World Journal of Gastroenterology

Mucosal healing (MH) is vital in maintaining homeostasis within the gut and protecting against injury and infections. Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/repair. However, when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier auto-immune disease results, particularly inflammatory bowel disease (IBD). Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions, with the mechanisms of regulation just beginning to be understood. Consequently, there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes, so tissue damage in the gastrointestinal tract of patients, even those in clinical remission, persists. With increased understanding of the molecular mechanisms of IBD and MH, tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body’s own healing response. In this review, we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.

[1]  P. Dhawan,et al.  The diet-microbiota axis: a key regulator of intestinal permeability in human health and disease , 2022, Tissue barriers.

[2]  M. Dubinsky,et al.  Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials , 2022, The Lancet.

[3]  Chenghai Yang,et al.  Gut microbiota-derived butyrate regulates gut mucus barrier repair by activating the macrophage/WNT/ERK signaling pathway. , 2022, Clinical science.

[4]  P. Saas,et al.  Pro-Resolving Factors Released by Macrophages After Efferocytosis Promote Mucosal Wound Healing in Inflammatory Bowel Disease , 2021, Frontiers in Immunology.

[5]  R. Tyagi,et al.  Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice , 2021, Cells.

[6]  M. Enculescu,et al.  Redox Mechanism of Azathioprine and Its Interaction with DNA , 2021, International journal of molecular sciences.

[7]  A. Kruglov,et al.  Interplay Between Microbiota, Toll-Like Receptors and Cytokines for the Maintenance of Epithelial Barrier Integrity , 2021, Frontiers in Medicine.

[8]  A. Nusrat,et al.  JAM‐A signals through the Hippo pathway to regulate intestinal epithelial proliferation , 2021, The FASEB Journal.

[9]  M. Neurath,et al.  Intestinal Mucosal Wound Healing and Barrier Integrity in IBD–Crosstalk and Trafficking of Cellular Players , 2021, Frontiers in Medicine.

[10]  Anthony M. Haag,et al.  Bacteroides ovatus promotes IL-22 production and reduces trinitrobenzene sulfonic acid (TNBS)-driven colonic inflammation. , 2021, The American journal of pathology.

[11]  L. Ding,et al.  Cldn-7 deficiency promotes experimental colitis and associated carcinogenesis by regulating intestinal epithelial integrity , 2021, Oncoimmunology.

[12]  C. Guda,et al.  Gut Microbiota and Metabolic Specificity in Ulcerative Colitis and Crohn's Disease , 2020, Frontiers in Medicine.

[13]  L. Yao,et al.  NDRG2 regulates adherens junction integrity to restrict colitis and tumourigenesis , 2020, EBioMedicine.

[14]  M. Nitert,et al.  The Gut Microbiota and Inflammation: An Overview , 2020, International journal of environmental research and public health.

[15]  M. Stelmach-Mardas,et al.  Influence of Enteral Nutrition on Gut Microbiota Composition in Patients with Crohn’s Disease: A Systematic Review , 2020, Nutrients.

[16]  M. Goldberg,et al.  Microbiota-Sourced Purines Support Wound Healing and Mucous Barrier Function , 2020, iScience.

[17]  S. Miriuka,et al.  Downregulation of E-cadherin in pluripotent stem cells triggers partial EMT , 2020, Scientific Reports.

[18]  A. Schmitt,et al.  Essential role for autophagy protein ATG7 in the maintenance of intestinal stem cell integrity , 2020, Proceedings of the National Academy of Sciences.

[19]  H. Sokol,et al.  Gut microbiota-derived metabolites as key actors in inflammatory bowel disease , 2020, Nature Reviews Gastroenterology & Hepatology.

[20]  M. Georgiou,et al.  The multifarious regulation of the apical junctional complex , 2020, Open Biology.

[21]  J. Parker,et al.  Tight Junction Protein Claudin-7 Is Essential for Intestinal Epithelial Stem Cell Self-Renewal and Differentiation , 2019, Cellular and molecular gastroenterology and hepatology.

[22]  A. Cheifetz,et al.  Etiology and Management of Lack or Loss of Response to Anti-Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease. , 2019, Gastroenterology & hepatology.

[23]  Licheng Wu,et al.  Inflammation-induced Occludin Downregulation Limits Epithelial Apoptosis by Suppressing Caspase 3 Expression. , 2019, Gastroenterology.

[24]  M. Neurath,et al.  Targeting mucosal healing in Crohn’s disease: what the clinician needs to know , 2019, Therapeutic advances in gastroenterology.

[25]  P. Frenette,et al.  Cross talk between neutrophils and the microbiota. , 2019, Blood.

[26]  M. Washington,et al.  Upregulated Claudin-1 Expression Promotes Colitis-associated Cancer by promoting β-Catenin phosphorylation and activation in Notch/p-AKT Dependent Manner , 2019, Oncogene.

[27]  D. Rubin,et al.  Safety and Efficacy of Combination Treatment With Calcineurin Inhibitors and Vedolizumab in Patients With Refractory Inflammatory Bowel Disease , 2019, Clinical Gastroenterology and Hepatology.

[28]  Jessica K. Lang,et al.  The Crohn’s disease polymorphism, ATG16L1 T300A, alters the gut microbiota and enhances the local Th1/Th17 response , 2019, eLife.

[29]  H. Zhang,et al.  Novel strains of Bacteroides fragilis and Bacteroides ovatus alleviate the LPS-induced inflammation in mice , 2019, Applied Microbiology and Biotechnology.

[30]  P. Saas,et al.  Factors Produced by Macrophages Eliminating Apoptotic Cells Demonstrate Pro-Resolutive Properties and Terminate Ongoing Inflammation , 2018, Front. Immunol..

[31]  P. Rutgeerts,et al.  Efficacy of Ustekinumab for Inducing Endoscopic Healing in Patients With Crohn's Disease. , 2018, Gastroenterology.

[32]  Y. Cong,et al.  Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis , 2018, Nature Communications.

[33]  B. Muegge,et al.  Temporal Regulation of the Bacterial Metabolite Deoxycholate during Colonic Repair Is Critical for Crypt Regeneration. , 2018, Cell host & microbe.

[34]  S. Ryu,et al.  Mechanisms regulating intestinal barrier integrity and its pathological implications , 2018, Experimental & Molecular Medicine.

[35]  H. Meng,et al.  Impaired Autophagy in Intestinal Epithelial Cells Alters Gut Microbiota and Host Immune Responses , 2018, Applied and Environmental Microbiology.

[36]  R. Gearry,et al.  Treatment of Active Crohn’s Disease with Exclusive and Partial Enteral Nutrition: A Pilot Study in Adults , 2018, Inflammatory Intestinal Diseases.

[37]  T. Denning,et al.  Segmented filamentous bacteria‐induced immune responses: a balancing act between host protection and autoimmunity , 2018, Immunology.

[38]  Y. Naito,et al.  Gut microbiota in the pathogenesis of inflammatory bowel disease , 2018, Clinical Journal of Gastroenterology.

[39]  S. Vermeire,et al.  Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II) , 2017, Gut.

[40]  Y. Mori,et al.  Down-regulation of the Wnt/β-catenin signaling pathway by Cacnb4 , 2017, Molecular biology of the cell.

[41]  L. Albenberg,et al.  Gut microbiota and IBD: causation or correlation? , 2017, Nature Reviews Gastroenterology &Hepatology.

[42]  P. Dhawan,et al.  HDAC-4 regulates claudin-2 expression in EGFR-ERK1/2 dependent manner to regulate colonic epithelial cell differentiation , 2017, Oncotarget.

[43]  G. Núñez,et al.  Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease , 2017, Immunological reviews.

[44]  T. Denning,et al.  Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling. , 2017, The Journal of clinical investigation.

[45]  S. Ichinose,et al.  Intrinsic Autophagy Is Required for the Maintenance of Intestinal Stem Cells and for Irradiation-Induced Intestinal Regeneration. , 2017, Cell reports.

[46]  E. Campbell,et al.  Bacteroidales recruit IL-6 producing intraepithelial lymphocytes in the colon to promote barrier integrity , 2017, Mucosal Immunology.

[47]  Nirmal Rajasekaran,et al.  Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin , 2017, Scientific Reports.

[48]  Xiang Gao,et al.  Methotrexate for Refractory Crohn's Disease Compared with Thiopurines: A Retrospective Non-head-to-head Controlled Study , 2017, Inflammatory bowel diseases.

[49]  H. Miyoshi,et al.  Prostaglandin E2 promotes intestinal repair through an adaptive cellular response of the epithelium , 2017, The EMBO journal.

[50]  R. Goldszmid,et al.  Microbiota—myeloid cell crosstalk beyond the gut , 2016, Journal of leukocyte biology.

[51]  F. Bussière,et al.  Cryptosporidium parvum increases intestinal permeability through interaction with epithelial cells and IL‐1β and TNFα released by inflammatory monocytes , 2016, Cellular microbiology.

[52]  A. Abbas,et al.  Cutting Edge: Regulatory T Cells Facilitate Cutaneous Wound Healing , 2016, The Journal of Immunology.

[53]  G. Leoni,et al.  The microenvironment of injured murine gut elicits a local pro-restitutive microbiota , 2016, Nature Microbiology.

[54]  R. Jenq,et al.  Interleukin-22 Promotes Intestinal Stem Cell-Mediated Epithelial Regeneration , 2015, Nature.

[55]  P. Brigidi,et al.  The effect of short-chain fatty acids on human monocyte-derived dendritic cells , 2015, Scientific Reports.

[56]  N. Shen,et al.  Growth Factor FGF2 Cooperates with Interleukin-17 to Repair Intestinal Epithelial Damage. , 2015, Immunity.

[57]  T. Murdoch,et al.  Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target , 2015, The American Journal of Gastroenterology.

[58]  Jun Sun,et al.  Tight junction CLDN2 gene is a direct target of the vitamin D receptor , 2015, Scientific Reports.

[59]  Haijun Wan,et al.  Changes in the Expression and Distribution of Claudins, Increased Epithelial Apoptosis, and a Mannan-Binding Lectin-Associated Immune Response Lead to Barrier Dysfunction in Dextran Sodium Sulfate-Induced Rat Colitis , 2015, Gut and liver.

[60]  K. Faber,et al.  The ATG16L1–T300A allele impairs clearance of pathosymbionts in the inflamed ileal mucosa of Crohn's disease patients , 2014, Gut.

[61]  W. Ouyang,et al.  Homeostatic IL-23 receptor signaling limits Th17 response through IL-22–mediated containment of commensal microbiota , 2014, Proceedings of the National Academy of Sciences.

[62]  M. Washington,et al.  Claudin-1 overexpression in intestinal epithelial cells enhances susceptibility to adenamatous polyposis coli-mediated colon tumorigenesis , 2014, Molecular Cancer.

[63]  M. Sudol,et al.  ZO Proteins Redundantly Regulate the Transcription Factor DbpA/ZONAB* , 2014, The Journal of Biological Chemistry.

[64]  H. Al‐Salami,et al.  Inflammatory bowel disease: clinical aspects and treatments , 2014, Journal of inflammation research.

[65]  Bangmao Wang,et al.  Activation of Epidermal Growth Factor Receptor Mediates Mucin Production Stimulated by p40, a Lactobacillus rhamnosus GG-derived Protein* , 2014, The Journal of Biological Chemistry.

[66]  S. Kang,et al.  Short chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway , 2014, Mucosal Immunology.

[67]  Markus F. Neurath,et al.  Cytokines in inflammatory bowel disease , 2014, Nature Reviews Immunology.

[68]  G. Leoni,et al.  Redox signaling regulates commensal mediated mucosal homeostasis and restitution and requires formyl peptide receptor 1 (FPR1) , 2013, Mucosal Immunology.

[69]  D. Rubin,et al.  Mucosal Healing Is Associated with Improved Long-term Outcome of Maintenance Therapy with Natalizumab in Crohn's Disease , 2013, Inflammatory bowel diseases.

[70]  Å. Keita,et al.  Faecalibacterium prausnitzii supernatant improves intestinal barrier function in mice DSS colitis , 2013, Scandinavian journal of gastroenterology.

[71]  W. Garrett,et al.  The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis , 2013, Science.

[72]  S. Rutz,et al.  IL‐22, not simply a Th17 cytokine , 2013, Immunological reviews.

[73]  C. Buskens,et al.  Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues , 2013, Nature Immunology.

[74]  E. Walker,et al.  E-cadherin is required for intestinal morphogenesis in the mouse. , 2012, Developmental biology.

[75]  M. V. van Oijen,et al.  High mucosal healing rates in 5‐ASA‐treated ulcerative colitis patients: Results of a meta‐analysis of clinical trials , 2012, Inflammatory bowel diseases.

[76]  R. Jenq,et al.  Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. , 2012, Immunity.

[77]  C. Leifer,et al.  TLR9 is important for protection against intestinal damage and for intestinal repair , 2012, Scientific Reports.

[78]  H. Miyoshi,et al.  Igf2bp1 is required for full induction of Ptgs2 mRNA in colonic mesenchymal stem cells in mice. , 2012, Gastroenterology.

[79]  P. Rutgeerts,et al.  Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial. , 2012, Gastroenterology.

[80]  A. Zychlinsky,et al.  Neutrophil function: from mechanisms to disease. , 2012, Annual review of immunology.

[81]  L. Stronati,et al.  Randomised clinical trial: the effectiveness of Lactobacillus reuteri ATCC 55730 rectal enema in children with active distal ulcerative colitis , 2012, Alimentary pharmacology & therapeutics.

[82]  Loren S Myers,et al.  Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function. , 2012, The American journal of pathology.

[83]  Bernard Henrissat,et al.  Recognition and Degradation of Plant Cell Wall Polysaccharides by Two Human Gut Symbionts , 2011, PLoS biology.

[84]  C. Dai,et al.  VSL#3 probiotics regulate the intestinal epithelial barrier in vivo and in vitro via the p38 and ERK signaling pathways. , 2011, International journal of molecular medicine.

[85]  Takuya Suzuki,et al.  Interleukin-6 (IL-6) Regulates Claudin-2 Expression and Tight Junction Permeability in Intestinal Epithelium* , 2011, The Journal of Biological Chemistry.

[86]  Wei Sun,et al.  The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. , 2011, Cell metabolism.

[87]  Linheng Li,et al.  JAM‐A regulates epithelial proliferation through Akt/β‐catenin signalling , 2011, EMBO reports.

[88]  O. Kirak,et al.  Yap1 Acts Downstream of α-Catenin to Control Epidermal Proliferation , 2011, Cell.

[89]  Gary D Bader,et al.  Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling. , 2010, The Biochemical journal.

[90]  E. Kuipers,et al.  A short course of corticosteroids prior to surveillance colonoscopy to decrease mucosal inflammation in inflammatory bowel disease patients: results from a randomized controlled trial. , 2010, Journal of Crohn's & colitis.

[91]  M. Washington,et al.  p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice. , 2010, The Journal of clinical investigation.

[92]  H. Flint,et al.  Diversity of human colonic butyrate-producing bacteria revealed by analysis of the butyryl-CoA:acetate CoA-transferase gene. , 2010, Environmental microbiology.

[93]  Dan R. Littman,et al.  Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria , 2009, Cell.

[94]  D. Leckband,et al.  Cadherin and integrin regulation of epithelial cell migration. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[95]  C. V. Van Itallie,et al.  Physiology and function of the tight junction. , 2009, Cold Spring Harbor perspectives in biology.

[96]  M. Neurath,et al.  STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing , 2009, The Journal of experimental medicine.

[97]  S. Hogan,et al.  Intestinal barrier function: molecular regulation and disease pathogenesis. , 2009, The Journal of allergy and clinical immunology.

[98]  M. Zöller,et al.  Claudin-7 Regulates EpCAM-Mediated Functions in Tumor Progression , 2009, Molecular Cancer Research.

[99]  A. Murphy,et al.  Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. , 2008, Immunity.

[100]  Qiurong Li,et al.  Invasion of enteropathogenic Escherichia coli into host cells through epithelial tight junctions , 2008, The FEBS journal.

[101]  J. Doré,et al.  Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients , 2008, Proceedings of the National Academy of Sciences.

[102]  T. Noda,et al.  Megaintestine in claudin-15-deficient mice. , 2008, Gastroenterology.

[103]  R. Xavier,et al.  IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. , 2008, The Journal of clinical investigation.

[104]  A. Franco,et al.  Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and γ-secretase-dependent E-cadherin cleavage , 2007, Journal of Cell Science.

[105]  A. Blikslager,et al.  Restoration of barrier function in injured intestinal mucosa. , 2007, Physiological reviews.

[106]  P. Rutgeerts,et al.  Mucosal healing in inflammatory bowel disease: impossible ideal or therapeutic target? , 2007, Gut.

[107]  J. Fox,et al.  Disruption of Tight Junctions and Induction of Proinflammatory Cytokine Responses in Colonic Epithelial Cells by Campylobacter jejuni , 2006, Infection and Immunity.

[108]  P. Rutgeerts,et al.  Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. , 2006, Gastroenterology.

[109]  K. Kaukinen,et al.  Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells , 2005, Laboratory Investigation.

[110]  Jason M Doherty,et al.  Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[111]  Ruslan Medzhitov,et al.  Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis , 2004, Cell.

[112]  B. Hillenbrand,et al.  Functional crosstalk between Wnt signaling and Cdx-related transcriptional activation in the regulation of the claudin-2 promoter activity. , 2004, Biochemical and biophysical research communications.

[113]  M. Garrett,et al.  The ZO-1–associated Y-box factor ZONAB regulates epithelial cell proliferation and cell density , 2003, The Journal of cell biology.

[114]  P. Jeannesson,et al.  Butyrate affects differentiation, maturation and function of human monocyte‐derived dendritic cells and macrophages , 2002, Clinical and experimental immunology.

[115]  P. Rutgeerts,et al.  Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's disease , 2002, American Journal of Gastroenterology.

[116]  M. Jepson,et al.  Localization of Dysfunctional Tight Junctions inSalmonella enterica Serovar Typhimurium-Infected Epithelial Layers , 2000, Infection and Immunity.

[117]  P. Mortensen,et al.  Oxidation of short and medium chain C2-C8 fatty acids in Sprague-Dawley rat colonocytes. , 1997, Gut.

[118]  W. Falk,et al.  Neutralization of tumour necrosis factor (TNF) but not of IL‐1 reduces inflammation in chronic dextran sulphate sodium‐induced colitis in mice , 1997, Clinical and experimental immunology.

[119]  V. Dalal,et al.  Butyrate enema therapy stimulates mucosal repair in experimental colitis in the rat. , 1996, Gut.

[120]  P. Mortensen,et al.  Kinetic studies on colonocyte metabolism of short chain fatty acids and glucose in ulcerative colitis. , 1995, Gut.

[121]  M. Tanimoto,et al.  Elevation of interleukin-6 in inflammatory bowel disease is macrophage- and epithelial cell-dependent , 1995, Digestive Diseases and Sciences.

[122]  K. Rajewsky,et al.  Interleukin-10-deficient mice develop chronic enterocolitis , 1993, Cell.

[123]  G. Macfarlane,et al.  The control and consequences of bacterial fermentation in the human colon. , 1991, The Journal of applied bacteriology.

[124]  R. Modigliani,et al.  Clinical, biological, and endoscopic picture of attacks of Crohn's disease. Evolution on prednisolone. Groupe d'Etude Thérapeutique des Affections Inflammatoires Digestives. , 1990, Gastroenterology.

[125]  W. Roediger Utilization of nutrients by isolated epithelial cells of the rat colon. , 1982, Gastroenterology.

[126]  G. Abrams,et al.  Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. A comparison of germ-free and conventional mice. , 1963, Laboratory investigation; a journal of technical methods and pathology.

[127]  J. Turner,et al.  Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease. , 2018, Cold Spring Harbor perspectives in biology.

[128]  A. Nusrat,et al.  Immunopathology and Infectious Diseases The Bacterial Virulence Factor Lymphostatin Compromises Intestinal Epithelial Barrier Function by Modulating Rho GTPases , 2010 .

[129]  B. Ryffel,et al.  Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. , 2005, Immunity.

[130]  S. Eom,et al.  Regulation of beta-catenin signaling and maintenance of chondrocyte differentiation by ubiquitin-independent proteasomal degradation of alpha-catenin. , 2005, The Journal of biological chemistry.

[131]  R. Xavier,et al.  Transforming growth factor-beta mediates intestinal healing and susceptibility to injury in vitro and in vivo through epithelial cells. , 2003, The American journal of pathology.

[132]  園田 紀之 Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands : Evidence for direct involvement of claudins in tight junction barrier , 2002 .

[133]  P. Rutgeerts,et al.  Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis. , 1999, Gastroenterology.

[134]  G. Fick,et al.  Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. , 1995, Annals of internal medicine.