1 6743 236 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? INCORPORATING PRESENTATIONS ON SCOLIOGENY AT THE 2012 IRSSD AND SRS MEETINGS. THIS PAPER AIMS TO INTEGRATE INTO CURRENT UNDERSTANDING OF AIS CAUSATION, ETIOPATHOGENETIC INFORMATION PRESENTED AT TWO MEETINGS DURING 2012 NAMELY, THE INTERNATIONAL RESEARCH SOCIETY OF SPINAL DEFORMITIES (IRSSD) AND THE SCOLIOSIS RESEARCH SOCIETY (SRS). THE ULTIMATE HOPE IS TO PREVENT THE OCCURRENCE OR PROGRESSION OF THE SPINAL DEFORMITY OF AIS WITH NON-INVASIVE TREATMENT, POSSIBLY MEDICAL. THIS MIGHT BE ATTAINED BY PERSONALISED POLYMECHANISTIC PREVENTIVE THERAPY TARGETING THE APPROPRIATE ETIOLOGY AND/OR ETIOPATHOGENETIC PATHWAYS, TO AVOID FUSION AND MAINTAIN SPINAL MOBILITY. ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM. 2013 2 6742 197 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM. 2012 3 244 75 ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), ENVIRONMENT, EXPOSOME AND EPIGENETICS: A MOLECULAR PERSPECTIVE OF POSTNATAL NORMAL SPINAL GROWTH AND THE ETIOPATHOGENESIS OF AIS WITH CONSIDERATION OF A NETWORK APPROACH AND POSSIBLE IMPLICATIONS FOR MEDICAL THERAPY. GENETIC FACTORS ARE BELIEVED TO PLAY AN IMPORTANT ROLE IN THE ETIOLOGY OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS). DISCORDANT FINDINGS FOR MONOZYGOTIC (MZ) TWINS WITH AIS SHOW THAT ENVIRONMENTAL FACTORS INCLUDING DIFFERENT INTRAUTERINE ENVIRONMENTS ARE IMPORTANT IN ETIOLOGY, BUT WHAT THESE ENVIRONMENTAL FACTORS MAY BE IS UNKNOWN. RECENT EVIDENCE FOR COMMON CHRONIC NON-COMMUNICABLE DISEASES SUGGESTS EPIGENETIC DIFFERENCES MAY UNDERLIE MZ TWIN DISCORDANCE, AND BE THE LINK BETWEEN ENVIRONMENTAL FACTORS AND PHENOTYPIC DIFFERENCES. DNA METHYLATION IS ONE IMPORTANT EPIGENETIC MECHANISM OPERATING AT THE INTERFACE BETWEEN GENOME AND ENVIRONMENT TO REGULATE PHENOTYPIC PLASTICITY WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. THE WORD EXPOSOME REFERS TO THE TOTALITY OF ENVIRONMENTAL EXPOSURES FROM CONCEPTION ONWARDS, COMPRISING FACTORS IN EXTERNAL AND INTERNAL ENVIRONMENTS. THE WORD EXPOSOME IS USED HERE ALSO IN RELATION TO PHYSIOLOGIC AND ETIOPATHOGENETIC FACTORS THAT AFFECT NORMAL SPINAL GROWTH AND MAY INDUCE THE DEFORMITY OF AIS. IN NORMAL POSTNATAL SPINAL GROWTH WE PROPOSE A NEW TERM AND CONCEPT, PHYSIOLOGIC GROWTH-PLATE EXPOSOME FOR THE NORMAL PROCESSES PARTICULARLY OF THE INTERNAL ENVIRONMENTS THAT MAY HAVE EPIGENETIC EFFECTS ON GROWTH PLATES OF VERTEBRAE. IN AIS, WE PROPOSE A NEW TERM AND CONCEPT PATHOPHYSIOLOGIC SCOLIOGENIC EXPOSOME FOR THE ABNORMAL PROCESSES IN MOLECULAR PATHWAYS PARTICULARLY OF THE INTERNAL ENVIRONMENT CURRENTLY EXPRESSED AS ETIOPATHOGENETIC HYPOTHESES; THESE ARE SUGGESTED TO HAVE DEFORMING EFFECTS ON THE GROWTH PLATES OF VERTEBRAE AT CELL, TISSUE, STRUCTURE AND/OR ORGAN LEVELS THAT ARE CONSIDERED TO BE EPIGENETIC. NEW RESEARCH IS REQUIRED FOR CHROMATIN MODIFICATIONS INCLUDING DNA METHYLATION IN AIS SUBJECTS AND VERTEBRAL GROWTH PLATES EXCISED AT SURGERY. IN ADDITION, CONSIDERATION IS NEEDED FOR A POSSIBLE NETWORK APPROACH TO ETIOPATHOGENESIS BY CONSTRUCTING AIS DISEASOMES. THESE APPROACHES MAY LEAD THROUGH SCREENING, GENETIC, EPIGENETIC, BIOCHEMICAL, METABOLIC PHENOTYPES AND PHARMACOGENOMIC RESEARCH TO IDENTIFY SUSCEPTIBLE INDIVIDUALS AT RISK AND MODULATE ABNORMAL MOLECULAR PATHWAYS OF AIS. THE POTENTIAL OF EPIGENETIC-BASED MEDICAL THERAPY FOR AIS CANNOT BE ASSESSED AT PRESENT, AND MUST AWAIT NEW RESEARCH DERIVED FROM THE EVALUATION OF EPIGENETIC CONCEPTS OF SPINAL GROWTH IN HEALTH AND DEFORMITY. THE TENETS OUTLINED HERE FOR AIS ARE APPLICABLE TO OTHER MUSCULOSKELETAL GROWTH DISORDERS INCLUDING INFANTILE AND JUVENILE IDIOPATHIC SCOLIOSIS. 2011 4 2988 26 GENETIC FACTORS AND SYSTEMIC SCLEROSIS. SYSTEMIC SCLEROSIS (SSC) IS A RARE CONNECTIVE TISSUE DISEASE OF UNKNOWN ETIOLOGY CHARACTERIZED BY CHRONIC INFLAMMATION AND FIBROSIS OF THE SKIN, VASCULAR ABNORMALITIES, AND VARIABLE INVOLVEMENT OF ORGANS INCLUDING KIDNEYS, GASTROINTESTINAL TRACT, HEART, AND LUNGS. SSC SHOWS A COMPLEX ETIOLOGY IN WHICH BOTH ENVIRONMENTAL AND GENETIC FACTORS SEEM TO INFLUENCE THE ONSET AND OUTCOME OF THE DISEASE. WE PROVIDE AN EXTENSIVE OVERVIEW OF THE GENETIC FACTORS AND EPIGENETIC MODIFICATIONS AND WHAT THEIR KNOWLEDGE HAS REVEALED IN TERMS OF ETIOPATHOGENESIS OF SSC. 2016 5 6827 36 [GILLES DE LA TOURETTE'S DISEASE. SYMPTOMS, ETIOPATHOGENESIS AND THERAPEUTIC APPROACHES]. THE GILLES DE LA TOURETTE SYNDROME IS A USUALLY CHRONIC NEUROPSYCHIATRIC DISORDER WITH AN EARLY CHILDHOOD ONSET FEATURING MAINLY MOTOR AND VOCAL TICS. IT SEEMS THAT STRONG GENETIC FACTORS MAKE A MAJOR CONTRIBUTION TO THE ETIOLOGY OF THIS DISORDER, BUT THERE ARE ALSO CLUES THAT EPIGENETIC FACTORS ARE INVOLVED IN THE PATHOGENESIS OF TOURETTE'S SYNDROME, SUCH AS MATERNAL STRESS DURING PREGNANCY, BIRTH COMPLICATIONS AND HORMONAL INFLUENCES. FIRST IN LINE FOR ADEQUATE TREATMENT ARE NEUROLEPTIC COMPOUNDS OF HIGH POTENCY, BESIDES, SEVERAL OTHER PSYCHOACTIVE DRUGS HAVE SHOWN SOME THERAPEUTIC EFFECTS. LESS EVIDENT IS THE EFFICACY OF NEUROSURGICAL AND PSYCHOTHERAPEUTIC INTERVENTIONS. 1997 6 3173 31 GUT MICROBIOTA-MICRORNA INTERACTIONS IN ANKYLOSING SPONDYLITIS. ANKYLOSING SPONDYLITIS (AS) IS A CHRONIC AUTOIMMUNE INFLAMMATORY DISABILITY THAT IS PART OF THE RHEUMATIC DISEASE GROUP OF SPONDYLOARTHROPATHIES. AS COMMONLY INFLUENCES THE JOINTS OF THE AXIAL SKELETON. THE CONTRIBUTIONS TO AS PATHOGENESIS OF GENETIC SUSCEPTIBILITY (PARTICULARLY HLA-B27 AND ERAP-1) AND EPIGENETIC MODIFICATIONS, LIKE NON-CODING RNAS, AS WELL AS ENVIRONMENTAL FACTORS, HAVE BEEN INVESTIGATED OVER THE LAST FEW YEARS. BUT THE FUNDAMENTAL ETIOLOGY OF AS REMAINS ELUSIVE TO DATE. THE EVIDENCE SUMMARIZED HERE INDICATES THAT IN THE IMMUNOPATHOGENESIS OF AS, MICRORNAS AND THE GUT MICROBIOME PERFORM CRITICAL FUNCTIONS. WE DISCUSS SIGNIFICANT ADVANCES IN THE IMMUNOLOGICAL MECHANISMS UNDERLYING AS AND ADDRESS POTENTIAL CROSS-TALK BETWEEN THE GUT MICROBIOME AND HOST MICRORNAS. THIS CRITICAL INTERACTION IMPLICATES A CO-EVOLUTIONARY SYMBIOTIC LINK BETWEEN HOST IMMUNITY AND THE GUT MICROBIOME. 2021 7 4883 36 OVERVIEW OF THE MOLECULAR DETERMINANTS CONTRIBUTING TO THE EXPRESSION OF PSORIASIS AND PSORIATIC ARTHRITIS PHENOTYPES. PSORIASIS AND PSORIATIC ARTHRITIS ARE MULTIFACTORIAL CHRONIC DISORDERS WHOSE ETIOPATHOGENESIS ESSENTIALLY DERIVES FROM THE ALTERATION OF SEVERAL SIGNALLING PATHWAYS AND THE CO-OCCURRENCE OF GENETIC, EPIGENETIC AND NON-GENETIC SUSCEPTIBILITY FACTORS THAT ALTOGETHER AFFECT THE FUNCTIONAL AND STRUCTURAL PROPERTY OF THE SKIN. ALTHOUGH SHARED AND DIFFERENTIAL SUSCEPTIBILITY GENES AND MOLECULAR PATHWAYS ARE KNOWN TO CONTRIBUTE TO THE ONSET OF PATHOLOGICAL PHENOTYPES, FURTHER RESEARCH IS NEEDED TO DISSECT THE MOLECULAR CAUSES OF PSORIATIC DISEASE AND ITS PROGRESSION TOWARDS PSORIATIC ARTHRITIS. THIS REVIEW WILL THEREFORE BE ADDRESSED TO EXPLORE DIFFERENCES AND SIMILARITIES IN THE ETIOPATHOGENESIS AND PROGRESSION OF BOTH DISORDERS, WITH A PARTICULAR FOCUS ON GENES INVOLVED IN THE MAINTENANCE OF THE SKIN STRUCTURE AND INTEGRITY (KERATINS AND COLLAGENS), MODULATION OF PATTERNS OF RECOGNITION (THROUGH TOLL-LIKE RECEPTORS AND DECTIN-1) AND IMMUNO-INFLAMMATORY RESPONSE (BY NLRP3-DEPENDENT INFLAMMASOME) TO MICROBIAL PATHOGENS. IN ADDITION, SPECIAL EMPHASIS WILL BE GIVEN TO THE CONTRIBUTION OF EPIGENETIC ELEMENTS (METHYLATION PATTERN, NON-CODING RNAS, CHROMATIN MODIFIERS AND 3D GENOME ORGANIZATION) TO THE ETIOPATHOGENESIS AND PROGRESSION OF PSORIASIS AND PSORIATIC ARTHRITIS. THE EVIDENCE DISCUSSED IN THIS REVIEW HIGHLIGHTS HOW THE KNOWLEDGE OF PATIENTS' CLINICAL AND (EPI)GENOMIC MAKE-UP COULD BE HELPFUL FOR IMPROVING THE AVAILABLE THERAPEUTIC STRATEGIES FOR PSORIASIS AND PSORIATIC ARTHRITIS TREATMENT. 2020 8 6021 37 THE BENEFICIAL AND DEBILITATING EFFECTS OF ENVIRONMENTAL AND MICROBIAL TOXINS, DRUGS, ORGANIC SOLVENTS AND HEAVY METALS ON THE ONSET AND PROGRESSION OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS), A CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM IS COMMON AMONGST YOUNG ADULTS, LEADING TO MAJOR PERSONAL AND SOCIOECONOMIC BURDENS. HOWEVER, IT IS STILL CONSIDERED COMPLEX AND CHALLENGING TO UNDERSTAND AND TREAT, IN SPITE OF THE EFFORTS MADE TO EXPLAIN ITS ETIOPATHOLOGY. DESPITE THE DISCOVERY OF MANY GENETIC AND ENVIRONMENTAL FACTORS THAT MIGHT BE RELATED TO ITS ETIOLOGY, NO CLEAR ANSWER WAS FOUND ABOUT THE CAUSES OF THE ILLNESS AND NEITHER ABOUT THE DETAILED MECHANISM OF THESE ENVIRONMENTAL TRIGGERS THAT MAKE INDIVIDUALS SUSCEPTIBLE TO MS. IN THIS REVIEW, WE WILL ATTEMPT TO EXPLORE THE MAJOR CONTRIBUTORS TO MS AUTOIMMUNITY INCLUDING GENETIC, EPIGENETIC AND ECOLOGICAL FACTORS WITH A PARTICULAR FOCUS ON TOXINS, CHEMICALS OR DRUGS THAT MAY TRIGGER, MODIFY OR PREVENT MS DISEASE. 2019 9 6343 42 THE ROLE OF EPIGENETICS AND IMMUNOLOGICAL IMBALANCE IN THE ETIOPATHOGENESIS OF PSORIASIS AND PSORIATIC ARTHRITIS. PSORIASIS (PS) AND PSORIATIC ARTHRITIS (PSA) REPRESENT A CLINICAL AND IMMUNOPATHOGENIC CONTINUUM, CALLED PSORIATIC DISEASE, CUMULATIVELY AFFECTING APPROXIMATELY 3% OF THE GENERAL POPULATION. PSORIATIC DISEASE IS A CHRONIC INFLAMMATORY DISORDER AFFECTING THE SKIN AND MUSCULOSKELETAL SYSTEM. THE IMMUNO-PATHOGENESIS IS CHARACTERIZED BY AN ACTIVATION OF THE TNF/IL-23/IL-17 CYTOKINE AXIS, LEADING TO AN IMMUNOLOGIC IMBALANCE OF T-CELLS RESIDENT IN ALL AFFECTED TISSUES, MAINLY ENTHESES. IN THE MAJORITY OF CASES, SKIN PS PREDATES RHEUMATOLOGICAL MANIFESTATIONS. SECONDARY TO THE HIGHER INCIDENCE AND THE AVAILABILITY OF MOUSE MODELS, THERE IS STRONGER DATA AVAILABLE ON SKIN PS, AND DATA ARE, IN MOST CASES, RELEVANT ALSO TO PSA. IN A WIDELY ACCEPTED MODEL, ENVIRONMENTAL TRIGGER FACTORS LIKE INFECTIONS OR TRAUMA ARE CAPABLE OF INITIATING AN INFLAMMATORY CASCADE, ULTIMATELY CREATING A SUSTAINED STATE OF CHRONIC INFLAMMATION IN GENETICALLY SUSCEPTIBLE INDIVIDUALS. BESIDES WELL-KNOWN GENETIC SUSCEPTIBILITY LOCI, EPIGENETIC DNA MODIFICATIONS, WHICH ARE ASSOCIATED WITH PS DEVELOPMENT HAVE BEEN CHARACTERIZED RECENTLY AND WILL BE DISCUSSED IN THIS ARTICLE. THE CURRENT EVIDENCE IS PROMISING IN THE POSSIBILITY TO PROVIDE NEW THERAPEUTIC AVENUES AND FILL THE UNMET NEED OF PATIENTS, FOR WHOM CURRENT TREATMENTS EITHER DO NOT ALLOW THE DISEASE TO BE CONTROLLED OR MUST BE CONTINUED FOR LIFE. 2019 10 5280 42 PROMOTING SYMPATHOVAGAL BALANCE IN MULTIPLE SCLEROSIS; PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES. ACCUMULATED EVIDENCE SUGGESTS THAT CARDIOVASCULAR AUTONOMIC NERVOUS SYSTEM (ANS) DYSFUNCTION MAY BE THE UNDERLYING CAUSE OF MANY MS CLINICAL PRESENTATIONS, INCLUDING NEURODEGENERATION AND REDUCED RESPONSE TO IMMUNOMODULATORY THERAPIES, DEPRESSION, FATIGUE AND SLEEP DISORDERS, MIGRAINE, OSTEOPOROSIS, AND CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY, THE NEWER MS VASCULAR ETIOLOGY. WE HAVE RECENTLY DESCRIBED THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS WITH THE POTENTIAL INFLUENCING ANS ACTIVITY, AND THE INTERACTIONS AMONG THESE FACTORS. THIS REVIEW EXPANDS UPON PREVIOUS ONES, DESCRIBING THE PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES THAT COULD BE ADOPTED TO PREVENT AND MINIMIZE THE DETERIORATION IN ANS FUNCTION, PROMOTING A STATE OF SYMPATHOVAGAL BALANCE. HOWEVER, THESE STRATEGIES SHOULD NOT BE APPLIED AS "ONE SIZE FITS ALL", BUT SHOULD TAKE INTO ACCOUNT THE NATURE AND THE DEGREE OF ANS DYSFUNCTION. THESE STRATEGIES WOULD BE EFFECTIVE IN IMPROVING ANS FUNCTION NOT ONLY IN MS, BUT ALSO IN OTHER AUTOIMMUNE AND NEURODEGENERATIVE DISEASES, WHERE THE DYSFUNCTION OF THIS SYSTEM PLAYS A ROLE. 2016 11 4962 50 PATHOGENESIS OF PSORIATIC ARTHRITIS. PSORIATIC ARTHRITIS (PSA) IS A CHRONIC INFLAMMATORY ARTHROPATHY INVOLVING SYNOVIAL AND ENTHESEAL STRUCTURES, ASSOCIATED WITH PSORIASIS OR SIMILAR CONDITIONS. THE ETIOPATHOGENETIC MECHANISMS UNDERLYING PSA REMAIN UNCLARIFIED. THE MOST ACCREDITED HYPOTHESIS INVOLVES A COMPLEX INTERACTION AMONG GENETIC, ENVIRONMENTAL, AND IMMUNOLOGICAL FACTORS. ENVIRONMENTAL AGENTS, PARTICULARLY TRAUMA, MECHANICAL STRESS, AND SMOKE HAVE BEEN CITED AS POSSIBLE FACTORS IN TRIGGERING THE DISEASE IN GENETICALLY PREDISPOSED SUBJECTS. LIKE OTHER FORMS OF SPONDYLOARTHROPATHIES, PSA SHOWS SEVERAL GENETIC ASSOCIATIONS WITH THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS I ALLELES LOCATED ON CHROMOSOME 6P21.3, PARTICULARLY THE HUMAN LEUKOCYTE ANTIGEN (HLA)-B27 IN AXIAL PHENOTYPES. RECENT STUDIES HAVE DEMONSTRATED THAT THE MOST COMMON EPIGENETIC MECHANISMS THAT REGULATE GENE EXPRESSION IN PSA ARE REPRESENTED BY DNA METHYLATION, PARENT OF ORIGIN EFFECT OR GENOMIC IMPRINTING, EXPRESSION OR ACTIVITY OF EPIGENETIC MODIFYING ENZYMES, AND RNA INTERFERENCE (RNAI) BY MICRORNAS (MIRNAS). THE MECHANISMS UNDERLYING PSA PATHOGENESIS ACTIVATE THE INNATE AND ADAPTIVE IMMUNE SYSTEM AND OVEREXPRESSION OF TNF ASSOCIATED WITH AMPLIFICATION OF THE IL-23/IL-17 AXIS. IN RECENT YEARS, MORE PSA SUSCEPTIBILITY GENES AND EPIGENETIC MECHANISMS HAVE BEEN IDENTIFIED. ADVANCES IN THE KNOWLEDGE OF INNATE AND ADAPTIVE IMMUNE MECHANISMS UNDERLYING PSA HAVE CONTRIBUTED TO A BETTER UNDERSTANDING OF THE HETEROGENEOUS CLINICAL EXPRESSION OF THE DISEASE AND, THUS, TO THERAPY STRATEGIES. THE COMPLEXITY OF THE PATHOGENETIC ASPECTS INVOLVING MULTIPLE CYTOKINES, CELL LINES, AND MOLECULES NEEDS TO BE FURTHER INVESTIGATED TO ADVANCE PERSONALIZED THERAPEUTIC STRATEGIES AND TO IMPROVE OUTCOMES OF PATIENTS AFFECTED BY PSA. 2019 12 2731 34 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 2675 40 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 14 1226 34 CRITICAL ROLE OF GUT MICROBIOTA AND EPIGENETIC FACTORS IN THE PATHOGENESIS OF BEHCET'S DISEASE. BEHCET'S DISEASE (BD) IS A CHRONIC REFRACTORY MULTISYSTEM AUTOINFLAMMATORY DISEASE, CHARACTERIZED BY TYPICAL CLINICAL FEATURES OF NON-SPECIFIC VASCULITIS, ORAL AND GENITAL ULCERS, UVEITIS, AS WELL AS SKIN LESIONS. THE EXACT ETIOPATHOGENESIS OF BD REMAINS UNKNOWN, EXISTING STUDIES HAVE INDICATED THAT GENETICS AND ENVIRONMENTAL FACTORS CONTRIBUTE TO THE INCREASED DEVELOPMENT OF BD. RECENTLY, SEVERAL STUDIES HAVE SHOWN THAT EXTERNAL ENVIRONMENTAL FACTORS CAN AFFECT THE PROCESS OF EPIGENETIC MODIFICATION, AND ABNORMALITIES OF EPIGENETIC FACTORS HAVE BEEN CONFIRMED TO BE INVOLVED IN THE OCCURRENCE OF BD. AT THE SAME TIME, ABNORMALITIES OF GUT MICROBIOTA (GM) IN THE BODY, HAVE ALSO BEEN CONFIRMED TO PARTICIPATE IN THE PATHOGENESIS OF BD BY REGULATING THE BALANCE OF TH17/TREGS. THIS ARTICLE REVIEWS THE PATHOGENESIS OF BD AND SUMMARIZES NUMEROUS CLINICAL STUDIES, FOCUSING ON THE MECHANISM OF GM AND EPIGENETIC FACTORS IMPACTING ON BD, AND PROVIDING NEW IDEAS FOR FURTHER ELUCIDATING THE PATHOGENESIS OF BD. 2021 15 4676 51 NEW INSIGHTS TOWARD THE PATHOGENESIS OF ANKYLOSING SPONDYLITIS; GENETIC VARIATIONS AND EPIGENETIC MODIFICATIONS. ANKYLOSING SPONDYLITIS (AS) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE, CHARACTERIZED BY TYPICALLY AN AXIAL ARTHRITIS. AS IS THE PROTOTYPE OF A GROUP OF DISORDERS CALLED SPONDYLOARTHROPATHIES, WHICH IS BELIEVED TO HAVE COMMON CLINICAL MANIFESTATIONS AND GENETIC PREDISPOSITION. TO DATE, THE EXACT ETIOLOGY OF AS REMAINS UNCLEAR. OVER THE PAST FEW YEARS, HOWEVER, THE ROLE OF GENETIC SUSCEPTIBILITY AND EPIGENETIC MODIFICATIONS CAUSED THROUGH ENVIRONMENTAL FACTORS HAVE BEEN EXTENSIVELY SURVEYED WITH RESPECT TO THE PATHOGENESIS OF AS, RESULTED IN IMPORTANT ADVANCES. THIS REVIEW ARTICLE FOCUSES ON THE RECENT ADVANCES IN THE FIELD OF AS RESEARCH, INCLUDING HLA AND NON-HLA SUSCEPTIBILITY GENES IDENTIFIED IN GENOME-WIDE ASSOCIATION STUDIES (GWAS), AND ABERRANT EPIGENETIC MODIFICATIONS OF GENE LOCI ASSOCIATED WITH AS. HLA GENES MOST SIGNIFICANTLY LINKED WITH AS SUSCEPTIBILITY INCLUDE HLA-B27 AND ITS SUBTYPES. NUMEROUS NON-HLA GENES SUCH AS THOSE IN UBIQUITINATION, AMINOPEPTIDASES AND MHC CLASS I PRESENTATION MOLECULES LIKE ERAP-1 WERE ALSO REPORTED. MOREOVER, EPIGENETIC MODIFICATIONS OCCURRED IN AS HAS BEEN SUMMARIZED. TAKEN TOGETHER, THE FINDINGS PRESENTED IN THIS REVIEW ATTEMPT TO EXPLAIN THE CIRCUMSTANCE BY WHICH BOTH GENETIC VARIATIONS AND EPIGENETIC MODIFICATIONS ARE INVOLVED IN TRIGGERING AND DEVELOPMENT OF AS. NONETHELESS, SEVERAL UNANSWERED DARK SIDES CONTINUE TO CLOG OUR EXHAUSTIVE UNDERSTANDING OF AS. FUTURE RESEARCHES IN THE FIELD OF EPIGENETICS SHOULD BE CARRIED OUT TO EXTEND OUR VISION OF AS ETIOPATHOGENESIS. 2017 16 2192 42 EPIGENETIC METHODS AND TWIN STUDIES. GENOMIC PREDISPOSITION FAILS TO FULLY EXPLAIN THE ONSET OF COMPLEX DISEASES, WHICH IS WELL ILLUSTRATED BY THE LARGELY INCOMPLETE CONCORDANCE AMONG MONOZYGOTIC TWINS. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, CHROMATIN REMODELING, AND NON-CODING RNA, ARE THE LINK BETWEEN ENVIRONMENTAL STIMULI AND DISEASE ONSET ON A PERMISSIVE GENETIC BACKGROUND IN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISEASES. AUTOIMMUNE DISEASES NOW INCLUDE ALMOST 100 CONDITIONS AND ARE ESTIMATED TO CUMULATIVELY AFFECT UP TO 5% OF THE WORLD POPULATION WITH A HEALTHCARE EXPENDITURE SUPERIOR TO CANCER WORLDWIDE. MANY ADVANCES IN MEDICINE HAVE BEEN MADE TO TREAT THESE CONDITIONS BUT THERE ARE STILL GAPS, AND AN INNOVATIVE AND EFFICIENT THERAPY IS NEEDED. SYSTEMIC AUTOIMMUNE DISEASES INCLUDE RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS, SYSTEMIC SCLEROSIS, SJOGREN SYNDROME, POLYMYOSITIS, AND DERMATOMYOSITIS. MONOZYGOTIC TWINS DISCORDANT FOR ANY DISEASE OFFER AN IDEAL STUDY DESIGN AS THEY ARE MATCHED FOR MANY FACTORS, INCLUDING GENETIC VARIATION AND THIS IS A REAL ADVANTAGE FOR EPIGENETICS STUDY. WE WILL HEREIN DISCUSS THE AVAILABLE DATA IN THE EPIGENETIC DIFFERENCES LEADING TO DISEASE DISCORDANCE IN MZ TWINS FOR SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AND SYSTEMIC SCLEROSIS. 2020 17 5670 53 SHARED (EPI)GENOMIC BACKGROUND CONNECTING NEURODEGENERATIVE DISEASES AND TYPE 2 DIABETES. THE PROGRESSIVE AGING OF POPULATIONS HAS RESULTED IN AN INCREASED PREVALENCE OF CHRONIC PATHOLOGIES, ESPECIALLY OF METABOLIC, NEURODEGENERATIVE AND MOVEMENT DISORDERS. IN PARTICULAR, TYPE 2 DIABETES (T2D), ALZHEIMER'S DISEASE (AD) AND PARKINSON'S DISEASE (PD) ARE AMONG THE MOST PREVALENT AGE-RELATED, MULTIFACTORIAL PATHOLOGIES THAT DESERVE PARTICULAR ATTENTION, GIVEN THEIR DRAMATIC IMPACT ON PATIENT QUALITY OF LIFE, THEIR ECONOMIC AND SOCIAL BURDEN AS WELL THE ETIOPATHOGENETIC MECHANISMS, WHICH MAY OVERLAP IN SOME CASES. INDEED, THE EXISTENCE OF COMMON TRIGGERING FACTORS REFLECTS THE CONTRIBUTION OF MUTUAL GENETIC, EPIGENETIC AND ENVIRONMENTAL FEATURES IN THE ETIOPATHOGENETIC MECHANISMS UNDERLYING T2D AND AD/PD. ON THIS SUBJECT, THIS REVIEW WILL SUMMARIZE THE SHARED (EPI)GENOMIC FEATURES THAT CHARACTERIZE THESE COMPLEX PATHOLOGIES. IN PARTICULAR, GENETIC VARIANTS AND GENE EXPRESSION PROFILES ASSOCIATED WITH T2D AND AD/PD WILL BE DISCUSSED AS POSSIBLE CONTRIBUTORS TO DETERMINE THE SUSCEPTIBILITY AND PROGRESSION TO THESE DISORDERS. MOREOVER, POTENTIAL SHARED EPIGENETIC MODIFICATIONS AND FACTORS AMONG T2D, AD AND PD WILL ALSO BE ILLUSTRATED. OVERALL, THIS REVIEW SHOWS THAT FINDINGS FROM GENOMIC STUDIES STILL DESERVES FURTHER RESEARCH TO EVALUATE AND IDENTIFY GENETIC FACTORS THAT DIRECTLY CONTRIBUTE TO THE SHARED ETIOPATHOGENESIS. MOREOVER, A COMMON EPIGENETIC BACKGROUND STILL NEEDS TO BE INVESTIGATED AND CHARACTERIZED. THE EVIDENCES DISCUSSED IN THIS REVIEW UNDERLINE THE IMPORTANCE OF INTEGRATING LARGE-SCALE (EPI)GENOMIC DATA WITH ADDITIONAL MOLECULAR INFORMATION AND CLINICAL AND SOCIAL BACKGROUND IN ORDER TO FINELY DISSECT THE COMPLEX ETIOPATHOGENIC NETWORKS THAT BUILD UP THE "DISEASE INTERACTOME" CHARACTERIZING T2D, AD AND PD. 2020 18 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 19 4981 39 PATHOPHYSIOLOGY OF SYSTEMIC SCLEROSIS: CURRENT UNDERSTANDING AND NEW INSIGHTS. INTRODUCTION: SYSTEMIC SCLEROSIS (SSC) IS A COMPLEX AUTOIMMUNE CONNECTIVE TISSUE DISEASE CHARACTERIZED BY CHRONIC AND PROGRESSIVE TISSUE AND ORGAN FIBROSIS WITH BROAD PATIENT-TO-PATIENT VARIABILITY. SOME RISK FACTORS ARE KNOWN AND INCLUDE COMBINATION OF PERSISTENT RAYNAUD'S PHENOMENON, STEROID HORMONE IMBALANCE, SELECTED CHEMICALS, THERMAL, OR OTHER INJURIES. ENDOGENOUS AND/OR EXOGENOUS ENVIRONMENTAL TRIGGER/RISK FACTORS PROMOTE EPIGENETIC MECHANISMS IN GENETICALLY PRIMED SUBJECTS. DISEASE PATHOGENESIS PRESENTS EARLY MICROVASCULAR CHANGES WITH ENDOTHELIAL CELL DYSFUNCTION, FOLLOWED BY THE ACTIVATION OF MECHANISMS PROMOTING THEIR TRANSITION INTO MYOFIBROBLASTS. A COMPLEX AUTOIMMUNE RESPONSE, INVOLVING INNATE AND ADAPTIVE IMMUNITY WITH SPECIFIC/FUNCTIONAL AUTOANTIBODY PRODUCTION, CHARACTERIZES THE DISEASE. PROGRESSIVE FIBROSIS AND ISCHEMIA INVOLVE SKIN AND VISCERAL ORGANS RESULTING IN THEIR IRREVERSIBLE DAMAGE/FAILURE. PROGENITOR CIRCULATING CELLS (MONOCYTES, FIBROCYTES), TOGETHER WITH GROWTH FACTORS AND CYTOKINES PARTICIPATE IN DISEASE DIFFUSION AND EVOLUTION. EPIGENETIC, VASCULAR AND IMMUNOLOGIC MECHANISMS IMPLICATED IN SYSTEMIC FIBROSIS, REPRESENT MAJOR TARGETS FOR INCOMING DISEASE MODIFYING THERAPEUTIC APPROACHES. AREAS COVERED: THIS REVIEW DISCUSSES CURRENT UNDERSTANDING AND NEW INSIGHTS OF SSC PATHOGENESIS, THROUGH AN OVERVIEW OF THE MOST RELEVANT ADVANCEMENTS TO PRESENT ASPECTS AND MECHANISMS INVOLVED IN DISEASE PATHOGENESIS. EXPERT OPINION: CONSIDERING SSC INTRICACY/HETEROGENEITY, EARLY COMBINATION THERAPY WITH VASODILATORS, IMMUNOSUPPRESSIVE AND ANTIFIBROTIC DRUGS SHOULD SUCCESSFULLY DOWNREGULATE THE DISEASE PROGRESSION, ESPECIALLY IF STARTED FROM THE BEGINNING. 2019 20 4274 51 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