1 3804 81 INTESTINAL MICROBIOTA, CHRONIC INFLAMMATION, AND COLORECTAL CANCER. IN ADDITION TO GENETIC AND EPIGENETIC FACTORS, VARIOUS ENVIRONMENTAL FACTORS, INCLUDING DIET, PLAY IMPORTANT ROLES IN THE DEVELOPMENT OF COLORECTAL CANCER (CRC). RECENTLY, THERE IS INCREASING INTEREST IN THE INTESTINAL MICROBIOTA AS AN ENVIRONMENTAL RISK FACTOR FOR CRC, BECAUSE DIET ALSO INFLUENCES THE COMPOSITION OF THE INTESTINAL MICROBIOTA. THE HUMAN INTESTINAL MICROBIOTA COMPRISES ABOUT 100 TRILLION MICROBES. THIS MICROBIOME THRIVES ON UNDIGESTED DIETARY RESIDUES IN THE INTESTINAL LUMEN AND PRODUCES VARIOUS METABOLITES. IT IS WELL KNOWN THAT THE DIETARY RISK FACTORS FOR CRC ARE MEDIATED BY DYSBIOSIS OF THE INTESTINAL MICROBIOTA AND THEIR METABOLITES. IN THIS REVIEW, WE DESCRIBE THE BACTERIAL TAXA ASSOCIATED WITH CRC, INCLUDING FUSOBACTERIUM NUCLEATUM, ENTEROTOXIGENIC BACTEROIDES FRAGILIS, ESCHERICHIA COLI, AND BUTYRATE-PRODUCING BACTERIA. WE ALSO DISCUSS THE HOST-DIET INTERACTION IN COLORECTAL CARCINOGENESIS. 2018 2 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 3 3601 34 IMPORTANCE OF PROBIOTICS IN THE PREVENTION AND TREATMENT OF COLORECTAL CANCER. COLORECTAL CANCER (CRC) REMAINS ONE OF THE MOST COMMON AND DEADLY CANCERS. INTESTINAL GUT MICROFLORA IS IMPORTANT TO MAINTAIN AND CONTRIBUTES TO SEVERAL INTESTINAL FUNCTIONS, INCLUDING THE DEVELOPMENT OF THE MUCOSAL IMMUNE SYSTEM, ABSORPTION OF COMPLEX MACROMOLECULES, SYNTHESIS OF AMINO ACIDS/VITAMINS AND THE PROTECTION AGAINST PATHOGENIC MICROORGANISMS. IT IS WELL KNOWN THAT THE GUT MICROBIOTA CHANGES OR DYSBIOSIS MAY HAVE AN ESSENTIAL IMPACT IN THE INITIATION AND PROMOTION OF CHRONIC INFLAMMATORY PATHWAYS AND ALSO HAVE A PROFOUND DIFFERENT GENETIC AND EPIGENETIC ALTERATIONS LEADING TO DYSPLASIA, CLONAL EXPANSION, AND MALIGNANT TRANSFORMATION. PROBIOTIC BACTERIA HAS ANTITUMOR ACTIVITY WITH VARIOUS MECHANISMS SUCH AS NONSPECIFIC PHYSIOLOGICAL AND IMMUNOLOGICAL MECHANISMS. THIS REVIEW EVALUATES THE EFFECTS OF MICROBIOTA AND PROBIOTICS IN CLINICAL TRIALS, IN VITRO AND ANIMAL MODEL STUDIES THAT HAVE EXPLORED HOW PROBIOTIC AGAINST CANCER DEVELOPMENT AND ALSO DISCUSSES THE POSSIBLE IMMUNOMODULATORY MECHANISMS. SEVERAL MECHANISMS ALTERATION OF THE INTESTINAL MICROFLORA; INACTIVATION OF CANCEROGENIC COMPOUNDS; COMPETITION WITH PUTREFACTIVE AND PATHOGENIC MICROBIOTA; IMPROVEMENT OF THE HOST'S IMMUNE RESPONSE; ANTIPROLIFERATIVE EFFECTS VIA REGULATION OF APOPTOSIS AND CELL DIFFERENTIATION; FERMENTATION OF UNDIGESTED FOOD; INHIBITION OF TYROSINE KINASE; REDUCES THE ENTEROPATHOGENIC COMPLICATIONS BEFORE AND AFTER COLON CANCER SURGERY AND IMPROVE DIARRHEA AND IT'S HAVE BEEN ABLE TO CREATE THE INTEGRITY OF GUT MUCOSAL AND HAVE STIMULATORY EFFECTS ON THE SYSTEMIC IMMUNE SYSTEM AND PREVENT THE CRC METASTASIS. RESEARCH IN CLINICAL TRIALS ENCOURAGING FINDINGS THAT SUPPORT A ROLE OF PROBIOTICS IN CRC PREVENTION AND IMPROVE THE SAFETY AND EFFECTIVENESS OF CANCER THERAPY EVEN THOUGH ADDITIONAL CLINICAL RESEARCH IS STILL NECESSARY. 2019 4 3692 29 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 5 1404 32 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 6 566 33 BASES FOR THE ADEQUATE DEVELOPMENT OF NUTRITIONAL RECOMMENDATIONS FOR PATIENTS WITH INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC AND RELAPSING INFLAMMATORY CONDITION OF THE GASTROINTESTINAL TRACT; IT IS A HETEROGENEOUS AND MULTIFACTORIAL DISORDER RESULTING FROM A COMPLEX INTERPLAY BETWEEN GENETIC VARIATION, INTESTINAL MICROBIOTA, THE HOST IMMUNE SYSTEM AND ENVIRONMENTAL FACTORS SUCH AS DIET, DRUGS, BREASTFEEDING AND SMOKING. THE INTERACTIONS BETWEEN DIETARY NUTRIENTS AND INTESTINAL IMMUNITY ARE COMPLEX. THERE IS A COMPELLING ARGUMENT FOR ENVIRONMENTAL FACTORS SUCH AS DIET PLAYING A ROLE IN THE CAUSE AND COURSE OF IBD, GIVEN THAT THREE IMPORTANT FACTORS IN THE PATHOGENESIS OF IBD CAN BE MODULATED AND CONTROLLED BY DIET: INTESTINAL MICROBIOTA, THE IMMUNE SYSTEM AND EPITHELIAL BARRIER FUNCTION. THE AIM OF THIS REVIEW IS TO SUMMARIZE THE EPIDEMIOLOGICAL FINDINGS REGARDING DIET AND TO FOCUS ON THE EFFECTS THAT NUTRIENTS EXERT ON THE INTESTINAL MUCOSA-MICROBIOTA-PERMEABILITY INTERACTION. THE NATURE OF THESE INTERACTIONS IN IBD IS INFLUENCED BY ALTERATIONS IN THE NUTRITIONAL METABOLISM OF THE GUT MICROBIOTA AND HOST CELLS THAT CAN INFLUENCE THE OUTCOME OF NUTRITIONAL INTERVENTION. A BETTER UNDERSTANDING OF DIET-HOST-MICROBIOTA INTERACTIONS IS ESSENTIAL FOR UNRAVELLING THE COMPLEX MOLECULAR BASIS OF EPIGENETIC, GENETIC AND ENVIRONMENTAL INTERACTIONS UNDERLYING IBD PATHOGENESIS AS WELL AS FOR OFFERING NEW THERAPEUTIC APPROACHES FOR THE TREATMENT OF IBD. 2019 7 6879 33 [RELATIONSHIP BETWEEN INTESTINAL HYPERPERMEABILITY AND OBESITY]. OBESITY IS A COMBINATION OF GENETIC, ENVIRONMENTAL FACTORS, AND SYSTEMIC INFLAMMATION OF ADIPOSE TISSUE. IN THE LAST DECADE, MORE AND MORE EVIDENCE SUGGESTS THAT INTESTINAL MICROBIOTA IS AN ENVIRONMENTAL FACTOR THAT PLAYS A CRUCIAL ROLE IN OBESITY AND ASSOCIATED METABOLIC DISORDERS. HERE, WE REVIEW THE ASSOCIATION BETWEEN INTESTINAL MICROBIOTA AND OBESITY BASED ON THE LITERATURE DATA AVAILABLE TO US. THE INTESTINAL FLORA, IN THE EQUILIBRIUM STATE OF CONVENTIONAL BACTERIA, PROTECTS THE HEALTH OF THE HOST AND HELPS THE DEVELOPMENT OF THE IMMUNE SYSTEM. THE GENOME, DIET, LIFESTYLE, AND EPIGENETIC CHANGES OF THE HOST CAN PATHOLOGICALLY ALTER THE COMPOSITION OF THE MICROBIOTA. IN DYSBIOSIS, THE DEVELOPMENT OF THE GUT-ASSOCIATED LYMPHOID TISSUE (GALT) ASSOCIATED WITH THE INTESTINAL TRACT IS IMPAIRED AND THE INTEGRITY OF THE INTESTINAL BARRIER IS IMPAIRED. DUE TO THE CONSEQUENT INTESTINAL HYPERPERMEABILITY, COMPONENTS OF PATHOGENIC PATHOGENS SUCH AS LIPOPOLYSACCHARIDES ENTER THE BLOODSTREAM. THESE COMPONENTS BIND TO RECEPTORS ON ADIPOSE TISSUE IMMUNE CELLS AS LIGANDS FOR MOLECULAR SAMPLES WITH PATHOGENIC PROPERTIES AND INDUCE ADIPOSE TISSUE DYSFUNCTION. THE SECRETION OF INFLAMMATORY CYTOKINES IN ADIPOSE TISSUE IS INCREASED. THIS INDUCES PERSISTENT LOW CHRONIC INFLAMMATION, WHICH IS RESPONSIBLE FOR THE DEVELOPMENT OF OBESITY. THE DAMAGE TO HEALTH CAUSED BY THE HYPERPERMEABILITY OF THE INTESTINAL BARRIER CAN BE REDUCED BY INTERVENTIONS, OR RESTORED EARLY IN THE PROCESS. KNOWING THE RELATIONSHIPS WILL HELP PREVENT AND TREAT OBESITY. 2022 8 4458 34 MOLECULAR MECHANISMS OF ALCOHOL-INDUCED COLORECTAL CARCINOGENESIS. THE ETIOLOGY OF COLORECTAL CANCER (CRC) IS COMPLEX. APPROXIMATELY, 10% OF INDIVIDUALS WITH CRC HAVE PREDISPOSING GERMLINE MUTATIONS THAT LEAD TO FAMILIAL CANCER SYNDROMES, WHEREAS MOST CRC PATIENTS HAVE SPORADIC CANCER RESULTING FROM A COMBINATION OF ENVIRONMENTAL AND GENETIC RISK FACTORS. IT HAS BECOME INCREASINGLY CLEAR THAT CHRONIC ALCOHOL CONSUMPTION IS ASSOCIATED WITH THE DEVELOPMENT OF SPORADIC CRC; HOWEVER, THE EXACT MECHANISMS BY WHICH ALCOHOL CONTRIBUTES TO COLORECTAL CARCINOGENESIS ARE LARGELY UNKNOWN. SEVERAL PROPOSED MECHANISMS FROM STUDIES IN CRC MODELS SUGGEST THAT ALCOHOL METABOLITES AND/OR ENZYMES ASSOCIATED WITH ALCOHOL METABOLISM ALTER CELLULAR REDOX BALANCE, CAUSE DNA DAMAGE, AND EPIGENETIC DYSREGULATION. IN ADDITION, ALCOHOL METABOLITES CAN CAUSE A DYSBIOTIC COLORECTAL MICROBIOME AND INTESTINAL PERMEABILITY, RESULTING IN BACTERIAL TRANSLOCATION, INFLAMMATION, AND IMMUNOSUPPRESSION. ALL OF THESE EFFECTS CAN INCREASE THE RISK OF DEVELOPING CRC. THIS REVIEW AIMS TO OUTLINE SOME OF THE MOST SIGNIFICANT AND RECENT FINDINGS ON THE MECHANISMS OF ALCOHOL IN COLORECTAL CARCINOGENESIS. WE EXAMINE THE EFFECT OF ALCOHOL ON THE GENERATION OF REACTIVE OXYGEN SPECIES, THE DEVELOPMENT OF GENOTOXIC STRESS, MODULATION OF ONE-CARBON METABOLISM, DISRUPTION OF THE MICROBIOME, AND IMMUNOSUPPRESSION. 2021 9 1400 24 DIET-REGULATING MICROBIOTA AND HOST IMMUNE SYSTEM IN LIVER DISEASE. THE GUT MICROBIOTA HAS BEEN KNOWN TO MODULATE THE IMMUNE RESPONSES IN CHRONIC LIVER DISEASES. RECENT EVIDENCE SUGGESTS THAT EFFECTS OF DIETARY FOODS ON HEALTH CARE AND HUMAN DISEASES ARE RELATED TO BOTH THE IMMUNE REACTION AND THE MICROBIOME. THE GUT-MICROBIOME AND INTESTINAL IMMUNE SYSTEM PLAY A CENTRAL ROLE IN THE CONTROL OF BACTERIAL TRANSLOCATION-INDUCED LIVER DISEASE. DYSBIOSIS, SMALL INTESTINAL BACTERIAL OVERGROWTH, TRANSLOCATION, ENDOTOXEMIA, AND THE DIRECT EFFECTS OF METABOLITES ARE THE MAIN EVENTS IN THE GUT-LIVER AXIS, AND IMMUNE RESPONSES ACT ON EVERY PATHWAYS OF CHRONIC LIVER DISEASE. MICROBIOME-DERIVED METABOLITES OR BACTERIA THEMSELVES REGULATE IMMUNE CELL FUNCTIONS SUCH AS RECOGNITION OR ACTIVATION OF RECEPTORS, THE CONTROL OF GENE EXPRESSION BY EPIGENETIC CHANGE, ACTIVATION OF IMMUNE CELLS, AND THE INTEGRATION OF CELLULAR METABOLISM. HERE, WE REVIEWED RECENT REPORTS ABOUT THE IMMUNOLOGIC ROLE OF GUT MICROBIOTAS IN LIVER DISEASE, HIGHLIGHTING THE ROLE OF DIET IN CHRONIC LIVER DISEASE. 2021 10 1395 34 DIET AND MICROBIOME IN THE BEGINNING OF THE SEQUENCE OF GUT INFLAMMATION. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC INFLAMMATORY CONDITION OF THE GASTROINTESTINAL TRACT DUE, AT LEAST PARTIALLY, TO AN ABERRANT AND EXCESSIVE MUCOSAL IMMUNE RESPONSE TO GUT BACTERIA IN GENETICALLY-PREDISPOSED INDIVIDUALS UNDER CERTAIN ENVIRONMENTAL FACTORS. THE INCIDENCE OF IBD IS RISING IN WESTERN AND NEWLY INDUSTRIALIZED COUNTRIES, PARALLELING THE INCREASE OF WESTERNIZED DIETARY PATTERNS, THROUGH NEW ANTIGENS, EPITHELIAL FUNCTION AND PERMEABILITY, EPIGENETIC MECHANISMS (E.G., DNA METHYLATION), AND ALTERATION OF THE GUT MICROBIOME. ALTERATION IN THE COMPOSITION AND FUNCTIONALITY OF THE GUT MICROBIOME (INCLUDING BACTERIA, VIRUSES AND FUNGI) SEEMS TO BE A NUCLEAR PATHOGENIC FACTOR. THE MICROBIOME ITSELF IS DYNAMIC, AND THE CHANGES IN FOOD QUALITY, DIETARY HABITS, LIVING CONDITIONS AND HYGIENE OF THESE WESTERN SOCIETIES, COULD INTERACT IN A COMPLEX MANNER AS MODULATORS OF DYSBIOSIS, THEREBY INFLUENCING THE ACTIVATION OF IMMUNE CELLS' PROMOTING INFLAMMATION. THE MICROBIOME PRODUCES DIVERSE SMALL MOLECULES VIA SEVERAL METABOLIC WAYS, WITH THE FIBER-DERIVED SHORT-CHAIN FATTY ACIDS (I.E., BUTYRATE) AS MAIN ELEMENTS AND HAVING ANTI-INFLAMMATORY EFFECTS. THESE METABOLITES AND SOME MICRONUTRIENTS OF THE DIET (I.E., VITAMINS, FOLIC ACID, BETA CAROTENE AND TRACE ELEMENTS) ARE REGULATORS OF INNATE AND ADAPTIVE INTESTINAL IMMUNE HOMEOSTASIS. AN EXCESSIVE AND UNHEALTHY CONSUMPTION OF SUGAR, ANIMAL FAT AND A LOW-VEGETABLE AND -FIBER DIET ARE RISK FACTORS FOR IBD APPEARANCE. FURTHERMORE, METABOLISM OF NUTRIENTS IN INTESTINAL EPITHELIUM AND IN GUT MICROBIOTA IS ALTERED BY INFLAMMATION, CHANGING THE DEMAND FOR NUTRIENTS NEEDED FOR HOMEOSTASIS. THIS ROLE OF FOOD AND A REDUCED GUT MICROBIAL DIVERSITY IN CAUSING IBD MIGHT ALSO HAVE A PROPHYLACTIC OR THERAPEUTIC ROLE FOR IBD. THE RELATIONSHIP BETWEEN DIETARY INTAKE, SYMPTOMS, AND BOWEL INFLAMMATION COULD LEAD TO DIETARY AND LIFESTYLE RECOMMENDATIONS, INCLUDING DIETS WITH ABUNDANT FRUITS, VEGETABLES, OLIVE OIL AND OILY FISH, WHICH HAVE ANTI-INFLAMMATORY EFFECTS AND COULD PREVENT DYSBIOSIS AND IBD. DIETARY MODULATION AND APPROPRIATE EXCLUSION DIETS MIGHT BE A NEW COMPLEMENTARY MANAGEMENT FOR TREATMENT AT DISEASE FLARES AND IN REFRACTORY PATIENTS, EVEN REDUCING COMPLICATIONS, HOSPITALIZATIONS AND SURGERY, THROUGH MODIFYING THE LUMINAL INTESTINAL ENVIRONMENT. 2021 11 6253 34 THE MICROBIOME AND HEPATOCELLULAR CARCINOMA. THE HUMAN MICROBIOME IS A VAST AND COMPLEX SYSTEM ENCOMPASSING ALL OF THE MICROBES AND THEIR GENES THAT OCCUPY THE ENVIRONMENTALLY EXPOSED SURFACES OF THE HUMAN BODY. THE GUT MICROBIOTA AND ITS ASSOCIATED MICROBIOME PLAY AN INTEGRAL ROLE IN MAMMALIAN METABOLISM AND IMMUNE TOLERANCE AS WELL AS IN IMMUNOCOMPETENCE. DISRUPTIONS IN THE HUMAN GUT MICROBIOME ARE ASSOCIATED WITH A CYCLE OF HEPATOCYTE INJURY AND REGENERATION CHARACTERISTIC OF CHRONIC LIVER DISEASE. THE PERSISTENCE OF THIS INFLAMMATION HAS BEEN SHOWN TO INDUCE THE ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES LEADING TO HEPATOCELLULAR CARCINOMA (HCC). THEREFORE, THE IMPORTANCE AND PROGNOSTIC INFLUENCE OF THE GUT MICROBIOME ON HEPATOCARCINOGENESIS HAS BEEN INCREASINGLY STUDIED IN RECENT YEARS. THIS REVIEW DISCUSSES THE MECHANISMS BY WHICH IMBALANCES IN THE GUT MICROBIOME DISTURB THE GUT-LIVER AXIS TO IMPACT HEPATOCARCINOGENESIS, INCLUDING DISRUPTION OF THE INTESTINAL BARRIER, CHANGES IN BILE ACID METABOLISM, AND REDUCTION IN TUMOR-SUPPRESSING MICRORNA. FURTHERMORE, THIS REVIEW SUMMARIZES RECENT ADVANCES IN POTENTIAL MICROBIOME-BASED THERAPEUTIC OPPORTUNITIES IN HCC. 2020 12 3585 29 IMPACT OF THE EXPOSOME ON THE EPIGENOME IN INFLAMMATORY BOWEL DISEASE PATIENTS AND ANIMAL MODELS. INFLAMMATORY BOWEL DISEASES (IBD) ARE CHRONIC INFLAMMATORY DISORDERS OF THE GASTROINTESTINAL TRACT THAT ENCOMPASS TWO MAIN PHENOTYPES, NAMELY CROHN'S DISEASE AND ULCERATIVE COLITIS. THESE CONDITIONS OCCUR IN GENETICALLY PREDISPOSED INDIVIDUALS IN RESPONSE TO ENVIRONMENTAL FACTORS. EPIGENETICS, ACTING BY DNA METHYLATION, POST-TRANSLATIONAL HISTONES MODIFICATIONS OR BY NON-CODING RNAS, COULD EXPLAIN HOW THE EXPOSOME (OR ALL ENVIRONMENTAL INFLUENCES OVER THE LIFE COURSE, FROM CONCEPTION TO DEATH) COULD INFLUENCE THE GENE EXPRESSION TO CONTRIBUTE TO INTESTINAL INFLAMMATION. WE PERFORMED A SCOPING SEARCH USING MEDLINE TO IDENTIFY ALL THE ELEMENTS OF THE EXPOSOME THAT MAY PLAY A ROLE IN INTESTINAL INFLAMMATION THROUGH EPIGENETIC MODIFICATIONS, AS WELL AS THE UNDERLYING MECHANISMS. THE ENVIRONMENTAL FACTORS EPIGENETICALLY INFLUENCING THE OCCURRENCE OF INTESTINAL INFLAMMATION ARE THE MATERNAL LIFESTYLE (MAINLY DIET, THE OCCURRENCE OF INFECTION DURING PREGNANCY AND SMOKING); BREASTFEEDING; MICROBIOTA; DIET (INCLUDING A LOW-FIBER DIET, HIGH-FAT DIET AND DEFICIENCY IN MICRONUTRIENTS); SMOKING HABITS, VITAMIN D AND DRUGS (E.G., IBD TREATMENTS, ANTIBIOTICS AND PROBIOTICS). INFLUENCED BY BOTH MICROBIOTA AND DIET, SHORT-CHAIN FATTY ACIDS ARE GUT MICROBIOTA-DERIVED METABOLITES RESULTING FROM THE ANAEROBIC FERMENTATION OF NON-DIGESTIBLE DIETARY FIBERS, PLAYING AN EPIGENETICALLY MEDIATED ROLE IN THE INTEGRITY OF THE EPITHELIAL BARRIER AND IN THE DEFENSE AGAINST INVADING MICROORGANISMS. ALTHOUGH THE IMPACT OF SOME ENVIRONMENTAL FACTORS HAS BEEN IDENTIFIED, THE EXPOSOME-INDUCED EPIMUTATIONS IN IBD REMAIN A LARGELY UNDEREXPLORED FIELD. HOW THESE ENVIRONMENTAL EXPOSURES INDUCE EPIGENETIC MODIFICATIONS (IN TERMS OF DURATION, FREQUENCY AND THE TIMING AT WHICH THEY OCCUR) AND HOW OTHER ENVIRONMENTAL FACTORS ASSOCIATED WITH IBD MODULATE EPIGENETICS DESERVE TO BE FURTHER INVESTIGATED. 2022 13 1168 35 CONTRIBUTION OF EPITHELIAL AND GUT MICROBIOME INFLAMMATORY BIOMARKERS TO THE IMPROVEMENT OF COLORECTAL CANCER PATIENTS' STRATIFICATION. IN ORDER TO ENSURE THAT PRIMARY ENDPOINTS OF CLINICAL STUDIES ARE ATTAINED, THE PATIENTS' STRATIFICATION IS AN IMPORTANT ASPECT. SELECTION CRITERIA INCLUDE AGE, GENDER, AND ALSO SPECIFIC BIOMARKERS, SUCH AS INFLAMMATION SCORES. THESE CRITERIA ARE NOT SUFFICIENT TO ACHIEVE A STRAIGHTFORWARD SELECTION, HOWEVER, IN CASE OF MULTIFACTORIAL DISEASES, WITH UNKNOWN OR PARTIALLY IDENTIFIED MECHANISMS, OCCASIONALLY INCLUDING HOST FACTORS, AND THE MICROBIOME. IN THESE CASES, THE EFFICACY OF INTERVENTIONS IS DIFFICULT TO PREDICT, AND AS A RESULT, THE SELECTION OF SUBJECTS IS OFTEN RANDOM. COLORECTAL CANCER (CRC) IS A HIGHLY HETEROGENEOUS DISEASE, WITH VARIABLE CLINICAL FEATURES, OUTCOMES, AND RESPONSE TO THERAPY; THE CRC ONSET AND PROGRESS INVOLVES MULTIPLE SEQUENTIAL STEPS WITH ACCUMULATION OF GENETIC ALTERATIONS, NAMELY, MUTATIONS, GENE AMPLIFICATION, AND EPIGENETIC CHANGES. THE GUT MICROBES, EITHER EUBIOTIC OR DYSBIOTIC, COULD INFLUENCE THE CRC EVOLUTION THROUGH A COMPLEX AND VERSATILE CROSSTALK WITH THE INTESTINAL AND IMMUNE CELLS, PERMANENTLY CHANGING THE TUMOR MICROENVIRONMENT. THERE HAVE BEEN SIGNIFICANT ADVANCES IN THE DEVELOPMENT OF PERSONALIZED APPROACHES FOR CRC SCREENING, TREATMENT, AND POTENTIAL PREVENTION. ADVANCES IN MOLECULAR TECHNIQUES BRING NEW CRITERIA FOR PATIENTS' STRATIFICATION-MUTATIONAL ANALYSIS AT THE TIME OF DIAGNOSIS TO GUIDE TREATMENT, FOR EXAMPLE. GUT MICROBIOME HAS EMERGED AS THE MAIN TRIGGER OF GUT MUCOSAL HOMEOSTASIS. THIS MAY IMPACT CANCER SUSCEPTIBILITY THROUGH MAINTENANCE OF THE EPITHELIAL/MUCUS BARRIER AND PRODUCTION OF PROTECTIVE METABOLITES, SUCH AS SHORT-CHAIN FATTY ACIDS (SCFAS) VIA INTERACTIONS WITH THE HOSTS' DIET AND METABOLISM. MICROBIOME DYSBIOSIS LEADS TO THE ENRICHMENT OF CANCER-PROMOTING BACTERIAL POPULATIONS, LOSS OF PROTECTIVE POPULATIONS OR MAINTAINING AN INFLAMMATORY CHRONIC STATE, ALL OF WHICH CONTRIBUTE TO THE DEVELOPMENT AND PROGRESSION OF CRC. MEANWHILE, VARIATIONS IN PATIENT RESPONSES TO ANTI-CANCER IMMUNO- AND CHEMOTHERAPIES WERE ALSO LINKED TO INTER-INDIVIDUAL DIFFERENCES IN INTESTINE MICROBIOMES. THE AUTHORS AIM TO HIGHLIGHT THE CONTRIBUTION OF EPITHELIAL AND GUT MICROBIOME INFLAMMATORY BIOMARKERS IN THE IMPROVEMENT OF CRC PATIENTS' STRATIFICATION TOWARDS A PERSONALIZED APPROACH OF EARLY DIAGNOSIS AND TREATMENT. 2021 14 838 35 CHEMISTRY MEETS BIOLOGY IN COLITIS-ASSOCIATED CARCINOGENESIS. THE INTESTINE COMPRISES AN EXCEPTIONAL VENUE FOR A DYNAMIC AND COMPLEX INTERPLAY OF NUMEROUS CHEMICAL AND BIOLOGICAL PROCESSES. HERE, MULTIPLE CHEMICAL AND BIOLOGICAL SYSTEMS, INCLUDING THE INTESTINAL TISSUE ITSELF, ITS ASSOCIATED IMMUNE SYSTEM, THE GUT MICROBIOTA, XENOBIOTICS, AND METABOLITES MEET AND INTERACT TO FORM A SOPHISTICATED AND TIGHTLY REGULATED STATE OF TISSUE HOMOEOSTASIS. DISTURBANCE OF THIS HOMEOSTASIS CAN CAUSE INFLAMMATORY BOWEL DISEASE (IBD)-A CHRONIC DISEASE OF MULTIFACTORIAL ETIOLOGY THAT IS STRONGLY ASSOCIATED WITH INCREASED RISK FOR CANCER DEVELOPMENT. THIS REVIEW ADDRESSES RECENT DEVELOPMENTS IN RESEARCH INTO CHEMICAL AND BIOLOGICAL MECHANISMS UNDERLYING THE ETIOLOGY OF INFLAMMATION-INDUCED COLON CANCER. BEGINNING WITH A GENERAL OVERVIEW OF REACTIVE CHEMICAL SPECIES GENERATED DURING COLONIC INFLAMMATION, THE MECHANISTIC INTERPLAY BETWEEN CHEMICAL AND BIOLOGICAL MEDIATORS OF INFLAMMATION, THE ROLE OF GENETIC TOXICOLOGY, AND MICROBIAL PATHOGENESIS IN DISEASE DEVELOPMENT ARE DISCUSSED. WHEN POSSIBLE, WE SYSTEMATICALLY COMPARE EVIDENCE FROM STUDIES UTILIZING HUMAN IBD PATIENTS WITH EXPERIMENTAL INVESTIGATIONS IN MICE. THE COMPARISON REVEALS THAT MANY STRONG PATHOLOGICAL AND MECHANISTIC CORRELATES EXIST BETWEEN MOUSE MODELS OF COLITIS-ASSOCIATED CANCER, AND THE CLINICALLY RELEVANT SITUATION IN HUMANS. WE ALSO SUMMARIZE SEVERAL EMERGING ISSUES IN THE FIELD, SUCH AS THE CARCINOGENIC POTENTIAL OF NOVEL INFLAMMATION-RELATED DNA ADDUCTS AND GENOTOXIC MICROBIAL FACTORS, THE SYSTEMIC DIMENSION OF INFLAMMATION-INDUCED GENOTOXICITY, AND THE COMPLEX ROLE OF GENOME MAINTENANCE MECHANISMS DURING THESE PROCESSES. TAKEN TOGETHER, CURRENT EVIDENCE POINTS TO THE INDUCTION OF GENETIC AND EPIGENETIC ALTERATIONS BY CHEMICAL AND BIOLOGICAL INFLAMMATORY STIMULI ULTIMATELY LEADING TO CANCER FORMATION. 2013 15 3919 37 LINKING DIET TO COLORECTAL CANCER: THE EMERGING ROLE OF MICRORNA IN THE COMMUNICATION BETWEEN PLANT AND ANIMAL KINGDOMS. ENVIRONMENTAL AND LIFESTYLE FACTORS, INCLUDING DIET AND NUTRITIONAL HABITS HAVE BEEN STRONGLY LINKED TO COLORECTAL CANCER (CRC). OF NOTE, UNHEALTHY DIETARY HABITS LEADING TO ADIPOSITY REPRESENT A MAIN RISK FACTOR FOR CRC AND ARE ASSOCIATED WITH A CHRONIC LOW-GRADE INFLAMMATORY STATUS. INFLAMMATION IS A HALLMARK OF ALMOST EVERY TYPE OF CANCER AND CAN BE MODULATED BY SEVERAL FOOD COMPOUNDS EXHIBITING EITHER PROTECTIVE OR PROMOTING EFFECTS. HOWEVER, IN SPITE OF AN EXTENSIVE RESEARCH, THE UNDERLYING MECHANISMS BY WHICH DIETARY PATTERNS OR BIOACTIVE FOOD COMPONENTS MAY INFLUENCE TUMOR ONSET AND OUTCOME HAVE NOT BEEN FULLY CLARIFIED YET. GROWING EVIDENCE INDICATES THAT DIET, COMBINING BENEFICIAL SUBSTANCES AND POTENTIALLY HARMFUL INGREDIENTS, HAS AN IMPACT ON THE EXPRESSION OF KEY REGULATORS OF GENE EXPRESSION SUCH AS THE NON-CODING RNA (NCRNA). SINCE THE EXPRESSION OF THESE MOLECULES IS DERANGED IN CHRONIC INFLAMMATION AND CANCER, MODULATING THEIR EXPRESSION MAY STRONGLY INFLUENCE THE CANCER PHENOTYPE AND OUTCOMES. IN ADDITION, THE RECENTLY ACQUIRED KNOWLEDGE ON THE EXISTENCE OF INTRICATE INTER-KINGDOM COMMUNICATION NETWORKS, IS OPENING NEW AVENUES FOR A DEEPER UNDERSTANDING OF THE INTIMATE RELATIONSHIPS LINKING DIET TO CRC. IN THIS NOVEL SCENARIO, DIET-MODULATED NCRNA MAY REPRESENT KEY ACTORS IN THE INTERACTION BETWEEN PLANT AND ANIMAL KINGDOMS, CAPABLE OF INFLUENCING DISEASE ONSET AND OUTCOME. IN THIS REVIEW, WE WILL SUMMARIZE THE STUDIES DEMONSTRATING A LINK BETWEEN BIOACTIVE FOOD COMPONENTS, INCLUDING FOOD-DERIVED, MICROBIOTA-PROCESSED, SECONDARY METABOLITES, AND HOST NCRNA. WE WILL FOCUS ON MICRORNA, HIGHLIGHTING HOW THIS PLANT/ANIMAL INTER-KINGDOM CROSS-TALK MAY HAVE AN IMPACT ON CRC ESTABLISHMENT AND PROGRESSION. 2017 16 3681 29 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 1180 27 CONVERGENCE OF GENETIC, NUTRITIONAL AND INFLAMMATORY FACTORS IN GASTROINTESTINAL CANCERS. GASTROINTESTINAL CANCERS ACCOUNT FOR 20% OF ALL CANCER INCIDENCES WORLDWIDE. COLORECTAL CANCER IS THE SECOND MOST COMMON CAUSE OF ALL CANCER-RELATED MORTALITY AND IS INCREASING IN WESTERN SOCIETIES. INFECTION AND INFLAMMATION CONTRIBUTE TO 15-20% OF ALL MALIGNANCIES, AND ARE PREDISPOSING RISK FACTORS FOR GASTROINTESTINAL CANCERS. HELICOBACTER PYLORI INFECTION IS COMMONLY ASSOCIATED WITH GASTRIC CANCERS, AND CHRONIC INFLAMMATION INCREASES THE RISK OF COLORECTAL CANCER BY 1% PER YEAR. MICRONUTRIENT STATUS AND COMMON GENETIC VARIATIONS IN HUMAN POPULATIONS MODIFY RISK FOR GASTROINTESTINAL CANCER. CHRONIC INFLAMMATION PROMOTES CARCINOGENESIS BY INDUCING GENE MUTATIONS, INHIBITING APOPTOSIS, AND STIMULATING ANGIOGENESIS AND CELL PROLIFERATION. INFLAMMATION ALSO INDUCES EPIGENETIC ALTERATIONS THAT ARE ASSOCIATED WITH CANCER DEVELOPMENT. TWO KEY GENES IN THE INFLAMMATORY PROCESS, CYCLOOXYGENASE-2 (COX-2) AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB), PROVIDE A MECHANISTIC LINK BETWEEN INFLAMMATION AND CANCER AND ARE TARGETS FOR CHEMOPREVENTION. DIETARY COMPONENTS, AND HUMAN GENETIC VARIATION THAT AFFECTS NUTRIENT UTILIZATION, CAN DIRECTLY MODIFY INFLAMMATORY PROCESSES AND/OR SUPPRESS GENOMIC ALTERATIONS THAT ARE THE MOLECULAR ANTECEDENTS OF CANCERS. THE PRESENT REPORT FOCUSES ON THE CONVERGENCE OF GENETIC, NUTRITIONAL, AND INFLAMMATORY FACTORS IN THE INITIATION AND PROGRESSION OF GASTROINTESTINAL CANCERS, AND THE EMERGING DIETARY STRATEGIES FOR CANCER PREVENTION. 2007 18 1149 30 CONNECTING THE IMMUNE SYSTEM, SYSTEMIC CHRONIC INFLAMMATION AND THE GUT MICROBIOME: THE ROLE OF SEX. UNRESOLVED LOW GRADE SYSTEMIC INFLAMMATION REPRESENTS THE UNDERLYING PATHOLOGICAL MECHANISM DRIVING IMMUNE AND METABOLIC PATHWAYS INVOLVED IN AUTOIMMUNE DISEASES (AID). MECHANISTIC STUDIES IN ANIMAL MODELS OF AID AND OBSERVATIONAL STUDIES IN PATIENTS HAVE FOUND ALTERATIONS IN GUT MICROBIOTA COMMUNITIES AND THEIR METABOLITES, SUGGESTING A MICROBIAL CONTRIBUTION TO THE ONSET OR PROGRESSION OF AID. THE GUT MICROBIOTA AND ITS METABOLITES HAVE BEEN SHOWN TO INFLUENCE IMMUNE FUNCTIONS AND IMMUNE HOMEOSTASIS BOTH WITHIN THE GUT AND SYSTEMATICALLY. MICROBIAL DERIVED-SHORT CHAIN FATTY ACID (SCFA) AND BIO-TRANSFORMED BILE ACID (BA) HAVE BEEN SHOWN TO INFLUENCE THE IMMUNE SYSTEM ACTING AS LIGANDS SPECIFIC CELL SIGNALING RECEPTORS LIKE GPRCS, TGR5 AND FXR, OR VIA EPIGENETIC PROCESSES. SIMILARLY, INTESTINAL PERMEABILITY (LEAKY GUT) AND BACTERIAL TRANSLOCATION ARE IMPORTANT CONTRIBUTORS TO CHRONIC SYSTEMIC INFLAMMATION AND, WITHOUT REPAIR OF THE INTESTINAL BARRIER, MIGHT REPRESENT A CONTINUOUS INFLAMMATORY STIMULUS CAPABLE OF TRIGGERING AUTOIMMUNE PROCESSES. RECENT STUDIES INDICATE GENDER-SPECIFIC DIFFERENCES IN IMMUNITY, WITH THE GUT MICROBIOTA SHAPING AND BEING CONCOMITANTLY SHAPED BY THE HORMONAL MILIEU GOVERNING DIFFERENCES BETWEEN THE SEXES. A BI-DIRECTIONAL CROSS-TALK BETWEEN MICROBIOTA AND THE ENDOCRINE SYSTEM IS EMERGING WITH BACTERIA BEING ABLE TO PRODUCE HORMONES (E.G. SEROTONIN, DOPAMINE AND SOMATOSTATINE), RESPOND TO HOST HORMONES (E.G. ESTROGENS) AND REGULATE HOST HORMONES' HOMEOSTASIS (E.G BY INHIBITING GENE PROLACTIN TRANSCRIPTION OR CONVERTING GLUCOCORTICOIDS TO ANDROGENS). WE REVIEW HEREIN HOW GUT MICROBIOTA AND ITS METABOLITES REGULATE IMMUNE FUNCTION, INTESTINAL PERMEABILITY AND POSSIBLY AID PATHOLOGICAL PROCESSES. FURTHER, WE DESCRIBE THE DYSBIOSIS WITHIN THE GUT MICROBIOTA OBSERVED IN DIFFERENT AID AND SPECULATE HOW RESTORING GUT MICROBIOTA COMPOSITION AND ITS REGULATORY METABOLITES BY DIETARY INTERVENTION INCLUDING PREBIOTICS AND PROBIOTICS COULD HELP IN PREVENTING OR AMELIORATING AID. FINALLY, WE SUGGEST THAT, GIVEN CONSISTENT OBSERVATIONS OF MICROBIOTA DYSBIOSIS ASSOCIATED WITH AID AND THE ABILITY OF SCFA AND BA TO REGULATE INTESTINAL PERMEABILITY AND INFLAMMATION, FURTHER MECHANISTIC STUDIES, EXAMINING HOW DIETARY MICROBIOTA MODULATION CAN PROTECT AGAINST AID, HOLD CONSIDERABLE POTENTIAL TO TACKLE INCREASED INCIDENCE OF AID AT THE POPULATION LEVEL. 2018 19 3920 27 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 20 2368 21 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