1 566 109 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 2 2657 30 EPITHELIAL DYSFUNCTION IN CHRONIC RESPIRATORY DISEASES, A SHARED ENDOTYPE? PURPOSE OF REVIEW: EPITHELIAL BARRIER DEFECTS ARE BEING APPRECIATED IN VARIOUS INFLAMMATORY DISORDERS; HOWEVER, CAUSAL UNDERLYING MECHANISMS ARE LACKING. IN THIS REVIEW, WE DESCRIBE THE DISRUPTION OF THE AIRWAY EPITHELIUM WITH REGARD TO UPPER AND LOWER AIRWAY DISEASES, THE ROLE OF EPIGENETIC ALTERATIONS UNDERLYING THIS PROCESS, AND POTENTIAL NOVEL WAYS OF INTERFERING WITH DYSFUNCTIONAL EPITHELIAL BARRIERS AS A NOVEL THERAPEUTIC APPROACH. RECENT FINDINGS: A DEFECTIVE EPITHELIAL BARRIER, IMPAIRED INNATE DEFENCE MECHANISMS OR HAMPERED EPITHELIAL CELL RENEWAL ARE FOUND IN UPPER AND LOWER AIRWAY DISEASES. BARRIER DYSFUNCTION MIGHT FACILITATE THE ENTRANCE OF FOREIGN SUBSTANCES, INITIATING AND FACILITATING THE ONSET OF DISEASE. LATEST DATA PROVIDED NOVEL INSIGHTS FOR POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS INDUCED BY INFLAMMATION OR OTHER UNKNOWN MECHANISMS AS A POTENTIAL MECHANISM RESPONSIBLE FOR EPITHELIAL DEFECTS. ADDITIONALLY, THESE MECHANISMS MIGHT PRECEDE DISEASE DEVELOPMENT, AND REPRESENT A NOVEL THERAPEUTIC APPROACH FOR RESTORING EPITHELIAL DEFECTS. SUMMARY: A BETTER UNDERSTANDING OF THE ROLE OF EPIGENETICS IN DRIVING AND MAINTAINING EPITHELIAL DEFECTS IN VARIOUS INFLAMMATORY DISEASES, USING STATE-OF-THE-ART BIOLOGY TOOLS WILL BE CRUCIAL IN DESIGNING NOVEL THERAPIES TO PROTECT OR RECONSTITUTE A DEFECTIVE AIRWAY EPITHELIAL BARRIER. 2020 3 4872 42 OUTSIDE-IN HYPOTHESIS REVISITED: THE ROLE OF MICROBIAL, EPITHELIAL, AND IMMUNE INTERACTIONS. OBJECTIVE: OUR UNDERSTANDING OF THE ORIGIN OF ALLERGIC DISEASES HAS INCREASED IN RECENT YEARS, HIGHLIGHTING THE IMPORTANCE OF MICROBIAL DYSBIOSIS AND EPITHELIAL BARRIER DYSFUNCTION IN AFFECTED TISSUES. EXPLORING THE MICROBIAL-EPITHELIAL-IMMUNE CROSSTALK UNDERLYING THE MECHANISMS OF ALLERGIC DISEASES WILL ALLOW THE DEVELOPMENT OF NOVEL PREVENTION AND TREATMENT STRATEGIES FOR ALLERGIC DISEASES. DATA SOURCES: THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN MICROBIAL, EPITHELIAL, AND IMMUNE INTERACTIONS IN ATOPIC DERMATITIS, ALLERGIC RHINITIS, CHRONIC RHINOSINUSITIS, AND ASTHMA. STUDY SELECTIONS: WE PERFORMED A LITERATURE SEARCH, IDENTIFYING RELEVANT RECENT PRIMARY ARTICLES AND REVIEW ARTICLES. RESULTS: DYNAMIC CROSSTALK BETWEEN THE ENVIRONMENTAL FACTORS AND MICROBIAL, EPITHELIAL, AND IMMUNE CELLS IN THE DEVELOPMENT OF ATOPIC DERMATITIS, ALLERGIC RHINITIS, CHRONIC RHINOSINUSITIS, AND ASTHMA UNDERLIES THE PATHOGENESIS OF THESE DISEASES. THERE IS SUBSTANTIAL EVIDENCE IN THE LITERATURE SUGGESTING THAT ENVIRONMENTAL FACTORS DIRECTLY AFFECT BARRIER FUNCTION OF THE EPITHELIUM. IN ADDITION, T-HELPER 2 (T(H)2) CELLS, TYPE 2 INNATE LYMPHOID CELLS, AND THEIR CYTOKINE INTERLEUKIN 13 (IL-13) DAMAGE SKIN AND LUNG BARRIERS. THE EFFECTS OF ENVIRONMENTAL FACTORS MAY AT LEAST IN PART BE MEDIATED BY EPIGENETIC MECHANISMS. HISTONE DEACETYLASE ACTIVATION BY TYPE 2 IMMUNE RESPONSE HAS A MAJOR EFFECT ON LEAKY BARRIERS AND BLOCKING OF HISTONE DEACETYLASE ACTIVITY CORRECTS THE DEFECTIVE BARRIER IN HUMAN AIR-LIQUID INTERFACE CULTURES AND MOUSE MODELS OF ALLERGIC ASTHMA WITH RHINITIS. WE ALSO PRESENT AND DISCUSS A NOVEL DEVICE TO DETECT AND MONITOR SKIN BARRIER DYSFUNCTION, WHICH PROVIDES AN OPPORTUNITY TO RAPIDLY AND ROBUSTLY ASSESS DISEASE SEVERITY. CONCLUSION: A COMPLEX INTERPLAY BETWEEN ENVIRONMENTAL FACTORS, EPITHELIUM, AND THE IMMUNE SYSTEM IS INVOLVED IN THE DEVELOPMENT OF SYSTEMIC ALLERGIC DISEASES. 2020 4 6708 36 VIRAL INDUCED EFFECTS ON A VULNERABLE EPITHELIUM; LESSONS LEARNED FROM PAEDIATRIC ASTHMA AND EOSINOPHILIC OESOPHAGITIS. THE EPITHELIUM IS INTEGRAL TO THE PROTECTION OF MANY DIFFERENT BIOLOGICAL SYSTEMS AND FOR THE MAINTENANCE OF BIOCHEMICAL HOMEOSTASIS. EMERGING EVIDENCE SUGGESTS THAT PARTICULAR CHILDREN HAVE EPITHELIAL VULNERABILITIES LEADING TO DYSREGULATED BARRIER FUNCTION AND INTEGRITY, THAT RESULTANTLY CONTRIBUTES TO DISEASE PATHOGENESIS. THESE EPITHELIAL VULNERABILITIES LIKELY DEVELOP IN UTERO OR IN EARLY LIFE DUE TO VARIOUS GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. ALTHOUGH VARIOUS EPITHELIA ARE UNIQUELY STRUCTURED WITH SPECIFIC FUNCTION, PREVALENT ALLERGIC-TYPE EPITHELIAL DISEASES IN CHILDREN POTENTIALLY HAVE COMMON OR PARALLEL DISEASE PROCESSES. THESE INCLUDE INFLAMMATION AND IMMUNE RESPONSE DYSREGULATION STEMMING FROM ATYPICAL EPITHELIAL BARRIER FUNCTION AND INTEGRITY. TWO DISEASES WHERE AETIOLOGY AND PATHOGENESIS ARE POTENTIALLY LINKED TO EPITHELIAL VULNERABILITIES INCLUDE PAEDIATRIC ASTHMA AND EOSINOPHILIC OESOPHAGITIS (EOE). FOR EXAMPLE, RHINOVIRUS C (RV-C) IS A KNOWN RISK FACTOR FOR PAEDIATRIC ASTHMA DEVELOPMENT AND IS KNOWN TO DISRUPT RESPIRATORY EPITHELIAL BARRIER FUNCTION CAUSING ACUTE INFLAMMATION. IN ADDITION, EOE, A PREVALENT ATOPIC CONDITION OF THE OESOPHAGEAL EPITHELIUM, IS CHARACTERISED BY SIMILAR INNATE IMMUNE AND EPITHELIAL RESPONSES TO VIRAL INJURY. THIS REVIEW EXAMINES THE CURRENT LITERATURE AND IDENTIFIES THE GAPS IN THE FIELD DEFINING VIRAL-INDUCED EFFECTS ON A VULNERABLE RESPIRATORY EPITHELIUM AND RESULTING CHRONIC INFLAMMATION, DRAWING FROM KNOWLEDGE GENERATED IN ACUTE WHEEZING ILLNESS, PAEDIATRIC ASTHMA AND EOE. BESIDES HIGHLIGHTING THE IMPORTANCE OF EPITHELIAL STRUCTURE AND BARRIER FUNCTION IN ALLERGIC DISEASE PATHOGENESIS REGARDLESS OF SPECIFIC EPITHELIAL SUB-TYPES, THIS REVIEW FOCUSES ON THE IMPORTANCE OF EXAMINING OTHER PARALLEL ALLERGIC-TYPE DISEASE PROCESSES THAT MAY UNCOVER COMMONALITIES DRIVING DISEASE PATHOGENESIS. THIS IN TURN MAY BE BENEFICIAL IN THE DEVELOPMENT OF COMMON THERAPEUTICS FOR CURRENT CLINICAL MANAGEMENT AND DISEASE PREVENTION IN THE FUTURE. 2021 5 4116 33 MECHANISMS OF AIRWAY EPITHELIAL INJURY AND ABNORMAL REPAIR IN ASTHMA AND COPD. THE AIRWAY EPITHELIUM COMPRISES OF DIFFERENT CELL TYPES AND ACTS AS A PHYSICAL BARRIER PREVENTING PATHOGENS, INCLUDING INHALED PARTICLES AND MICROBES, FROM ENTERING THE LUNGS. GOBLET CELLS AND SUBMUCOSAL GLANDS PRODUCE MUCUS THAT TRAPS PATHOGENS, WHICH ARE EXPELLED FROM THE RESPIRATORY TRACT BY CILIATED CELLS. BASAL CELLS ACT AS PROGENITOR CELLS, DIFFERENTIATING INTO DIFFERENT EPITHELIAL CELL TYPES, TO MAINTAIN HOMEOSTASIS FOLLOWING INJURY. ADHERENS AND TIGHT JUNCTIONS BETWEEN CELLS MAINTAIN THE EPITHELIAL BARRIER FUNCTION AND REGULATE THE MOVEMENT OF MOLECULES ACROSS IT. IN THIS REVIEW WE DISCUSS HOW ABNORMAL EPITHELIAL STRUCTURE AND FUNCTION, CAUSED BY CHRONIC INJURY AND ABNORMAL REPAIR, DRIVES AIRWAY DISEASE AND SPECIFICALLY ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN BOTH DISEASES, INHALED ALLERGENS, POLLUTANTS AND MICROBES DISRUPT JUNCTIONAL COMPLEXES AND PROMOTE CELL DEATH, IMPAIRING THE BARRIER FUNCTION AND LEADING TO INCREASED PENETRATION OF PATHOGENS AND A CONSTANT AIRWAY IMMUNE RESPONSE. IN ASTHMA, THE INFLAMMATORY RESPONSE PRECIPITATES THE EPITHELIAL INJURY AND DRIVES ABNORMAL BASAL CELL DIFFERENTIATION. THIS LEADS TO REDUCED CILIATED CELLS, GOBLET CELL HYPERPLASIA AND INCREASED EPITHELIAL MESENCHYMAL TRANSITION, WHICH CONTRIBUTE TO IMPAIRED MUCOCILIARY CLEARANCE AND AIRWAY REMODELLING. IN COPD, CHRONIC OXIDATIVE STRESS AND INFLAMMATION TRIGGER PREMATURE EPITHELIAL CELL SENESCENCE, WHICH CONTRIBUTES TO LOSS OF EPITHELIAL INTEGRITY AND AIRWAY INFLAMMATION AND REMODELLING. INCREASED NUMBERS OF BASAL CELLS SHOWING DEREGULATED DIFFERENTIATION, CONTRIBUTES TO CILIARY DYSFUNCTION AND MUCOUS HYPERPRODUCTION IN COPD AIRWAYS. DEFECTIVE ANTIOXIDANT, ANTIVIRAL AND DAMAGE REPAIR MECHANISMS, POSSIBLY DUE TO GENETIC OR EPIGENETIC FACTORS, MAY CONFER SUSCEPTIBILITY TO AIRWAY EPITHELIAL DYSFUNCTION IN THESE DISEASES. THE CURRENT EVIDENCE SUGGESTS THAT A CONSTANT CYCLE OF INJURY AND ABNORMAL REPAIR OF THE EPITHELIUM DRIVES CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA AND COPD. MECHANISTIC UNDERSTANDING OF INJURY SUSCEPTIBILITY AND DAMAGE RESPONSE MAY LEAD TO IMPROVED THERAPIES FOR THESE DISEASES. 2023 6 4274 45 MICROBIOTA IN INFLAMMATORY BOWEL DISEASE PATHOGENESIS AND THERAPY: IS IT ALL ABOUT DIET? INFLAMMATORY BOWEL DISEASE (IBD), INCLUDING ULCERATIVE COLITIS, CROHN'S DISEASE, AND UNCLASSIFIED IBD, CONTINUES TO CAUSE SIGNIFICANT MORBIDITY. WHILE ITS INCIDENCE IS INCREASING, NO CLEAR ETIOLOGY AND NO CURE HAVE YET BEEN DISCOVERED. RECENT FINDINGS SUGGEST THAT IBD MAY HAVE A MULTIFACTORIAL ETIOLOGY, WHERE COMPLEX INTERACTIONS BETWEEN GENETICS, EPIGENETICS, ENVIRONMENTAL FACTORS (INCLUDING DIET BUT ALSO INFECTIONS, ANTIBIOTICS, AND SANITATION), AND HOST IMMUNE SYSTEM LEAD TO ABNORMAL IMMUNE RESPONSES AND CHRONIC INFLAMMATION. OVER THE PAST YEARS, THE ROLE OF ALTERED GUT MICROBIOTA (IN BOTH COMPOSITION AND FUNCTION) IN IBD PATHOGENESIS HAS EMERGED AS AN OUTSTANDING AREA OF INTEREST. ACCORDING TO NEW FINDINGS, GUT DYSBIOSIS MAY APPEAR AS A KEY ELEMENT IN INITIATION OF INFLAMMATION IN IBD AND ITS COMPLICATIONS. MOREOVER, COMPLEX METAGENOMIC STUDIES PROVIDE POSSIBILITIES TO DISTINGUISH BETWEEN IBD TYPES AND APPRECIATE SEVERITY AND PROGNOSIS OF THE DISEASE, AS WELL AS RESPONSE TO THERAPY. THIS REVIEW PROVIDES AN UPDATED KNOWLEDGE OF RECENT FINDINGS LINKING ALTERED BACTERIAL COMPOSITION AND FUNCTIONS, VIRUSES, AND FUNGI TO IBD PATHOGENESIS. IT ALSO HIGHLIGHTS THE COMPLEX GENETIC, EPIGENETIC, IMMUNE, AND MICROBIAL INTERACTIONS IN RELATION TO ENVIRONMENTAL FACTORS (INCLUDING DIET). WE OVERVIEW THE ACTUAL OPTIONS TO MANIPULATE THE ALTERED MICROBIOTA, SUCH AS MODIFIED DIET, PROBIOTICS, PREBIOTICS, SYNBIOTICS, ANTIBIOTICS, AND FECAL TRANSPLANTATION. FUTURE POSSIBLE THERAPIES ARE ALSO INCLUDED. TARGETING ALTERED MICROBIOTA COULD BE THE NEXT THERAPEUTIC PERSONALIZED APPROACH, BUT MORE RESEARCH AND WELL-DESIGNED COMPARATIVE PROSPECTIVE STUDIES ARE REQUIRED TO FORMULATE ADEQUATE DIRECTIONS FOR PREVENTION AND THERAPY. 2015 7 3920 28 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 8 2617 47 EPIGENOME TARGETING BY PROBIOTIC METABOLITES. BACKGROUND: THE INTESTINAL MICROBIOTA PLAYS AN IMPORTANT ROLE IN IMMUNE DEVELOPMENT AND HOMEOSTASIS. A DISTURBED MICROBIOTA DURING EARLY INFANCY IS ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING INFLAMMATORY AND ALLERGIC DISEASES LATER IN LIFE. THE MECHANISMS UNDERLYING THESE EFFECTS ARE POORLY UNDERSTOOD BUT ARE LIKELY TO INVOLVE ALTERATIONS IN MICROBIAL PRODUCTION OF FERMENTATION-DERIVED METABOLITES, WHICH HAVE POTENT IMMUNE MODULATING PROPERTIES AND ARE REQUIRED FOR MAINTENANCE OF HEALTHY MUCOSAL IMMUNE RESPONSES. PROBIOTICS ARE BENEFICIAL BACTERIA THAT HAVE THE CAPACITY TO ALTER THE COMPOSITION OF BACTERIAL SPECIES IN THE INTESTINE THAT CAN IN TURN INFLUENCE THE PRODUCTION OF FERMENTATION-DERIVED METABOLITES. PRINCIPAL AMONG THESE METABOLITES ARE THE SHORT-CHAIN FATTY ACIDS BUTYRATE AND ACETATE THAT HAVE POTENT ANTI-INFLAMMATORY ACTIVITIES IMPORTANT IN REGULATING IMMUNE FUNCTION AT THE INTESTINAL MUCOSAL SURFACE. THEREFORE STRATEGIES AIMED AT RESTORING THE MICROBIOTA PROFILE MAY BE EFFECTIVE IN THE PREVENTION OR TREATMENT OF ALLERGIC AND INFLAMMATORY DISEASES. PRESENTATION OF THE HYPOTHESIS: PROBIOTIC BACTERIA HAVE DIVERSE EFFECTS INCLUDING ALTERING MICROBIOTA COMPOSITION, REGULATING EPITHELIAL CELL BARRIER FUNCTION AND MODULATING OF IMMUNE RESPONSES. THE PRECISE MOLECULAR MECHANISMS MEDIATING THESE PROBIOTIC EFFECTS ARE NOT WELL UNDERSTOOD. SHORT-CHAIN FATTY ACIDS SUCH AS BUTYRATE ARE A CLASS OF HISTONE DEACETYLASE INHIBITORS IMPORTANT IN THE EPIGENETIC CONTROL OF HOST CELL RESPONSES. IT IS HYPOTHESIZED THAT THE BIOLOGICAL FUNCTION OF PROBIOTICS MAY BE A RESULT OF EPIGENETIC MODIFICATIONS THAT MAY EXPLAIN THE WIDE RANGE OF EFFECTS OBSERVED. STUDIES DELINEATING THE EFFECTS OF PROBIOTICS ON SHORT-CHAIN FATTY ACID PRODUCTION AND THE EPIGENETIC ACTIONS OF SHORT-CHAIN FATTY ACIDS WILL ASSIST IN UNDERSTANDING THE ASSOCIATION BETWEEN MICROBIOTA AND ALLERGIC OR AUTOIMMUNE DISORDERS. TESTING THE HYPOTHESIS: WE PROPOSE THAT TREATMENT WITH SPECIFIC PROBIOTIC BACTERIA UNDER IN VIVO CONDITIONS WOULD OFFER THE IDEAL CONDITIONS TO EXAMINE THE MICROBIOLOGICAL, IMMUNOLOGICAL AND EPIGENETIC MECHANISMS OF ACTION. ADVANCES IN EPIGENETIC TECHNOLOGY NOW ALLOW INVESTIGATORS TO BETTER UNDERSTAND THE COMPLEX BIOLOGICAL PROPERTIES OF PROBIOTICS AND THEIR METABOLITES. IMPLICATIONS OF THE HYPOTHESIS: DETERMINING THE PRECISE MECHANISMS OF PROBIOTIC ACTION WILL LEAD TO MORE SPECIFIC AND EFFICACIOUS THERAPEUTIC STRATEGIES IN THE PREVENTION OR TREATMENT OF CHRONIC INFLAMMATORY CONDITIONS. 2010 9 1149 38 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 10 1395 52 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 5454 27 REPURPOSING BELINOSTAT FOR ALLEVIATION OF ATOPIC DERMATITIS. ATOPIC DERMATITIS (AD) IS A HIGHLY PREVALENT CHRONIC INFLAMMATORY SKIN DISEASE THAT IS CHARACTERIZED BY INTENSE PRURITUS, SERIOUSLY AFFECTING PATIENTS' QUALITY OF LIFE. ITS PATHOPHYSIOLOGY, WHICH INVOLVES BOTH THE ADAPTIVE AND INNATE IMMUNE RESPONSES AS WELL AS SKIN BARRIER DEFECTS, IS STILL POORLY UNDERSTOOD. WE RECENTLY IDENTIFIED A MICRORNA, MIR-335, AS A KEY DRIVER OF KERATINOCYTE DIFFERENTIATION AND CORNIFICATION, WHICH IS ESSENTIAL FOR THE ESTABLISHMENT OF A HEALTHY SKIN BARRIER. HOWEVER, EXPRESSION OF MIR-335 IS LOST IN AD, LEADING TO BARRIER DEFECT. WE FURTHER DEMONSTRATED HOW BELINOSTAT, A HISTONE DEACETYLASE INHIBITOR, CAN EFFECTIVELY RESTORE MIR-335 AND RESOLVE THE BARRIER DEFECT IN A DRY SKIN MODEL. HERE, IN THIS COMMENTARY, WE HIGHLIGHT THE ROLE OF BELINOSTAT IN THE TREATMENT OF AD AND DISCUSS THE NEED FOR MORE RESEARCH INTO CROSSTALK BETWEEN EPIGENETIC AND NON-CODING RNA-BASED REGULATION, AS WELL AS POSSIBLE THERAPEUTIC STRATEGIES TARGETING THE EPIGENOME. 2021 12 2731 32 EXPLORING THE COMPLEX RELATIONSHIP BETWEEN MICROBIOTA AND SYSTEMIC LUPUS ERYTHEMATOSUS. PURPOSE OF REVIEW: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY VARIOUS AUTOANTIBODIES AND MULTI-ORGAN. MICROBIOTA DYSBIOSIS IN THE GUT, SKIN, ORAL, AND OTHER SURFACES HAS A SIGNIFICANT IMPACT ON SLE DEVELOPMENT. THIS ARTICLE SUMMARIZES RELEVANT RESEARCH AND PROVIDES NEW MICROBIOME-RELATED STRATEGIES FOR EXPLORING THE MECHANISMS AND TREATING PATIENTS WITH SLE. RECENT FINDINGS: SLE PATIENTS HAVE DISRUPTIONS IN MULTIPLE MICROBIOMES, WITH THE GUT MICROBIOTA (BACTERIA, VIRUSES, AND FUNGI) AND THEIR METABOLITES BEING THE MOST THOROUGHLY RESEARCHED. THIS DYSBIOSIS CAN PROMOTE SLE PROGRESSION THROUGH MECHANISMS SUCH AS THE LEAKY GUT, MOLECULAR MIMICRY, AND EPIGENETIC REGULATION. NOTWITHSTANDING STUDY CONSTRAINTS ON THE RELATIONSHIP BETWEEN MICROBIOTA AND SLE, SPECIFIC INTERVENTIONS TARGETING THE GUT MICROBIOTA, SUCH AS PROBIOTICS, DIETARY MANAGEMENT, AND FECAL MICROBIOTA TRANSPLANTATION, HAVE EMERGED AS PROMISING SLE THERAPEUTICS. 2023 13 4337 29 MICROTUBULES AS MAJOR REGULATORS OF ENDOTHELIAL FUNCTION: IMPLICATION FOR LUNG INJURY. ENDOTHELIAL DYSFUNCTION HAS BEEN ATTRIBUTED AS ONE OF THE MAJOR COMPLICATIONS IN COVID-19 PATIENTS, A GLOBAL PANDEMIC THAT HAS ALREADY CAUSED OVER 4 MILLION DEATHS WORLDWIDE. THE DYSFUNCTION OF ENDOTHELIAL BARRIER IS CHARACTERIZED BY AN INCREASE IN ENDOTHELIAL PERMEABILITY AND INFLAMMATORY RESPONSES, AND HAS EVEN BROADER IMPLICATIONS IN THE PATHOGENESIS OF ACUTE RESPIRATORY SYNDROMES SUCH AS ARDS, SEPSIS AND CHRONIC ILLNESSES REPRESENTED BY PULMONARY ARTERIAL HYPERTENSION AND INTERSTITIAL LUNG DISEASE. THE STRUCTURAL INTEGRITY OF ENDOTHELIAL BARRIER IS MAINTAINED BY CYTOSKELETON ELEMENTS, CELL-SUBSTRATE FOCAL ADHESION AND ADHESIVE CELL JUNCTIONS. AGONIST-MEDIATED CHANGES IN ENDOTHELIAL PERMEABILITY ARE DIRECTLY ASSOCIATED WITH REORGANIZATION OF ACTOMYOSIN CYTOSKELETON LEADING TO CELL CONTRACTION AND OPENING OF INTERCELLULAR GAPS OR ENHANCEMENT OF CORTICAL ACTIN CYTOSKELETON ASSOCIATED WITH STRENGTHENING OF ENDOTHELIAL BARRIER. THE ROLE OF ACTIN CYTOSKELETON REMODELING IN ENDOTHELIAL BARRIER REGULATION HAS TAKEN THE CENTRAL STAGE, BUT THE IMPACT OF MICROTUBULES IN THIS PROCESS REMAINS LESS EXPLORED AND UNDER-APPRECIATED. THIS REVIEW WILL SUMMARIZE THE CURRENT KNOWLEDGE ON THE CROSSTALK BETWEEN MICROTUBULES DYNAMICS AND ACTIN CYTOSKELETON REMODELING, DESCRIBE THE SIGNALING MECHANISMS MEDIATING THIS CROSSTALK, DISCUSS EPIGENETIC REGULATION OF MICROTUBULES STABILITY AND ITS NEXUS WITH ENDOTHELIAL BARRIER MAINTENANCE, AND OVERVIEW A ROLE OF MICROTUBULES IN TARGETED DELIVERY OF SIGNALING MOLECULES REGULATING ENDOTHELIAL PERMEABILITY AND INFLAMMATION. 2021 14 1404 37 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 15 2368 33 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 16 2065 28 EPIGENETIC CONTROL OF INTESTINAL BARRIER FUNCTION AND INFLAMMATION IN ZEBRAFISH. THE INTESTINAL EPITHELIUM FORMS A BARRIER PROTECTING THE ORGANISM FROM MICROBES AND OTHER PROINFLAMMATORY STIMULI. THE INTEGRITY OF THIS BARRIER AND THE PROPER RESPONSE TO INFECTION REQUIRES PRECISE REGULATION OF POWERFUL IMMUNE HOMING SIGNALS SUCH AS TUMOR NECROSIS FACTOR (TNF). DYSREGULATION OF TNF LEADS TO INFLAMMATORY BOWEL DISEASES (IBD), BUT THE MECHANISM CONTROLLING THE EXPRESSION OF THIS POTENT CYTOKINE AND THE EVENTS THAT TRIGGER THE ONSET OF CHRONIC INFLAMMATION ARE UNKNOWN. HERE, WE SHOW THAT LOSS OF FUNCTION OF THE EPIGENETIC REGULATOR UBIQUITIN-LIKE PROTEIN CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IN ZEBRAFISH LEADS TO A REDUCTION IN TNFA PROMOTER METHYLATION AND THE INDUCTION OF TNFA EXPRESSION IN INTESTINAL EPITHELIAL CELLS (IECS). THE INCREASE IN IEC TNFA LEVELS IS MICROBE-DEPENDENT AND RESULTS IN IEC SHEDDING AND APOPTOSIS, IMMUNE CELL RECRUITMENT, AND BARRIER DYSFUNCTION, CONSISTENT WITH CHRONIC INFLAMMATION. IMPORTANTLY, TNFA KNOCKDOWN IN UHRF1 MUTANTS RESTORES IEC MORPHOLOGY, REDUCES CELL SHEDDING, AND IMPROVES BARRIER FUNCTION. WE PROPOSE THAT LOSS OF EPIGENETIC REPRESSION AND TNF INDUCTION IN THE INTESTINAL EPITHELIUM CAN LEAD TO IBD ONSET. 2015 17 1275 41 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 18 3692 41 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 19 324 43 ALL DISEASE BEGINS IN THE (LEAKY) GUT: ROLE OF ZONULIN-MEDIATED GUT PERMEABILITY IN THE PATHOGENESIS OF SOME CHRONIC INFLAMMATORY DISEASES. IMPROVED HYGIENE LEADING TO REDUCED EXPOSURE TO MICROORGANISMS HAS BEEN IMPLICATED AS ONE POSSIBLE CAUSE FOR THE RECENT "EPIDEMIC" OF CHRONIC INFLAMMATORY DISEASES (CIDS) IN INDUSTRIALIZED COUNTRIES. THAT IS THE ESSENCE OF THE HYGIENE HYPOTHESIS THAT ARGUES THAT RISING INCIDENCE OF CIDS MAY BE, AT LEAST IN PART, THE RESULT OF LIFESTYLE AND ENVIRONMENTAL CHANGES THAT HAVE MADE US TOO "CLEAN" FOR OUR OWN GOOD, SO CAUSING CHANGES IN OUR MICROBIOTA. APART FROM GENETIC MAKEUP AND EXPOSURE TO ENVIRONMENTAL TRIGGERS, INAPPROPRIATE INCREASE IN INTESTINAL PERMEABILITY (WHICH MAY BE INFLUENCED BY THE COMPOSITION OF THE GUT MICROBIOTA), A "HYPER-BELLIGERENT" IMMUNE SYSTEM RESPONSIBLE FOR THE TOLERANCE-IMMUNE RESPONSE BALANCE, AND THE COMPOSITION OF GUT MICROBIOME AND ITS EPIGENETIC INFLUENCE ON THE HOST GENOMIC EXPRESSION HAVE BEEN IDENTIFIED AS THREE ADDITIONAL ELEMENTS IN CAUSING CIDS. DURING THE PAST DECADE, A GROWING NUMBER OF PUBLICATIONS HAVE FOCUSED ON HUMAN GENETICS, THE GUT MICROBIOME, AND PROTEOMICS, SUGGESTING THAT LOSS OF MUCOSAL BARRIER FUNCTION, PARTICULARLY IN THE GASTROINTESTINAL TRACT, MAY SUBSTANTIALLY AFFECT ANTIGEN TRAFFICKING, ULTIMATELY INFLUENCING THE CLOSE BIDIRECTIONAL INTERACTION BETWEEN GUT MICROBIOME AND OUR IMMUNE SYSTEM. THIS CROSS-TALK IS HIGHLY INFLUENTIAL IN SHAPING THE HOST GUT IMMUNE SYSTEM FUNCTION AND ULTIMATELY SHIFTING GENETIC PREDISPOSITION TO CLINICAL OUTCOME. THIS OBSERVATION LED TO A RE-VISITATION OF THE POSSIBLE CAUSES OF CIDS EPIDEMICS, SUGGESTING A KEY PATHOGENIC ROLE OF GUT PERMEABILITY. PRE-CLINICAL AND CLINICAL STUDIES HAVE SHOWN THAT THE ZONULIN FAMILY, A GROUP OF PROTEINS MODULATING GUT PERMEABILITY, IS IMPLICATED IN A VARIETY OF CIDS, INCLUDING AUTOIMMUNE, INFECTIVE, METABOLIC, AND TUMORAL DISEASES. THESE DATA OFFER NOVEL THERAPEUTIC TARGETS FOR A VARIETY OF CIDS IN WHICH THE ZONULIN PATHWAY IS IMPLICATED IN THEIR PATHOGENESIS. 2020 20 5540 41 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