1 1275 135 DAMAGE-ASSOCIATED MOLECULAR PATTERNS IN INFLAMMATORY BOWEL DISEASE: FROM BIOMARKERS TO THERAPEUTIC TARGETS. THE CHRONIC INFLAMMATORY PROCESS UNDERLYING INFLAMMATORY BOWEL DISEASE (IBD), COMPRISING CROHN'S DISEASE AND ULCERATIVE COLITIS, DERIVES FROM THE INTERPLAY OF SEVERAL COMPONENTS IN A GENETICALLY SUSCEPTIBLE HOST. THESE COMPONENTS INCLUDE ENVIRONMENTAL ELEMENTS AND GUT MICROBIOTA A DYSBIOSIS. FOR DECADES, IMMUNE ABNORMALITIES HAVE BEEN INVESTIGATED AS CRITICALLY IMPORTANT IN IBD PATHOGENESIS, AND ATTEMPTS TO DEVELOP EFFECTIVE THERAPIES HAVE PREDOMINANTLY TARGETED THE IMMUNE SYSTEM. NEVERTHELESS, IMMUNE EVENTS REPRESENT ONLY ONE OF THE CONSTITUENTS CONTRIBUTING TO IBD PATHOGENESIS WITHIN THE CONTEXT OF THE COMPLEX CELLULAR AND MOLECULAR NETWORK UNDERLYING CHRONIC INTESTINAL INFLAMMATION. THESE FACTORS NEED TO BE APPRECIATED WITHIN THE MILIEU OF NON-IMMUNE COMPONENTS. DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPS), WHICH ARE ESSENTIALLY ENDOGENOUS STRESS PROTEINS EXPRESSED OR RELEASED AS A RESULT OF CELL OR TISSUE DAMAGE, HAVE BEEN SHOWN TO ACT AS DIRECT PRO-INFLAMMATORY MEDIATORS. EXCESSIVE OR PERSISTENT SIGNALLING MEDIATED BY SUCH MOLECULES CAN UNDERLIE SEVERAL CHRONIC INFLAMMATORY DISORDERS, INCLUDING IBD. THE RELEASE OF ENDOGENOUS DAMPS AMPLIFIES THE INFLAMMATORY RESPONSE DRIVEN BY IMMUNE AND NON-IMMUNE CELLS AND PROMOTES EPIGENETIC REPROGRAMMING IN IBD. THE EFFECTS DETERMINE PATHOLOGIC CHANGES, WHICH MAY SUSTAIN CHRONIC INTESTINAL INFLAMMATION AND ALSO UNDERLIE SPECIFIC DISEASE PHENOTYPES. IN ADDITION TO HIGHLIGHTING THE POTENTIAL USE OF DAMPS SUCH AS CALPROTECTIN AS BIOMARKERS, RESEARCH ON DAMPS MAY REVEAL NOVEL MECHANISTIC ASSOCIATIONS IN IBD PATHOGENESIS AND IS EXPECTED TO UNCOVER PUTATIVE THERAPEUTIC TARGETS. 2018 2 2675 47 ETIOPATHOGENESIS OF INFLAMMATORY BOWEL DISEASE: TODAY AND TOMORROW. PURPOSE OF REVIEW: CROHN'S DISEASE AND ULCERATIVE COLITIS, THE TWO MAJOR FORMS OF INFLAMMATORY BOWEL DISEASE (IBD), REPRESENT CHRONIC DISEASES OF UNKNOWN CAUSE, AND THEY ARE REGARDED AS PROTOTYPICAL COMPLEX DISEASES. DESPITE ALL THE RECENT ADVANCES, A COMPLETE APPRECIATION OF THE PATHOGENESIS OF IBD IS STILL LIMITED. IN THIS REVIEW, WE PRESENT RECENT INFORMATION CONTRIBUTING TO A BETTER UNDERSTANDING OF MECHANISMS UNDERLYING IBD. RECENT FINDINGS: HERE, WE ATTEMPT TO HIGHLIGHT NOVEL ENVIRONMENTAL TRIGGERS, DATA ON THE GUT MICROBIOTA, ITS INTERACTION WITH THE HOST, AND THE POTENTIAL INFLUENCE OF DIET AND FOOD COMPONENTS. WE DISCUSS RECENT FINDINGS ON DEFECTIVE SIGNALING PATHWAYS AND THE POTENTIAL EFFECTS ON THE IMMUNE RESPONSE, AND WE PRESENT NEW DATA ON EPIGENETIC CHANGES, INFLAMMASOME, AND DAMAGE-ASSOCIATED MOLECULAR PATTERNS ASSOCIATED WITH IBD. SUMMARY: THE CONTINUING IDENTIFICATION OF SEVERAL EPIGENETIC, TRANSCRIPTOMIC, PROTEOMIC, AND METABOLOMIC ALTERATIONS IN PATIENTS WITH IBD REFLECTS THE COMPLEX NATURE OF THE DISEASE AND SUGGESTS THE NEED FOR INNOVATIVE APPROACHES SUCH AS SYSTEMS BIOLOGY FOR IDENTIFYING NOVEL RELEVANT TARGETS IN IBD. 2017 3 2601 50 EPIGENETICS, DNA ORGANIZATION, AND INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASES (IBDS) ARE CHRONIC INFLAMMATORY DISORDERS AFFECTING THE GASTROINTESTINAL TRACT. THE INCIDENCE OF IBD IS INCREASING, WITH MORE CASES OCCURRING IN DEVELOPED COUNTRIES. MULTIPLE FACTORS SUCH AS GENETICS, ENVIRONMENTAL CHANGES, GUT MICROBIOTA, AND IMMUNE ABNORMALITIES HAVE BEEN ASSOCIATED WITH DEVELOPMENT OF IBD. IN RECENT YEARS, IT HAS BECOME INCREASINGLY APPARENT THAT EPIGENETIC MODIFICATIONS OF CHROMATIN AND THE MANNER IN WHICH CHROMATIN IS ORGANIZED IN THE NUCLEUS ARE ADDITIONALLY IMPORTANT ELEMENTS THAT CAN INFLUENCE RESPONSES INDUCED BY THE FACTORS DESCRIBED ABOVE, AND MAY THEREFORE CONTRIBUTE TO THE ONSET AND PATHOGENESIS OF IBD. EPIGENETICS AND CHROMATIN ORGANIZATION REGULATE DIVERSE FUNCTIONS THAT INCLUDE MAINTENANCE OF HOMEOSTASIS IN THE INTESTINAL EPITHELIUM, THE DEVELOPMENT AND DIFFERENTIATION OF IMMUNE CELLS, AND MODULATION OF RESPONSES GENERATED BY THE IMMUNE SYSTEM TO DEFEND AGAINST POTENTIAL PATHOGENS. FURTHERMORE, CHANGES IN EPIGENETIC CHROMATIN MARKS AND IN CHROMATIN ORGANIZATION HAVE NOW BEEN LINKED TO DIFFERENTIAL GENE EXPRESSION IN IBD PATIENT CELLS. ALTHOUGH DIRECT EVIDENCE FOR A ROLE OF HISTONE MODIFICATIONS IN IBD IS CURRENTLY VERY LIMITED, IN THIS REVIEW, WE SUMMARIZE THE LINKS BETWEEN VARIOUS EPIGENETIC MODIFICATIONS, THE PROTEINS THAT CATALYZE OR RECOGNIZE THESE MODIFICATIONS, AND THE DEVELOPMENT OR PROGRESSION OF IBD IN HUMAN AND EXPERIMENTAL IBD. WE ALSO DISCUSS HOW EPIGENETICS INFLUENCE THE ORGANIZATION OF DNA CONTACTS TO REGULATE GENE EXPRESSION AND THE IMPLICATIONS THIS MAY HAVE FOR DIAGNOSING AND TREATING IBD. 2019 4 4670 38 NEW INSIGHTS INTO THE EPIGENETIC REGULATION OF INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC INFLAMMATORY DISEASE OF THE COLONIC MUCOSA. ENVIRONMENTAL FACTORS, GENETICS, INTESTINAL MICROBIOTA, AND THE IMMUNE SYSTEM ARE ALL INVOLVED IN THE PATHOPHYSIOLOGY OF IBD. LATELY, ACCUMULATING EVIDENCE HAS SHOWN THAT ABNORMAL EPIGENETIC CHANGES IN DNA METHYLATION, HISTONE MARKERS, AND NON-CODING RNA EXPRESSION GREATLY CONTRIBUTE TO THE DEVELOPMENT OF THE ENTIRE DISEASE. EPIGENETICS REGULATES MANY FUNCTIONS, SUCH AS MAINTAINING THE HOMEOSTASIS OF THE INTESTINAL EPITHELIUM AND REGULATING THE IMMUNE SYSTEM OF THE IMMUNE CELLS. IN THE PRESENT STUDY, WE SYSTEMATICALLY SUMMARIZED THE LATEST ADVANCES IN EPIGENETIC MODIFICATION OF IBD AND HOW EPIGENETICS REVEALS NEW MECHANISMS OF IBD. OUR PRESENT REVIEW PROVIDED NEW INSIGHTS INTO THE PATHOPHYSIOLOGY OF IBD. MOREOVER, EXPLORING THE PATTERNS OF DNA METHYLATION AND HISTONE MODIFICATION THROUGH EPIGENETICS CAN NOT ONLY BE USED AS BIOMARKERS OF IBD BUT ALSO AS A NEW TARGET FOR THERAPEUTIC INTERVENTION IN IBD PATIENTS. 2022 5 3541 40 IMMUNOEPIGENETIC REGULATION OF INFLAMMATORY BOWEL DISEASE: CURRENT INSIGHTS INTO NOVEL EPIGENETIC MODULATIONS OF THE SYSTEMIC IMMUNE RESPONSE. THE IMMUNE SYSTEM AND ENVIRONMENTAL FACTORS ARE INVOLVED IN VARIOUS DISEASES, SUCH AS INFLAMMATORY BOWEL DISEASE (IBD), THROUGH THEIR EFFECT ON GENETICS, WHICH MODULATES IMMUNE CELLS. IBD ENCOMPASSES TWO MAIN PHENOTYPES, CROHN'S DISEASE, AND ULCERATIVE COLITIS, WHICH ARE MANIFESTED AS CHRONIC AND SYSTEMIC RELAPSE-REMITTING GASTROINTESTINAL TRACT DISORDERS WITH RISING GLOBAL INCIDENCE AND PREVALENCE. THE PATHOPHYSIOLOGY OF IBD IS COMPLEX AND NOT FULLY UNDERSTOOD. EPIGENETIC RESEARCH HAS RESULTED IN VALUABLE INFORMATION FOR UNRAVELING THE ETIOLOGY OF THIS IMMUNE-MEDIATED DISEASE. THUS, THE MAIN OBJECTIVE OF THE PRESENT REVIEW IS TO SUMMARIZE THE CURRENT FINDINGS ON THE ROLE OF EPIGENETIC MECHANISMS IN IBD TO SHED LIGHT ON THEIR POTENTIAL CLINICAL RELEVANCE. THIS REVIEW FOCUSES ON THE LATEST EVIDENCE REGARDING PERIPHERAL BLOOD MONONUCLEAR CELLS AND EPIGENETIC CHANGES IN HISTONE MODIFICATION, DNA METHYLATION, AND TELOMERE SHORTENING IN IBD. THE VARIOUS IDENTIFIED EPIGENETIC DNA PROFILES WITH CLINICAL VALUE IN IBD COULD BE USED AS BIOMARKERS FOR MORE ACCURATELY PREDICTING DISEASE DEVELOPMENT, TREATMENT RESPONSE, AND THERAPY-RELATED ADVERSE EVENTS. ULTIMATELY, THE INFORMATION PRESENTED HERE COULD BE OF POTENTIAL RELEVANCE FOR FUTURE CLINICAL PRACTICE IN DEVELOPING MORE EFFICIENT AND PRECISE MEDICINE TO IMPROVE THE QUALITY OF LIFE FOR PATIENTS WITH IBD. 2023 6 5528 32 RNA MODIFICATION IN INFLAMMATORY BOWEL DISEASES. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC INFLAMMATORY DISORDER CHARACTERIZED BY DAMAGE TO THE INTESTINAL MUCOSA, WHICH IS CAUSED BY A COMBINATION OF FACTORS. THESE INCLUDE GENETIC AND EPIGENETIC ALTERATIONS, ENVIRONMENTAL INFLUENCE, MICROORGANISM INTERACTIONS, AND IMMUNE CONDITIONS. SOME POPULATIONS WITH IBD SHOW A CANCER-PRONE PHENOTYPE. RECENT STUDIES HAVE PROVIDED INSIGHT INTO THE INVOLVEMENT OF RNA MODIFICATIONS IN THE SPECIFIC PATHOGENESIS OF IBD THROUGH REGULATION OF RNA BIOLOGY IN EPITHELIAL AND IMMUNE CELLS. STUDIES OF SEVERAL RNA MODIFICATION-TARGETING REAGENTS HAVE SHOWN PREFERABLE OUTCOMES IN PATIENTS WITH COLITIS. HERE, WE NOTE A NEW AWARENESS OF RNA MODIFICATION IN THE TARGETING OF IBD AND RELATED DISEASES, WHICH WILL CONTRIBUTE TO EARLY DIAGNOSIS, DISEASE MONITORING, AND POSSIBLE CONTROL BY INNOVATIVE THERAPEUTIC APPROACHES. 2022 7 3017 33 GENETICS AND EPIGENETICS OF INFLAMMATORY BOWEL DISEASE. THE RELEVANCE OF GENETIC AND EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE (IBD) IS STILL POORLY UNDERSTOOD. SO FAR, 240 RISK GENE LOCI HAVE BEEN ASSOCIATED WITH IBD. THEY ARE MAINLY INVOLVED IN REGULATING INNATE AND ADAPTIVE IMMUNITY, AS WELL AS MAINTAINING INTESTINAL EPITHELIAL BARRIER FUNCTION. HOWEVER, THE FUNCTIONAL CONSEQUENCES OF THE IDENTIFIED GENETIC POLYMORPHISMS FOR IBD PATHOGENESIS IN VIVO ARE OFTEN UNKNOWN. EVEN LESS IS KNOWN ABOUT THE ROLE FOR EPIGENETIC MODIFICATIONS IN IBD PATHOGENESIS. THOUGH A NUMBER OF EPIGENETIC EVENTS SEEM TO BE CAUSATIVELY INVOLVED IBD PATHOGENESIS, OUR KNOWLEDGE ABOUT THE FUNCTIONAL RELEVANCE OF THOSE EPIGENETIC MODIFICATIONS IS SCANTY. THIS OPENS UP A BROAD RESEARCH FIELD THAT GENERATES NOVEL INSIGHTS INTO THE PATHOPHYSIOLOGY OF INTESTINAL AND CHRONIC INFLAMMATORY DISEASE. PATTERNS OF DNA METHYLATION AND HISTONE MODIFICATIONS MIGHT SERVE NOT ONLY AS BIOMARKERS OF DISEASE ACTIVITY OR DISEASE COURSE, BUT ALSO AS NEW TARGETS IN THERAPEUTIC INTERVENTIONS IN IBD PATIENTS. 2018 8 1404 45 DIETARY COMPOSITION AND EFFECTS IN INFLAMMATORY BOWEL DISEASE. DRAMATIC CHANGES IN THE ENVIRONMENT AND HUMAN LIFESTYLE HAVE BEEN ASSOCIATED WITH THE RISE OF VARIOUS CHRONIC COMPLEX DISEASES, SUCH AS INFLAMMATORY BOWEL DISEASE (IBD). A DYSBIOTIC GUT MICROBIOTA HAS BEEN PROPOSED AS A CRUCIAL PATHOGENIC ELEMENT, CONTRIBUTING TO IMMUNE IMBALANCES AND FOSTERING A PROINFLAMMATORY MILIEU, WHICH MAY BE ASSOCIATED WITH DISEASE RELAPSES OR EVEN THE INITIATION OF IBD. IN ADDITION TO REPRESENTING IMPORTANT REGULATORS OF THE MUCOSAL IMMUNITY AND THE COMPOSITION OF THE GUT MICROBIOTA, FOOD COMPONENTS HAVE BEEN SHOWN TO BE POTENTIAL ENVIRONMENTAL TRIGGERS OF EPIGENETIC MODIFICATIONS. IN THE CONTEXT OF CHRONIC INTESTINAL INFLAMMATION, DIETARY HABITS AND SPECIFIC FOOD COMPONENTS HAVE BEEN IMPLICATED AS IMPORTANT MODULATORS OF EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, WHICH MAY PREDISPOSE A PERSON TO THE INCREASED RISK OF THE INITIATION AND EVOLUTION OF IBD. THIS REVIEW PROVIDES NOVEL INSIGHTS ABOUT HOW DIETARY FACTORS MAY INTERACT WITH THE INTESTINAL MUCOSA AND MODULATE IMMUNE HOMEOSTASIS BY SHAPING THE INTESTINAL ECOSYSTEM, AS WELL AS THE POTENTIAL INFLUENCE OF DIET IN THE ETIOPATHOGENESIS AND MANAGEMENT OF IBD. 2019 9 2368 36 EPIGENETIC REGULATION OF T HELPER CELLS AND INTESTINAL PATHOGENICITY. INFLAMMATORY BOWEL DISEASES (IBDS) ARE CHARACTERIZED BY RELAPSING AND REMITTING CHRONIC INTESTINAL INFLAMMATION. PREVIOUS STUDIES HAVE DEMONSTRATED THE CONTRIBUTIONS OF GENETIC BACKGROUND, ENVIRONMENTAL FACTORS (FOOD, MICROBIOTA, USE OF ANTIBIOTICS), AND HOST IMMUNITY IN THE DEVELOPMENT OF IBDS. MORE THAN 200 GENES HAVE BEEN SHOWN TO INFLUENCE IBD SUSCEPTIBILITY, MOST OF WHICH ARE INVOLVED IN IMMUNITY. THE VERTEBRATE IMMUNE SYSTEM COMPRISES A COMPLEX NETWORK OF INNATE AND ADAPTIVE IMMUNE CELLS THAT PROTECT THE HOST FROM INFECTION AND CANCER. DYSREGULATION OF THE MUTUALISTIC RELATIONSHIP BETWEEN THE IMMUNE SYSTEM AND THE GUT ENVIRONMENT RESULTS IN IBD. CONSIDERING THE FUNDAMENTAL ROLE OF EPIGENETIC REGULATION IN IMMUNE CELLS, EPIGENETIC MECHANISMS, PARTICULARLY IN T HELPER (TH) CELLS, MAY PLAY A MAJOR ROLE IN THE COMPLEX REGULATION OF MUCOSAL IMMUNITY. EPIGENETIC REGULATION AND DYSREGULATION OF TH CELLS ARE INVOLVED IN THE MAINTENANCE OF INTESTINAL HOMEOSTASIS AND ITS BREAKDOWN IN IBD. 2019 10 3920 33 LINKING IMMUNITY, EPIGENETICS, AND CANCER IN INFLAMMATORY BOWEL DISEASE. MOST OF WHAT IS KNOWN ABOUT THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE (IBD) PERTAINS TO COMPLEX INTERPLAY BETWEEN HOST GENETICS, IMMUNITY, AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS PLAY PIVOTAL ROLES IN INTESTINAL IMMUNITY AND MUCOSAL HOMEOSTASIS AS WELL AS MEDIATING GENE-ENVIRONMENT INTERACTIONS. IN THIS ARTICLE, WE PROVIDE A HISTORICAL ACCOUNT OF EPIGENETIC RESEARCH EITHER DIRECTLY RELATED OR PERTINENT TO THE PATHOGENESIS AND MANAGEMENT OF IBD. WE FURTHER COLLATE EMERGING EVIDENCE SUPPORTING ROLES FOR EPIGENETIC MECHANISMS IN RELEVANT ASPECTS OF IBD BIOLOGY, INCLUDING DEREGULATED IMMUNITY, HOST-PATHOGEN RECOGNITION AND MUCOSAL INTEGRITY. FINALLY, WE HIGHLIGHT KEY EPIGENETIC MECHANISMS THAT LINK CHRONIC INFLAMMATION TO SPECIFIC IBD COMORBIDITIES, INCLUDING COLITIS-ASSOCIATED CANCER AND DISCUSS THEIR POTENTIAL UTILITY AS NOVEL BIOMARKERS OR PHARMACOLOGIC TARGETS IN IBD THERAPY. 2014 11 4365 38 MIRNA MOLECULES-LATE BREAKING TREATMENT FOR INFLAMMATORY BOWEL DISEASES? MICRORNAS (MIRNAS) ARE A GROUP OF NON-CODING RNAS THAT PLAY A CRITICAL ROLE IN REGULATING EPIGENETIC MECHANISMS IN INFLAMMATION-RELATED DISEASES. INFLAMMATORY BOWEL DISEASES (IBDS), WHICH PRIMARILY INCLUDE ULCERATIVE COLITIS (UC) AND CROHN'S DISEASE (CD), ARE CHARACTERIZED BY CHRONIC RECURRENT INFLAMMATION OF INTESTINAL TISSUES. DUE TO THE MULTIFACTORIAL ETIOLOGY OF THESE DISEASES, THE DEVELOPMENT OF INNOVATIVE TREATMENT STRATEGIES THAT CAN EFFECTIVELY MAINTAIN REMISSION AND ALLEVIATE DISEASE SYMPTOMS IS A MAJOR CHALLENGE. IN RECENT YEARS, EVIDENCE FOR THE REGULATORY ROLE OF MIRNAS IN THE PATHOGENETIC MECHANISMS OF VARIOUS DISEASES, INCLUDING IBD, HAS BEEN ACCUMULATING. IN LIGHT OF THESE FINDINGS, MIRNAS REPRESENT POTENTIAL INNOVATIVE CANDIDATES FOR THERAPEUTIC APPLICATION IN IBD. IN THIS REVIEW, WE DISCUSS RECENT FINDINGS ON THE ROLE OF MIRNAS IN REGULATING INFLAMMATORY RESPONSES, MAINTAINING INTESTINAL BARRIER INTEGRITY, AND DEVELOPING FIBROSIS IN CLINICAL AND EXPERIMENTAL IBD. THE FOCUS IS ON THE EXISTING LITERATURE, INDICATING POTENTIAL THERAPEUTIC APPLICATION OF MIRNAS IN BOTH PRECLINICAL EXPERIMENTAL IBD MODELS AND TRANSLATIONAL DATA IN THE CONTEXT OF CLINICAL IBD. TO DATE, A LARGE AND DIVERSE DATA SET, WHICH IS GROWING RAPIDLY, SUPPORTS THE POTENTIAL USE OF MIRNA-BASED THERAPIES IN CLINICAL PRACTICE, ALTHOUGH MANY QUESTIONS REMAIN UNANSWERED. 2023 12 1876 35 EMERGING ROLES FOR EPIGENETIC PROGRAMMING IN THE CONTROL OF INFLAMMATORY SIGNALING INTEGRATION IN HEATH AND DISEASE. MACROPHAGES AND DENDRITIC CELLS INITIATE THE INNATE IMMUNE RESPONSE TO INFECTION AND INJURY AND CONTRIBUTE TO INFLAMMATORY SIGNALING TO MAINTAIN THE HOMEOSTASIS OF VARIOUS TISSUES, WHICH INCLUDES RESIDENT MACROPHAGES FOR THE ELIMINATION OF INVADING MICROORGANISMS AND TISSUE DAMAGE. INAPPROPRIATE INFLAMMATORY SIGNALING CAN LEAD TO PERSISTENT INFLAMMATION AND FURTHER DEVELOP INTO AUTOIMMUNE AND INFLAMMATION-ASSOCIATED DISEASES. INFLAMMATORY SIGNALING PATHWAYS HAVE BEEN WELL CHARACTERIZED, BUT HOW THESE SIGNALING PATHWAYS ARE CONVERTED INTO SUSTAINED AND DIVERSE PATTERNS OF EXPRESSION OF CYTOKINES, CHEMOKINES, AND OTHER GENES IN RESPONSE TO ENVIRONMENTAL CHALLENGES IS UNCLEAR. EMERGING EVIDENCE SUGGESTS THE IMPORTANT ROLE OF EPIGENETIC MECHANISMS IN FINELY TUNING THE OUTCOME OF THE HOST INNATE IMMUNE RESPONSE. AN UNDERSTANDING OF EPIGENETIC REGULATION OF INNATE IMMUNE CELL IDENTITY AND FUNCTION WILL ENABLE THE IDENTIFICATION OF THE MECHANISM BETWEEN GENE-SPECIFIC HOST DEFENSES AND INFLAMMATORY DISEASE AND WILL ALSO ALLOW FOR EXPLORATION OF THE PROGRAM OF INNATE IMMUNE MEMORY IN HEALTH AND DISEASE. THIS INFORMATION COULD BE USED TO DEVELOP THERAPEUTIC AGENTS TO ENHANCE THE HOST RESPONSE, PREVENTING CHRONIC INFLAMMATION THROUGH PRESERVING TISSUES AND SIGNALING INTEGRITY. 2017 13 1173 45 CONTRIBUTION OF TLR SIGNALING TO THE PATHOGENESIS OF COLITIS-ASSOCIATED CANCER IN INFLAMMATORY BOWEL DISEASE. IN THE INTESTINE A BALANCE BETWEEN PROINFLAMMATORY AND REPAIR SIGNALS OF THE IMMUNE SYSTEM IS ESSENTIAL FOR THE MAINTENANCE OF INTESTINAL HOMEOSTASIS. THE INNATE IMMUNITY ENSURES A PRIMARY HOST RESPONSE TO MICROBIAL INVASION, WHICH INDUCES AN INFLAMMATORY PROCESS TO LOCALIZE THE INFECTION AND PREVENT SYSTEMIC DISSEMINATION OF PATHOGENS. THE KEY ELEMENTS OF THIS PROCESS ARE THE GERMLINE ENCODED PATTERN RECOGNITION RECEPTORS INCLUDING TOLL-LIKE RECEPTORS (TLRS). IF PATHOGENS CANNOT BE ELIMINATED, THEY MAY ELICIT CHRONIC INFLAMMATION, WHICH MAY BE PARTLY MEDIATED VIA TLRS. ADDITIONALLY, CHRONIC INFLAMMATION HAS LONG BEEN SUGGESTED TO TRIGGER TISSUE TUMOROUS TRANSFORMATION. INFLAMMATION, THE SEVENTH HALLMARK OF CANCER, MAY AFFECT ALL PHASES OF TUMOR DEVELOPMENT, AND EVADE THE IMMUNE SYSTEM. INFLAMMATION ACTS AS A CELLULAR STRESSOR AND MAY TRIGGER DNA DAMAGE OR GENETIC INSTABILITY. FURTHERMORE, CHRONIC INFLAMMATION CAN PROVOKE GENETIC MUTATIONS AND EPIGENETIC MECHANISMS THAT PROMOTE MALIGNANT CELL TRANSFORMATION. COLORECTAL CANCERS IN INFLAMMATORY BOWEL DISEASE PATIENTS ARE CONSIDERED TYPICAL EXAMPLES OF INFLAMMATION-RELATED CANCERS. ALTHOUGH DATA REGARDING THE ROLE OF TLRS IN THE PATHOMECHANISM OF CANCER-ASSOCIATED COLITIS ARE RATHER CONFLICTING, FUNCTIONALLY THESE MOLECULES CAN BE CLASSIFIED AS "LARGELY ANTITUMORIGENIC" AND "LARGELY PRO-TUMORIGENIC" WITH THE CAVEAT THAT THE UNDERLYING SIGNALING PATHWAYS ARE MAINLY CONTEXT (I.E., ORGAN-, TISSUE-, CELL-) AND LIGAND-DEPENDENT. 2014 14 5932 37 TARGETING EPIGENETIC REGULATORS FOR INFLAMMATION: MECHANISMS AND INTERVENTION THERAPY. EMERGING EVIDENCE INDICATES THAT RESOLUTION OF INFLAMMATION IS A CRITICAL AND DYNAMIC ENDOGENOUS PROCESS FOR HOST TISSUES DEFENDING AGAINST EXTERNAL INVASIVE PATHOGENS OR INTERNAL TISSUE INJURY. IT HAS LONG BEEN KNOWN THAT AUTOIMMUNE DISEASES AND CHRONIC INFLAMMATORY DISORDERS ARE CHARACTERIZED BY DYSREGULATED IMMUNE RESPONSES, LEADING TO EXCESSIVE AND UNCONTROL TISSUE INFLAMMATION. THE DYSREGULATION OF EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS TO HISTONE PROTEINS, AND NONCODING RNA EXPRESSION HAS BEEN IMPLICATED IN A HOST OF INFLAMMATORY DISORDERS AND THE IMMUNE SYSTEM. THE INFLAMMATORY RESPONSE IS CONSIDERED AS A CRITICAL TRIGGER OF EPIGENETIC ALTERATIONS THAT IN TURN INTERCEDE INFLAMMATORY ACTIONS. THUS, UNDERSTANDING THE MOLECULAR MECHANISM THAT DICTATES THE OUTCOME OF TARGETING EPIGENETIC REGULATORS FOR INFLAMMATORY DISEASE IS REQUIRED FOR INFLAMMATION RESOLUTION. IN THIS ARTICLE, WE ELUCIDATE THE CRITICAL ROLE OF THE NUCLEAR FACTOR-KAPPAB SIGNALING PATHWAY, JAK/STAT SIGNALING PATHWAY, AND THE NLRP3 INFLAMMASOME IN CHRONIC INFLAMMATORY DISEASES. AND WE FORMULATE THE RELATIONSHIP BETWEEN INFLAMMATION, CORONAVIRUS DISEASE 2019, AND HUMAN CANCERS. ADDITIONALLY, WE REVIEW THE MECHANISM OF EPIGENETIC MODIFICATIONS INVOLVED IN INFLAMMATION AND INNATE IMMUNE CELLS. ALL THAT MATTERS IS THAT WE PROPOSE AND DISCUSS THE REJUVENATION POTENTIAL OF INTERVENTIONS THAT TARGET EPIGENETIC REGULATORS AND REGULATORY MECHANISMS FOR CHRONIC INFLAMMATION-ASSOCIATED DISEASES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 15 3692 34 INFLAMMATORY BOWEL DISEASES: THE ROLE OF GUT MICROBIOTA. INFLAMMATORY BOWEL DISEASES (IBD) ARE CHRONIC MULTIFACTORIAL DISEASES CHARACTERIZED BY PARTIALLY UNCLEAR PATHOGENIC MECHANISMS INCLUDING CHANGES IN INTESTINAL MICROBIOTA. DESPITE THE MICROBIOTA, ALTERATION IS WELL ESTABLISHED IN IBD PATIENTS, AS REPORTED BY 16RNA SEQUENCING ANALYSIS, AN IMPORTANT GOAL IS TO DEFINE IF IT IS JUST A CONSEQUENCE OF THE DISEASE PROGRESSION OR A TRIGGER FACTOR OF THE DISEASE ITSELF. TO DATE, GUT MICROBIOTA COMPOSITION AND GUT MICROBIOTA-RELATED METABOLITES SEEM TO AFFECT THE HOST HEALTHY STATE BOTH BY MODULATING METABOLIC PATHWAYS OR ACTING ON THE EXPRESSION OF DIFFERENT GENES THROUGH EPIGENETIC EFFECTS. BECAUSE OF THIS, IT HAS BEEN SUGGESTED THAT INTESTINAL MICROBIOTA MIGHT REPRESENT A PROMISING THERAPEUTIC TARGET FOR IBD PATIENTS. THE AIM OF THIS REVIEW IS TO SUMMARIZE BOTH THE MOST RECENT ACQUISITIONS IN THE FIELD OF GUT MICROBIOTA AND ITS INVOLVEMENT IN INTESTINAL INFLAMMATION TOGETHER WITH THE AVAILABLE STRATEGIES FOR THE MODULATION OF MICROBIOTA, SUCH AS PREBIOTICS AND/OR PROBIOTICS ADMINISTRATION OR FECAL MICROBIOTA TRANSPLANTATION. 2020 16 3681 44 INFLAMMATION, DNA METHYLATION AND COLITIS-ASSOCIATED CANCER. INFLAMMATION CAN RESULT FROM A RANGE OF SOURCES INCLUDING MICROBIAL INFECTIONS, EXPOSURE TO ALLERGENS AND TOXIC CHEMICALS, AUTOIMMUNE DISEASE AND OBESITY. A WELL-BALANCED IMMUNE RESPONSE CAN BE ANTI-TUMORIGENIC; HOWEVER, A SUSTAINED OR CHRONIC INFLAMMATORY RESPONSE IS GENERALLY HARMFUL AS THE IMMUNE RESPONSE BECOMES DISTORTED. A CAUSAL LINK BETWEEN CHRONIC INFLAMMATION AND CANCER IS NOW WELL ACCEPTED AND MANY CHRONICALLY INFLAMED ORGANS OF THE GASTROINTESTINAL TRACT SHOW THIS ASSOCIATION. FOR EXAMPLE, PATIENTS WITH INFLAMMATORY BOWEL DISEASE (IBD), INCLUDING BOTH ULCERATIVE COLITIS AND CROHN'S DISEASE, HAVE A 2- TO 3-FOLD GREATER LIFETIME RISK OF DEVELOPING COLORECTAL CANCER COMPARED WITH THE GENERAL POPULATION. THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER (CAC) IS THOUGHT TO BE MULTIFACETED AND IS PROBABLY DUE TO A COMBINATION OF GENETIC FACTORS, EPIGENETIC FACTORS AND THE DURATION, EXTENT AND SEVERITY OF DISEASE. RECENTLY, EPIGENETIC ALTERATIONS, IN PARTICULAR ALTERATIONS IN DNA METHYLATION, HAVE BEEN OBSERVED DURING INFLAMMATION AND INFLAMMATION-ASSOCIATED CARCINOGENESIS. THE MEDIATORS OF THIS, THE SIGNIFICANCE OF THESE CHANGES IN DNA METHYLATION AND THE EFFECT THIS HAS ON GENE EXPRESSION AND THE MALIGNANT TRANSFORMATION OF THE EPITHELIAL CELLS DURING IBD AND CAC ARE DISCUSSED IN THIS REVIEW. THE RECENT ADVANCES IN TECHNOLOGIES TO STUDY GENOME-WIDE DNA METHYLATION AND THE THERAPEUTIC POTENTIAL OF UNDERSTANDING THESE MOLECULAR MECHANISMS ARE ALSO HIGHLIGHTED. 2012 17 5540 34 ROLE OF DIET AND GUT MICROBIOTA ON COLORECTAL CANCER IMMUNOMODULATION. COLORECTAL CANCER (CRC) IS ONE OF THE MOST COMMONLY DIAGNOSED CANCERS, AND IT IS CHARACTERIZED BY GENETIC AND EPIGENETIC ALTERATIONS, AS WELL AS BY INFLAMMATORY CELL INFILTRATION AMONG MALIGNANT AND STROMAL CELLS. HOWEVER, THIS DYNAMIC INFILTRATION CAN BE INFLUENCED BY THE MICROENVIRONMENT TO PROMOTE TUMOR PROLIFERATION, SURVIVAL AND METASTASIS OR CANCER INHIBITION. IN PARTICULAR, THE CANCER MICROENVIRONMENT METABOLITES CAN REGULATE THE INFLAMMATORY CELLS TO INDUCE A CHRONIC INFLAMMATORY RESPONSE THAT CAN BE A PREDISPOSING CONDITION FOR CRC RETENTION. IN ADDITION, SOME NUTRITIONAL COMPONENTS MIGHT CONTRIBUTE TO A CHRONIC INFLAMMATORY CONDITION BY REGULATING VARIOUS IMMUNE AND INFLAMMATORY PATHWAYS. BESIDES THAT, DIET STRONGLY MODULATES THE GUT MICROBIOTA COMPOSITION, WHICH HAS A KEY ROLE IN MAINTAINING GUT HOMEOSTASIS AND IS ASSOCIATED WITH THE MODULATION OF HOST INFLAMMATORY AND IMMUNE RESPONSES. THEREFORE, DIET HAS A FUNDAMENTAL ROLE IN CRC INITIATION, PROGRESSION AND PREVENTION. IN PARTICULAR, FUNCTIONAL FOODS SUCH AS PROBIOTICS, PREBIOTICS AND SYMBIOTICS CAN HAVE A POTENTIALLY POSITIVE EFFECT ON HEALTH BEYOND BASIC NUTRITION AND HAVE ANTI-INFLAMMATORY EFFECTS. IN THIS REVIEW, WE DISCUSS THE INFLUENCE OF DIET ON GUT MICROBIOTA COMPOSITION, FOCUSING ON ITS ROLE ON GUT INFLAMMATION AND IMMUNITY. FINALLY, WE DESCRIBE THE POTENTIAL BENEFITS OF USING PROBIOTICS AND PREBIOTICS TO MODULATE THE HOST INFLAMMATORY RESPONSE, AS WELL AS ITS APPLICATION IN CRC PREVENTION AND TREATMENT. 2019 18 6353 30 THE ROLE OF GENETIC AND EPIGENETIC REGULATION IN INTESTINAL FIBROSIS IN INFLAMMATORY BOWEL DISEASE: A DESCENDING PROCESS OR A PROGRAMMED CONSEQUENCE? INFLAMMATORY BOWEL DISEASES (IBDS) ARE A GROUP OF CHRONIC DISEASES CHARACTERIZED BY RECURRING PERIODS OF EXACERBATION AND REMISSION. FIBROSIS OF THE INTESTINE IS ONE OF THE MOST COMMON COMPLICATIONS OF IBD. BASED ON CURRENT ANALYSES, IT IS EVIDENT THAT GENETIC FACTORS AND MECHANISMS, AS WELL AS EPIGENETIC FACTORS, PLAY A ROLE IN THE INDUCTION AND PROGRESSION OF INTESTINAL FIBROSIS IN IBD. KEY GENETIC FACTORS AND MECHANISMS THAT APPEAR TO BE SIGNIFICANT INCLUDE NOD2, TGF-BETA, TLRS, IL23R, AND ATG16L1. DEOXYRIBONUCLEIC ACID (DNA) METHYLATION, HISTONE MODIFICATION, AND RIBONUCLEIC ACID (RNA) INTERFERENCE ARE THE PRIMARY EPIGENETIC MECHANISMS. GENETIC AND EPIGENETIC MECHANISMS, WHICH SEEM TO BE IMPORTANT IN THE PATHOPHYSIOLOGY AND PROGRESSION OF IBD, MAY POTENTIALLY BE USED IN TARGETED THERAPY IN THE FUTURE. THEREFORE, THE AIM OF THIS STUDY WAS TO GATHER AND DISCUSS SELECTED MECHANISMS AND GENETIC FACTORS, AS WELL AS EPIGENETIC FACTORS. 2023 19 2233 44 EPIGENETIC MODIFICATIONS OF THE NUCLEAR FACTOR KAPPA B SIGNALLING PATHWAY AND ITS IMPACT ON INFLAMMATORY BOWEL DISEASE. BACKGROUND: INFLAMMATORY BOWEL DISEASE (IBD) IS A MULTIFACTORIAL CONDITION INFLUENCED BY THE IMMUNE SYSTEM, THE INTESTINAL MICROBIOTA, ENVIRONMENTAL FACTORS, GENETIC AND EPIGENETIC FACTORS. GENETIC- AND ENVIRONMENT- INDUCED DYSREGULATION OF THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) TRANSCRIPTION FACTOR PATHWAY HAS BEEN LINKED TO IBD PATHOGENESIS. OBJECTIVE: TO ASSESS THE CURRENT EVIDENCE IN RELATION TO THE CONTRIBUTION OF THE CLASSICAL AND ALTERNATIVE NF-KAPPAB PATHWAYS IN IBD AND TO DISCUSS THE EPIGENETIC MECHANISMS THAT IMPACT ON NF-KAPPAB FUNCTION. METHODS: A MEDLINE SEARCH FOR 'NF-KAPPAB/NF-KAPPAB', IN COMBINATION WITH TERMS INCLUDING 'INFLAMMATORY BOWEL DISEASE/IBD', 'INTESTINAL INFLAMMATION', 'CROHN'S DISEASE', 'ULCERATIVE COLITIS', 'COLITIS'; 'EPIGENETICS', 'DNA METHYLATION', 'HISTONES', 'MICRORNAS/MIRNAS' AND 'SHORT NON-CODING/LONG NON-CODING RNAS' WAS PERFORMED. RESULTS: BOTH NF-KAPPAB PATHWAYS CONTRIBUTE TO THE CHRONIC INFLAMMATION UNDERLYING IBD BY REGULATING THE INFLAMMATORY IMMUNE RESPONSES AND HOMEOSTASIS OF THE INTESTINAL EPITHELIUM (CLASSICAL PATHWAY) OR REGULATING BOWEL INFLAMMATION AND EPITHELIAL MICROFOLD (M) CELL FUNCTION (ALTERNATIVE PATHWAY). DNA METHYLATION IS A COMMON EPIGENETIC MODIFICATION IN INTESTINAL INFLAMMATION, INCLUDING NFKB1 AND RELA LOCI. CONVERSELY, LITTLE IS UNDERSTOOD REGARDING EPIGENETIC EFFECTS ON GENES ENCODING OTHER NF-KAPPAB SUBUNITS, PARTICULARLY THOSE OF THE ALTERNATIVE PATHWAY, AND IN THE CONTEXT OF IBD. HOWEVER, NF-KAPPAB INTERACTION WITH CHROMATIN MODIFIERS IS ALSO SEEN TO BE AN ESSENTIAL MECHANISM OF REGULATION OF DOWNSTREAM TARGET GENES RELEVANT TO NF-KAPPAB-MEDIATED INFLAMMATORY RESPONSES. CONCLUSION: FURTHER RESEARCH IS CLEARLY WARRANTED IN THIS AREA, AS UNDERSTANDING THE CELL-SPECIFIC REGULATION OF THE NF-KAPPAB PATHWAYS WILL BRING RESEARCHERS INTO A POSITION TO ACHIEVE MORE EFFICIENT STRATIFICATION OF IBD PATIENTS, AND MORE TARGETED AND EFFECTIVE CHOICE OF TREATMENT. 2021 20 4273 41 MICROBIOTA AND EPIGENETICS: HEALTH IMPACT. EPIGENETIC CHANGES ASSOCIATED WITH DISEASE DEVELOPMENT AND PROGRESSIONS ARE OF INCREASING IMPORTANCE BECAUSE OF THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. SEVERAL EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC METABOLIC DISORDERS HAVE BEEN STUDIED IN VARIOUS DISEASES. EPIGENETIC CHANGES ARE MOSTLY MODULATED BY ENVIRONMENTAL FACTORS, INCLUDING THE HUMAN MICROBIOTA LIVING IN DIFFERENT PARTS OF OUR BODIES. THE MICROBIAL STRUCTURAL COMPONENTS AND THE MICROBIALLY DERIVED METABOLITES DIRECTLY INTERACT WITH HOST CELLS, THEREBY MAINTAINING HOMEOSTASIS. MICROBIOME DYSBIOSIS, ON THE OTHER HAND, IS KNOWN TO PRODUCE ELEVATED LEVELS OF DISEASE-LINKED METABOLITES, WHICH MAY DIRECTLY AFFECT A HOST METABOLIC PATHWAY OR INDUCE EPIGENETIC CHANGES THAT CAN LEAD TO DISEASE DEVELOPMENT. DESPITE THEIR IMPORTANT ROLE IN HOST PHYSIOLOGY AND SIGNAL TRANSDUCTION, THERE HAS BEEN LITTLE RESEARCH INTO THE MECHANICS AND PATHWAYS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. THIS CHAPTER FOCUSES ON THE RELATIONSHIP BETWEEN MICROBES AND THEIR EPIGENETIC EFFECTS IN DISEASED PATHOLOGY, AS WELL AS ON THE REGULATION AND METABOLISM OF THE DIETARY OPTIONS AVAILABLE TO THE MICROBES. FURTHERMORE, THIS CHAPTER ALSO PROVIDES A PROSPECTIVE LINK BETWEEN THESE TWO IMPORTANT PHENOMENA, TERMED "MICROBIOME AND EPIGENETICS." 2023