders as an herbal medicine in China. The aim of this study was to investigate the anti‐inflammatory activities of BBR in a mouse model with acute graft‐versus‐host disease (aGVHD). Mice were intravenously injected with bone marrow cells from donors combined with splenocytes to develop aGVHD. The body weight, survival rate and clinical scores were monitored. Then the levels of inflammatory cytokines, histological changes (lung, liver and colon), colonic mucosal barrier and gut microbiota were analysed. Moreover, the toll‐like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (Myd88)/nuclear factor‐κB signalling pathway, NLRP3 inflammasome and its cytokines’ expressions were determined. The results showed that the gavage of BBR lessened GVHD‐induced weight loss, high mortality and clinical scores, inhibited inflammation and target organs damages and prevented GVHD‐indued colonic barrier damage. Additionally, BBR modulated gut microbiota, suppressed the activation of the TLR4 signaling pathway and inhibited NLRP3 inflammasome and its cytokine release. This study indicated that BBR might be a potential therapy for aGVHD through NLRP3 inflammasome inhibition.

[1]  Xiaoying Lin,et al.  Simiao Decoction Alleviates Gouty Arthritis by Modulating Proinflammatory Cytokines and the Gut Ecosystem , 2020, Frontiers in Pharmacology.

[2]  M. Ratajczak,et al.  The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis , 2020, Leukemia.

[3]  Zhongxing Jiang,et al.  Berberine combined with cyclosporine A alleviates acute graft-versus-host disease in murine models. , 2020, International immunopharmacology.

[4]  P. Higgins,et al.  Temporal Gut Microbial Changes Predict Recurrent Clostridiodes Difficile Infection in Patients With and Without Ulcerative Colitis. , 2020, Inflammatory bowel diseases.

[5]  H. Morita,et al.  Berberine improved experimental chronic colitis by regulating interferon-γ- and IL-17A-producing lamina propria CD4+ T cells through AMPK activation , 2019, Scientific Reports.

[6]  A. Schuetz.  Emerging agents of gastroenteritis: Aeromonas, Plesiomonas, and the diarrheagenic pathotypes of Escherichia coli. , 2019, Seminars in diagnostic pathology.

[7]  Donglu Wu,et al.  A Natural Isoquinoline Alkaloid With Antitumor Activity: Studies of the Biological Activities of Berberine , 2019, Front. Pharmacol..

[8]  M. Brink,et al.  Gut microbiota injury in allogeneic haematopoietic stem cell transplantation , 2018, Nature Reviews Cancer.

[9]  Liping Zhao,et al.  Remodelling of the gut microbiota by hyperactive NLRP3 induces regulatory T cells to maintain homeostasis , 2017, Nature Communications.

[10]  R. Knobler,et al.  Cutaneous Graft-Versus-Host Disease: Diagnosis and Treatment , 2017, American Journal of Clinical Dermatology.

[11]  G. Núñez,et al.  Mechanism and Regulation of NLRP3 Inflammasome Activation. , 2016, Trends in biochemical sciences.

[12]  Xin Gao,et al.  Lipid profiling of the therapeutic effects of berberine in patients with nonalcoholic fatty liver disease , 2016, Journal of Translational Medicine.

[13]  T. Vatanen,et al.  Dysbiosis, inflammation, and response to treatment: a longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease , 2016, Genome Medicine.

[14]  M. Kolev,et al.  Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses , 2015, Immunity.

[15]  Ning Li,et al.  Berberine prevents damage to the intestinal mucosal barrier during early phase of sepsis in rat through mechanisms independent of the NOD-like receptors signaling pathway. , 2014, European journal of pharmacology.

[16]  D. Sachs,et al.  Induction of tolerance through mixed chimerism. , 2014, Cold Spring Harbor perspectives in medicine.

[17]  C. V. Van Itallie,et al.  Claudin interactions in and out of the tight junction , 2013, Tissue barriers.

[18]  A. Sung,et al.  Concise Review: Acute Graft‐Versus‐Host Disease: Immunobiology, Prevention, and Treatment , 2013, Stem cells translational medicine.

[19]  J. Hampe,et al.  Oral glutamine supplementation improves intestinal permeability dysfunction in a murine acute graft-vs.-host disease model. , 2011, American journal of physiology. Gastrointestinal and liver physiology.

[20]  M. Lamkanfi,et al.  Toll or Interleukin-1 Receptor (TIR) Domain-containing Adaptor Inducing Interferon-β (TRIF)-mediated Caspase-11 Protease Production Integrates Toll-like Receptor 4 (TLR4) Protein- and Nlrp3 Inflammasome-mediated Host Defense against Enteropathogens* , 2012, The Journal of Biological Chemistry.

[21]  R. Khanin,et al.  Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation , 2012, The Journal of experimental medicine.

[22]  G. Núñez,et al.  Sensing and reacting to microbes through the inflammasomes , 2012, Nature Immunology.

[23]  J. Crow.  Microbiome: That healthy gut feeling , 2011, Nature.

[24]  Junling Han,et al.  Modulating gut microbiota as an anti-diabetic mechanism of berberine , 2011, Medical science monitor : international medical journal of experimental and clinical research.

[25]  J. Dipersio,et al.  Mouse models of graft-versus-host disease: advances and limitations , 2011, Disease Models & Mechanisms.

[26]  Wei-Jia Kong,et al.  Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. , 2010, Metabolism: clinical and experimental.

[27]  S. Tsao,et al.  Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. , 2009, Journal of ethnopharmacology.

[28]  E. Alnemri,et al.  Cutting Edge: NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression1 , 2009, The Journal of Immunology.

[29]  R. Komorowski,et al.  Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. , 2007, Blood.

[30]  W. Shlomchik,et al.  Graft-versus-host disease , 2007, Nature Reviews Immunology.

[31]  J. Schölmerich,et al.  Probiotic effects on experimental graft-versus-host disease: let them eat yogurt. , 2004, Blood.

[32]  J. Ferrara,et al.  Acute graft-versus-host disease does not require alloantigen expression on host epithelium , 2002, Nature Medicine.

[33]  J. Ferrara,et al.  Acute graft-versus-host disease does not require alloantigen expression on host epithelium , 2002, Nature Medicine.

[34]  J. Crawford,et al.  An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. , 1996, Blood.

[35]  K. Wilson,et al.  Sutterella wadsworthensis gen. nov., sp. nov., bile-resistant microaerophilic Campylobacter gracilis-like clinical isolates. , 1996, International Journal of Systematic Bacteriology.

[36]  G. Ledderose,et al.  Modulation of acute graft-versus-host-disease after allogeneic bone marrow transplantation by tumor necrosis factor alpha (TNF alpha) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNF alpha , 1995, Blood.

[37]  F. P. Nestel,et al.  Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease , 1992, The Journal of experimental medicine.

[38]  K. Sullivan,et al.  Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment. , 1983, The New England journal of medicine.