1 4428 107 MOLECULAR BASIS OF THE IRRITABLE BOWEL SYNDROME. IRRITABLE BOWEL SYNDROME (IBS) IS A FUNCTIONAL DISORDER CHARACTERIZED BY ABDOMINAL PAIN, DISCOMFORT AND BLOATING. THE PATHOPHYSIOLOGY OF IBS IS POORLY UNDERSTOOD, BUT THE PRESENCE OF PSYCHOSOCIAL BASIS IS NOW KNOWN. THERE IS AN INCREASING NUMBER OF PUBLICATIONS SUPPORTING THE ROLE OF GENETICS IN IBS. MOST OF THE VARIATIONS ARE FOUND IN GENES ASSOCIATED WITH THE BRAIN-GUT AXIS, REVEALING THE STRONG CORRELATION OF BRAIN-GUT AXIS AND IBS. MIRNAS, WHICH PLAY CRITICAL ROLES IN PHYSIOLOGICAL PROCESSES, ARE NOT WELL STUDIED IN IBS. HOWEVER, SO FAR THERE IS FOUND AN INVOLVEMENT OF ALTERATIONS IN MIRNA EXPRESSION OR SEQUENCE, IN IBS SYMPTOMS. IBS PHENOTYPE IS AFFECTED BY EPIGENETIC ALTERATION AND ENVIRONMENT. CHANGES IN DNA AND HISTONE METHYLATION ARE OBSERVED IN PATIENTS WHO SUFFERED CHILDHOOD TRAUMA OR ABUSE, RESULTING IN ALTERED GENE EXPRESSION, SUCH AS THE GLUCOCORTICOID RECEPTOR GENE. FINALLY, DIET IS ANOTHER FACTOR ASSOCIATED WITH IBS, WHICH MAY CONTRIBUTE TO SYMPTOM ONSET. CERTAIN FOODS MAY AFFECT ON BACTERIAL METABOLISM AND EPIGENETIC MODIFICATIONS, PREDISPOSING TO IBS. 2014 2 2167 52 EPIGENETIC MECHANISMS IN IRRITABLE BOWEL SYNDROME. IRRITABLE BOWEL SYNDROME (IBS) IS A BRAIN-GUT AXIS DISORDER CHARACTERIZED BY ABDOMINAL PAIN AND ALTERED BOWEL HABITS. IBS IS A MULTIFACTORIAL, STRESS-SENSITIVE DISORDER WITH EVIDENCE FOR FAMILIAL CLUSTERING ATTRIBUTED TO GENETIC OR SHARED ENVIRONMENTAL FACTORS. HOWEVER, THERE ARE WEAK GENETIC ASSOCIATIONS REPORTED WITH IBS AND A LACK OF EVIDENCE TO SUGGEST THAT MAJOR GENETIC FACTOR(S) CONTRIBUTE TO IBS PATHOPHYSIOLOGY. STUDIES ON ANIMAL MODELS OF STRESS, INCLUDING EARLY LIFE STRESS, SUGGEST A ROLE FOR ENVIRONMENTAL FACTORS, SPECIFICALLY, STRESS ASSOCIATED WITH DYSREGULATION OF CORTICOTROPIN RELEASING FACTOR AND HYPOTHALAMUS-PITUITARY-ADRENAL (HPA) AXIS PATHWAYS IN THE PATHOPHYSIOLOGY OF IBS. RECENT EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS, WHICH CONSTITUTE MOLECULAR CHANGES NOT DRIVEN BY A CHANGE IN GENE SEQUENCE, CAN MEDIATE ENVIRONMENTAL EFFECTS ON CENTRAL AND PERIPHERAL FUNCTION. EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION CHANGES, HISTONE MODIFICATIONS, AND DIFFERENTIAL EXPRESSION OF NON-CODING RNAS (MICRORNA [MIRNA] AND LONG NON-CODING RNA) HAVE BEEN ASSOCIATED WITH SEVERAL DISEASES. THE OBJECTIVE OF THIS REVIEW IS TO ELUCIDATE THE MOLECULAR FACTORS IN THE PATHOPHYSIOLOGY OF IBS WITH AN EMPHASIS ON EPIGENETIC MECHANISMS. EMERGING EVIDENCE FOR EPIGENETIC CHANGES IN IBS INCLUDES CHANGES IN DNA METHYLATION IN ANIMAL MODELS OF IBS AND PATIENTS WITH IBS, AND VARIOUS MIRNAS THAT HAVE BEEN ASSOCIATED WITH IBS AND ENDOPHENOTYPES, SUCH AS INCREASED VISCERAL SENSITIVITY AND INTESTINAL PERMEABILITY. DNA METHYLATION, IN PARTICULAR, IS AN EMERGING FIELD IN THE REALM OF COMPLEX DISEASES AND A PROMISING MECHANISM WHICH CAN PROVIDE IMPORTANT INSIGHTS INTO IBS PATHOGENESIS AND IDENTIFY POTENTIAL TARGETS FOR TREATMENT. 2020 3 4673 39 NEW INSIGHTS INTO THE PATHOGENESIS AND TREATMENT OF IRRITABLE BOWEL SYNDROME. IRRITABLE BOWEL SYNDROME (IBS) IS ONE OF THE MOST COMMON FUNCTIONAL GASTROINTESTINAL DISORDERS (FGID), CHARACTERIZED BY ABDOMINAL PAIN AND A CHANGE IN STOOL FORM THAT CANNOT BE EXPLAINED BY STRUCTURAL ABNORMALITIES. ITS PREVALENCE RANGES FROM 9 TO 23% OF THE WORLDWIDE POPULATION. THE PATHOPHYSIOLOGY OF IBS IS DIVERSE AND NOT WELL UNDERSTOOD. BIOPSYCHOSOCIAL CONCEPT ASSUMES THAT THE DISEASE IS A PRODUCT OF PSYCHOSOCIAL FACTORS AND ALTERED AT MULTIPLE LEVELS OF GUT PHYSIOLOGY INTERACTIONS. SOME AETIOLOGICAL FACTORS HAVE BEEN IDENTIFIED, YET. ONE OF THE MOST IMPORTANT IS THE DISRUPTION OF BRAIN-GUT MUTUAL COMMUNICATION THAT LEADS TO VISCERAL HYPERSENSITIVITY. ALSO GENETIC AND EPIGENETIC FACTORS ARE INVOLVED. CHRONIC STRESS MAY PREDISPOSE TO IBS AS WELL AS EXACERBATE ITS SYMPTOMS. BOTH QUANTITATIVE AND QUALITATIVE DISORDERS OF THE GUT MICROBIOTA ARE OBSERVED. THERE IS ALSO A RELATIONSHIP BETWEEN THE IBS SYMPTOMS AND THE INTAKE OF A SPECIFIC TYPE OF FOOD PRODUCTS. IN THE DIARRHOEA TYPE OF IBS THE ROLE OF PREVIOUS GASTROINTESTINAL INFECTION IS DEMONSTRATED. RECENT STUDIES HAVE SUGGESTED THAT VISCERAL HYPERSENSITIVITY IN PATIENTS WITH IBS MAY BE SECONDARY TO THE ACTIVATION OF THE IMMUNE CELLS AND LOW-GRADE INFLAMMATION. CLINICAL SYMPTOMS OF IBS INCLUDE ABDOMINAL PAIN AND CHANGE IN BOWEL HABITS AS WELL AS SOMATIC AND PSYCHIATRIC COMORBIDITIES. IBS IS DIAGNOSED ON THE BASIS OF ROME DIAGNOSTIC CRITERIA. RECENTLY, THEIR NEWEST VERSION (ROME IV) HAS BEEN PRESENTED. THE AIM OF THIS REVIEW IS TO SUMMARIZE THE PAST DECADE PROGRESS IN IBS DIAGNOSIS, MAIN PATHOPHYSIOLOGICAL ASPECTS AND THERAPEUTIC MANAGEMENT STRATEGY. 2017 4 5835 28 STRESS-INDUCED VISCERAL PAIN: TOWARD ANIMAL MODELS OF IRRITABLE-BOWEL SYNDROME AND ASSOCIATED COMORBIDITIES. VISCERAL PAIN IS A GLOBAL TERM USED TO DESCRIBE PAIN ORIGINATING FROM THE INTERNAL ORGANS, WHICH IS DISTINCT FROM SOMATIC PAIN. IT IS A HALLMARK OF FUNCTIONAL GASTROINTESTINAL DISORDERS SUCH AS IRRITABLE-BOWEL SYNDROME (IBS). CURRENTLY, THE TREATMENT STRATEGIES TARGETING VISCERAL PAIN ARE UNSATISFACTORY, WITH DEVELOPMENT OF NOVEL THERAPEUTICS HINDERED BY A LACK OF DETAILED KNOWLEDGE OF THE UNDERLYING MECHANISMS. STRESS HAS LONG BEEN IMPLICATED IN THE PATHOPHYSIOLOGY OF VISCERAL PAIN IN BOTH PRECLINICAL AND CLINICAL STUDIES. HERE, WE DISCUSS THE COMPLEX ETIOLOGY OF VISCERAL PAIN REVIEWING OUR CURRENT UNDERSTANDING IN THE CONTEXT OF THE ROLE OF STRESS, GENDER, GUT MICROBIOTA ALTERATIONS, AND IMMUNE FUNCTIONING. FURTHERMORE, WE REVIEW THE ROLE OF GLUTAMATE, GABA, AND EPIGENETIC MECHANISMS AS POSSIBLE THERAPEUTIC STRATEGIES FOR THE TREATMENT OF VISCERAL PAIN FOR WHICH THERE IS AN UNMET MEDICAL NEED. MOREOVER, WE DISCUSS THE MOST WIDELY DESCRIBED RODENT MODELS USED TO MODEL VISCERAL PAIN IN THE PRECLINICAL SETTING. THE THEORY BEHIND, AND APPLICATION OF, ANIMAL MODELS IS KEY FOR BOTH THE UNDERSTANDING OF UNDERLYING MECHANISMS AND DESIGN OF FUTURE THERAPEUTIC INTERVENTIONS. TAKEN TOGETHER, IT IS APPARENT THAT STRESS-INDUCED VISCERAL PAIN AND ITS PSYCHIATRIC COMORBIDITIES, AS TYPIFIED BY IBS, HAS A MULTIFACETED ETIOLOGY. MOREOVER, TREATMENT STRATEGIES STILL LAG FAR BEHIND WHEN COMPARED TO OTHER PAIN MODALITIES. THE DEVELOPMENT OF NOVEL, EFFECTIVE, AND SPECIFIC THERAPEUTICS FOR THE TREATMENT OF VISCERAL PAIN HAS NEVER BEEN MORE PERTINENT. 2015 5 4518 23 MULTI-OMICS FOR BIOMARKER APPROACHES IN THE DIAGNOSTIC EVALUATION AND MANAGEMENT OF ABDOMINAL PAIN AND IRRITABLE BOWEL SYNDROME: WHAT LIES AHEAD. RELIABLE BIOMARKERS FOR COMMON DISORDERS OF GUT-BRAIN INTERACTION CHARACTERIZED BY ABDOMINAL PAIN, INCLUDING IRRITABLE BOWEL SYNDROME (IBS), ARE CRITICALLY NEEDED TO ENHANCE CARE AND DEVELOP INDIVIDUALIZED THERAPIES. THE DYNAMIC AND HETEROGENEOUS NATURE OF THE PATHOPHYSIOLOGICAL MECHANISMS THAT UNDERLIE VISCERAL HYPERSENSITIVITY HAVE CHALLENGED SUCCESSFUL BIOMARKER DEVELOPMENT. CONSEQUENTLY, EFFECTIVE THERAPIES FOR PAIN IN IBS ARE LACKING. HOWEVER, RECENT ADVANCES IN MODERN OMICS TECHNOLOGIES OFFER NEW OPPORTUNITIES TO ACQUIRE DEEP BIOLOGICAL INSIGHTS INTO MECHANISMS OF PAIN AND NOCICEPTION. NEWER METHODS FOR LARGE-SCALE DATA INTEGRATION OF COMPLEMENTARY OMICS APPROACHES HAVE FURTHER EXPANDED OUR ABILITY TO BUILD A HOLISTIC UNDERSTANDING OF COMPLEX BIOLOGICAL NETWORKS AND THEIR CO-CONTRIBUTIONS TO ABDOMINAL PAIN. HERE, WE REVIEW THE MECHANISMS OF VISCERAL HYPERSENSITIVITY, FOCUSING ON IBS. WE DISCUSS CANDIDATE BIOMARKERS FOR PAIN IN IBS IDENTIFIED THROUGH SINGLE OMICS STUDIES AND SUMMARIZE EMERGING MULTI-OMICS APPROACHES FOR DEVELOPING NOVEL BIOMARKERS THAT MAY TRANSFORM CLINICAL CARE FOR PATIENTS WITH IBS AND ABDOMINAL PAIN. 2023 6 105 37 A REVIEW OF MICROBIOTA AND IRRITABLE BOWEL SYNDROME: FUTURE IN THERAPIES. IRRITABLE BOWEL SYNDROME (IBS), ONE OF THE MOST FREQUENT DIGESTIVE DISORDERS, IS CHARACTERIZED BY CHRONIC AND RECURRENT ABDOMINAL PAIN AND ALTERED BOWEL HABIT. THE ORIGIN SEEMS TO BE MULTIFACTORIAL AND IS STILL NOT WELL DEFINED FOR THE DIFFERENT SUBTYPES. GENETIC, EPIGENETIC AND SEX-RELATED MODIFICATIONS OF THE FUNCTIONING OF THE NERVOUS AND IMMUNE-ENDOCRINE SUPERSYSTEMS AND REGULATION OF BRAIN-GUT PHYSIOLOGY AND BILE ACID PRODUCTION AND ABSORPTION ARE CERTAINLY INVOLVED. ACQUIRED PREDISPOSITION MAY ACT IN CONJUNCTION WITH INFECTIOUS, TOXIC, DIETARY AND LIFE EVENT-RELATED FACTORS TO ENHANCE EPITHELIAL PERMEABILITY AND ELICIT MUCOSAL MICROINFLAMMATION, IMMUNE ACTIVATION AND DYSBIOSIS. NOTABLY, STRONG EVIDENCE SUPPORTS THE ROLE OF BACTERIAL, VIRAL AND PARASITIC INFECTIONS IN TRIGGERING IBS, AND TARGETING MICROBIOTA SEEMS PROMISING IN VIEW OF THE POSITIVE RESPONSE TO MICROBIOTA-RELATED THERAPIES IN SOME PATIENTS. HOWEVER, THE LACK OF HIGHLY PREDICTIVE DIAGNOSTIC BIOMARKERS AND THE COMPLEXITY AND HETEROGENEITY OF IBS PATIENTS MAKE MANAGEMENT DIFFICULT AND UNSATISFACTORY IN MANY CASES, REDUCING PATIENT HEALTH-RELATED QUALITY OF LIFE AND INCREASING THE SANITARY BURDEN. THIS ARTICLE REVIEWS SPECIFIC ALTERATIONS AND INTERVENTIONS TARGETING THE GUT MICROBIOTA IN IBS, INCLUDING PREBIOTICS, PROBIOTICS, SYNBIOTICS, NON-ABSORBABLE ANTIBIOTICS, DIETS, FECAL TRANSPLANTATION AND OTHER POTENTIAL FUTURE APPROACHES USEFUL FOR THE DIAGNOSIS, PREVENTION AND TREATMENT OF IBS. 2018 7 4144 33 MECHANISMS OF STRESS-INDUCED VISCERAL PAIN. EVIDENCE SUGGESTS THAT LONG-TERM STRESS FACILITATES VISCERAL PAIN THROUGH SENSITIZATION OF PAIN PATHWAYS AND PROMOTES CHRONIC VISCERAL PAIN DISORDERS SUCH AS THE IRRITABLE BOWEL SYNDROME (IBS). THIS REVIEW WILL DESCRIBE THE IMPORTANCE OF STRESS IN EXACERBATING IBS-INDUCED ABDOMINAL PAIN. ADDITIONALLY, WE WILL BRIEFLY REVIEW OUR UNDERSTANDING OF THE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BY BOTH CHRONIC ADULT STRESS AND FOLLOWING EARLY LIFE STRESS IN THE PATHOGENESIS OF IBS. THE REVIEW WILL FOCUS ON THE GLUCOCORTICOID RECEPTOR AND CORTICOTROPIN-RELEASING HORMONE-MEDIATED MECHANISMS IN THE AMYGDALA INVOLVED IN STRESS-INDUCED VISCERAL HYPERSENSITIVITY. ONE POTENTIAL MECHANISM UNDERLYING PERSISTENT EFFECTS OF STRESS ON VISCERAL SENSITIVITY COULD BE EPIGENETIC MODULATION OF GENE EXPRESSION. WHILE THERE ARE RELATIVELY FEW STUDIES EXAMINING EPIGENETICALLY MEDIATED MECHANISMS INVOLVED IN STRESS-INDUCED VISCERAL NOCICEPTION, ALTERATIONS IN DNA METHYLATION AND HISTONE ACETYLATION PATTERNS WITHIN THE BRAIN, HAVE BEEN LINKED TO ALTERATIONS IN NOCICEPTIVE SIGNALING VIA INCREASED EXPRESSION OF PRO-NOCICEPTIVE NEUROTRANSMITTERS. THIS REVIEW WILL DISCUSS THE LATEST STUDIES INVESTIGATING THE LONG-TERM EFFECTS OF STRESS ON VISCERAL SENSITIVITY. ADDITIONALLY, WE WILL CRITICALLY REVIEW THE IMPORTANCE OF EXPERIMENTAL MODELS OF ADULT STRESS AND EARLY LIFE STRESS IN ENHANCING OUR UNDERSTANDING OF THE BASIC MOLECULAR MECHANISMS OF NOCICEPTIVE PROCESSING. 2018 8 5869 36 SUSCEPTIBILITY TO STRESS-INDUCED VISCERAL SENSITIVITY: A BAD LEGACY FOR NEXT GENERATIONS. DESPITE HIGH PREVALENCE, THE PRECISE IRRITABLE BOWEL SYNDROME (IBS) PATHOPHYSIOLOGY REMAINS POORLY UNDERSTOOD LIKELY DUE TO THE HETEROGENEITY OF IBS POPULATIONS AND THE MULTIFACTORIAL ETIOLOGY OF THIS DISORDER. AMONG RISK FACTORS, GENETIC PREDISPOSITION AND EARLY LIFE TRAUMA HAVE BEEN REPORTED. IN THIS CONTEXT, THE DEBATE ON GENETIC OR ENVIRONMENTAL INFLUENCES IN THE IBS PATHOGENESIS IS STILL OPEN. THE STUDY BY VAN DER WIJNGAARD ET AL., REPORTING FOR THE FIRST TIME THAT SUSCEPTIBILITY TO STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN MATERNALLY SEPARATED RATS CAN BE TRANSFERRED TO THE NEXT GENERATION WITHOUT ANY FURTHER EXPOSURE OF F2 INDIVIDUALS TO MATERNAL SEPARATION, SUPPORTS THE IMPORTANCE OF ENVIRONMENTAL INFLUENCE IN THE IBS PHENOTYPE. EPIGENETIC MECHANISMS SUCH AS HYPERMETHYLATION IN THE PROMOTER REGION OF THE GLUCOCORTICOID RECEPTOR GENE MEDIATING THE LONG-TERM AND TRANSGENERATIONAL BEHAVIORAL EFFECTS OF MATERNAL CARE ON THE DEVELOPMENT HAVE BEEN SHOWN IN SOME BUT NOT IN ALL STUDIES. VAN DER WIJNGAARD ET AL. INCRIMINATED MATERNAL CARE IN THE TRANSMITTED SUSCEPTIBILITY TO STRESS-INDUCED VISCERAL HYPERSENSITIVITY, BUT NOT CHANGES IN GLUCOCORTICOID RECEPTOR PROTEIN EXPRESSION IN THE BRAIN. THIS FINDING OPENS A BROAD FIELD OF FUTURE DIRECTIONS AIMED AT EVALUATING THE MECHANISMS INVOLVED IN THE TRANSMISSION ACROSS GENERATIONS OF THE DIGESTIVE FEATURES OF IBS, INCLUDING, FOR EXAMPLE, ON THE ROLE OF GUT MICROBIOTA CHANGES IN VERTICAL TRANSMISSION OR EPIGENETIC MODIFICATIONS OF INTESTINAL MAST CELLS AND THE JUNCTIONAL REGION OF INTESTINAL EPITHELIAL CELLS IN VERTICAL TRANSFER. 2013 9 5831 40 STRESS-INDUCED CHRONIC VISCERAL PAIN OF GASTROINTESTINAL ORIGIN. VISCERAL PAIN IS GENERALLY POORLY LOCALIZED AND CHARACTERIZED BY HYPERSENSITIVITY TO A STIMULUS SUCH AS ORGAN DISTENSION. IN CONCERT WITH CHRONIC VISCERAL PAIN, THERE IS A HIGH COMORBIDITY WITH STRESS-RELATED PSYCHIATRIC DISORDERS INCLUDING ANXIETY AND DEPRESSION. THE MECHANISMS LINKING VISCERAL PAIN WITH THESE OVERLAPPING COMORBIDITIES REMAIN TO BE ELUCIDATED. EVIDENCE SUGGESTS THAT LONG TERM STRESS FACILITATES PAIN PERCEPTION AND SENSITIZES PAIN PATHWAYS, LEADING TO A FEED-FORWARD CYCLE PROMOTING CHRONIC VISCERAL PAIN DISORDERS SUCH AS IRRITABLE BOWEL SYNDROME (IBS). EARLY LIFE STRESS (ELS) IS A RISK-FACTOR FOR THE DEVELOPMENT OF IBS, HOWEVER THE MECHANISMS RESPONSIBLE FOR THE PERSISTENT EFFECTS OF ELS ON VISCERAL PERCEPTION IN ADULTHOOD REMAIN INCOMPLETELY UNDERSTOOD. IN RODENT MODELS, STRESS IN ADULT ANIMALS INDUCED BY RESTRAINT AND WATER AVOIDANCE HAS BEEN EMPLOYED TO INVESTIGATE THE MECHANISMS OF STRESS-INDUCE PAIN. ELS MODELS SUCH AS MATERNAL SEPARATION, LIMITED NESTING, OR ODOR-SHOCK CONDITIONING, WHICH ATTEMPT TO MODEL EARLY CHILDHOOD EXPERIENCES SUCH AS NEGLECT, POVERTY, OR AN ABUSIVE CAREGIVER, CAN PRODUCE CHRONIC, SEXUALLY DIMORPHIC INCREASES IN VISCERAL SENSITIVITY IN ADULTHOOD. CHRONIC VISCERAL PAIN IS A CLASSIC EXAMPLE OF GENE X ENVIRONMENT INTERACTION WHICH RESULTS FROM MALADAPTIVE CHANGES IN NEURONAL CIRCUITRY LEADING TO NEUROPLASTICITY AND ABERRANT NEURONAL ACTIVITY-INDUCED SIGNALING. ONE POTENTIAL MECHANISM UNDERLYING THE PERSISTENT EFFECTS OF STRESS ON VISCERAL SENSITIVITY COULD BE EPIGENETIC MODULATION OF GENE EXPRESSION. WHILE THERE ARE RELATIVELY FEW STUDIES EXAMINING EPIGENETICALLY MEDIATED MECHANISMS INVOLVED IN VISCERAL NOCICEPTION, STRESS-INDUCED VISCERAL PAIN HAS BEEN LINKED TO ALTERATIONS IN DNA METHYLATION AND HISTONE ACETYLATION PATTERNS WITHIN THE BRAIN, LEADING TO INCREASED EXPRESSION OF PRO-NOCICEPTIVE NEUROTRANSMITTERS. THIS REVIEW WILL DISCUSS THE POTENTIAL NEURONAL PATHWAYS AND MECHANISMS RESPONSIBLE FOR STRESS-INDUCED EXACERBATION OF CHRONIC VISCERAL PAIN. ADDITIONALLY, WE WILL REVIEW THE IMPORTANCE OF SPECIFIC EXPERIMENTAL MODELS OF ADULT STRESS AND ELS IN ENHANCING OUR UNDERSTANDING OF THE BASIC MOLECULAR MECHANISMS OF PAIN PROCESSING. 2017 10 2252 35 EPIGENETIC MODULATION OF VISCERAL NOCICEPTION. EPIGENETICS IS A PROCESS THAT ALTERS GENE ACTIVITY OR PHENOTYPE WITHOUT ANY CHANGES IN THE UNDERLYING DNA SEQUENCE OR GENOTYPE. THESE BIOLOGICAL CHANGES MAY HAVE DELETERIOUS EFFECTS AND CAN LEAD TO VARIOUS HUMAN DISEASES. ONGOING RESEARCH IS CONTINUING TO ILLUMINATE THE ROLE OF EPIGENETICS IN A VARIETY OF PATHOPHYSIOLOGIC PROCESSES. SEVERAL CATEGORIES OF EPIGENETIC MECHANISMS HAVE BEEN STUDIED INCLUDING CHROMATIN REMODELING, DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA MECHANISMS. THESE EPIGENETIC CHANGES CAN HAVE A LONG-TERM EFFECT ON GENE EXPRESSION WITHOUT ANY UNDERLYING CHANGES IN THE DNA SEQUENCES. THE UNDERLYING PATHOPHYSIOLOGY OF DISORDERS OF BRAIN-GUT INTERACTION AND STRESS-INDUCED VISCERAL PAIN ARE NOT FULLY UNDERSTOOD AND THE ROLE OF EPIGENETIC MECHANISMS IN THESE DISORDERS ARE STARTING TO BE BETTER UNDERSTOOD. CURRENT WORK IS UNDERWAY TO DETERMINE HOW EPIGENETICS PLAYS A ROLE IN THE NEUROBIOLOGY OF PATIENTS WITH CHRONIC VISCERAL PAIN AND HEIGHTENED VISCERAL NOCICEPTION. MORE RECENTLY, BOTH ANIMAL MODELS AND HUMAN STUDIES HAVE SHOWN HOW EPIGENETIC REGULATION MODULATES STRESS-INDUCED VISCERAL PAIN. WHILE MUCH MORE WORK IS NEEDED TO FULLY DELINEATE THE MECHANISTIC ROLE OF EPIGENETICS IN THE NEUROBIOLOGY OF CHRONIC VISCERAL NOCICEPTION, THE CURRENT STUDY BY LOUWIES ET AL., IN NEUROGASTROENTEROLOGY AND MOTILITY PROVIDES ADDITIONAL EVIDENCE SUPPORTING THE INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE CENTRAL NUCLEUS OF THE AMYGDALA IN STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN RODENTS. 2022 11 6375 41 THE ROLE OF NEURO-IMMUNE INTERACTION IN CHRONIC PAIN CONDITIONS; FUNCTIONAL SOMATIC SYNDROME, NEUROGENIC INFLAMMATION, AND PERIPHERAL NEUROPATHY. FUNCTIONAL SOMATIC SYNDROMES ARE INCREASINGLY DIAGNOSED IN CHRONICALLY ILL PATIENTS PRESENTING WITH AN ARRAY OF SYMPTOMS NOT ATTRIBUTED TO PHYSICAL AILMENTS. CONDITIONS SUCH AS CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME, OR IRRITABLE BOWEL SYNDROME ARE COMMON DISORDERS THAT BELONG IN THIS BROAD CATEGORY. SUCH SYNDROMES ARE CHARACTERISED BY THE PRESENCE OF ONE OR MULTIPLE CHRONIC SYMPTOMS INCLUDING WIDESPREAD MUSCULOSKELETAL PAIN, FATIGUE, SLEEP DISORDERS, AND ABDOMINAL PAIN, AMONGST OTHER ISSUES. SYMPTOMS ARE BELIEVED TO RELATE TO A COMPLEX INTERACTION OF BIOLOGICAL AND PSYCHOSOCIAL FACTORS, WHERE A DEFINITE AETIOLOGY HAS NOT BEEN ESTABLISHED. THEORIES SUGGEST CAUSATIVE PATHWAYS BETWEEN THE IMMUNE AND NERVOUS SYSTEMS OF AFFECTED INDIVIDUALS WITH SEVERAL RISK FACTORS IDENTIFIED IN PATIENTS PRESENTING WITH ONE OR MORE FUNCTIONAL SYNDROMES. RISK FACTORS INCLUDING STRESS AND CHILDHOOD TRAUMA ARE NOW RECOGNISED AS IMPORTANT CONTRIBUTORS TO CHRONIC PAIN CONDITIONS. EMOTIONAL, PHYSICAL, AND SEXUAL ABUSE DURING CHILDHOOD IS CONSIDERED A SEVERE STRESSOR HAVING A HIGH PREVALENCE IN FUNCTIONAL SOMATIC SYNDROME SUFFERS. SUCH TRAUMA PERMANENTLY ALTERS THE BIOLOGICAL STRESS RESPONSE OF THE SUFFERS LEADING TO NEUROEXCITATORY AND OTHER NERVE ISSUES ASSOCIATED WITH CHRONIC PAIN IN ADULTS. TRAUMATIC AND CHRONIC STRESS RESULTS IN EPIGENETIC CHANGES IN STRESS RESPONSE GENES, WHICH ULTIMATELY LEADS TO DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY AXIS, THE AUTONOMIC NERVOUS SYSTEM, AND THE IMMUNE SYSTEM MANIFESTING IN A BROAD ARRAY OF SYMPTOMS. IMPORTANTLY, THESE SYSTEMS ARE KNOWN TO BE DYSREGULATED IN PATIENTS SUFFERING FROM FUNCTIONAL SOMATIC SYNDROME. FUNCTIONAL SOMATIC SYNDROMES ARE ALSO HIGHLY PREVALENT CO-MORBIDITIES OF PSYCHIATRIC CONDITIONS, MOOD DISORDERS, AND ANXIETY. CONSEQUENTLY, THIS REVIEW AIMS TO PROVIDE INSIGHT INTO THE ROLE OF THE NERVOUS SYSTEM AND IMMUNE SYSTEM IN CHRONIC PAIN DISORDERS ASSOCIATED WITH THE MUSCULOSKELETAL SYSTEM, AND CENTRAL AND PERIPHERAL NERVOUS SYSTEMS. 2022 12 6254 32 THE MICROBIOME AND IRRITABLE BOWEL SYNDROME - A REVIEW ON THE PATHOPHYSIOLOGY, CURRENT RESEARCH AND FUTURE THERAPY. IRRITABLE BOWEL SYNDROME (IBS) IS A FUNCTIONAL DISORDER WHICH AFFECTS A LARGE PROPORTION OF THE POPULATION GLOBALLY. THE PRECISE ETIOLOGY OF IBS IS STILL UNKNOWN, ALTHOUGH CONSENSUS UNDERSTANDING PROPOSES IBS TO BE OF MULTIFACTORIAL ORIGIN WITH YET UNDEFINED SUBTYPES. GENETIC AND EPIGENETIC FACTORS, STRESS-RELATED NERVOUS AND ENDOCRINE SYSTEMS, IMMUNE DYSREGULATION AND THE BRAIN-GUT AXIS SEEM TO BE CONTRIBUTING FACTORS THAT PREDISPOSE INDIVIDUALS TO IBS. IN ADDITION TO FOOD HYPERSENSITIVITY, TOXINS AND ADVERSE LIFE EVENTS, CHRONIC INFECTIONS AND DYSBIOTIC GUT MICROBIOTA HAVE BEEN SUGGESTED TO TRIGGER IBS SYMPTOMS IN TANDEM WITH THE PREDISPOSING FACTORS. THIS REVIEW WILL SUMMARIZE THE PATHOPHYSIOLOGY OF IBS AND THE ROLE OF GUT MICROBIOTA IN RELATION TO IBS. CURRENT METHODOLOGIES FOR MICROBIOME STUDIES IN IBS SUCH AS GENOME SEQUENCING, METAGENOMICS, CULTUROMICS AND ANIMAL MODELS WILL BE DISCUSSED. THE MYRIAD OF THERAPY OPTIONS SUCH AS IMMUNOGLOBULINS (IMMUNE-BASED THERAPY), PROBIOTICS AND PREBIOTICS, DIETARY MODIFICATIONS INCLUDING FODMAP RESTRICTION DIET AND GLUTEN-FREE DIET, AS WELL AS FECAL TRANSPLANTATION WILL BE REVIEWED. FINALLY THIS REVIEW WILL HIGHLIGHT FUTURE DIRECTIONS IN IBS THERAPY RESEARCH, INCLUDING IDENTIFICATION OF NEW MOLECULAR TARGETS, APPLICATION OF 3-D GUT MODEL, GUT-ON-A-CHIP AND PERSONALIZED THERAPY. 2019 13 2963 21 GENETIC AND EPIGENETIC MECHANISMS LINKING PAIN AND PSYCHIATRIC DISORDERS. THE NEUROPHYSIOLOGICAL LINK BETWEEN NEUROPATHIC PAIN AND DEPRESSION REMAINS UNKNOWN DESPITE EVIDENT HIGH COMORBIDITY OF THESE TWO DISORDERS. HOWEVER, THERE IS CONVINCING EVIDENCE THAT GENOTYPE PLAYS A ROLE IN BOTH PAIN AND DEPRESSION. USING VARIOUS TYPES OF GENETIC ANALYSIS - POPULATION GENETICS, CYTOGENETICS AND MOLECULAR TECHNOLOGIES - SPECIFIC GENES HAVE BEEN IMPLICATED IN MEDIATING ALMOST ALL ASPECTS OF NOCICEPTION AND MOOD DISORDERS. THE CURRENT REVIEW ATTEMPTS TO IDENTIFY SPECIFIC GENES AND EPIGENETIC MECHANISMS COMMON TO BOTH DISORDERS. IT IS CONCLUDED THAT EXTERNAL AND INTERNAL FACTORS (INFLAMMATION, STRESS, GENDER, ETC.) THAT CONTRIBUTE TO THE PATHOLOGIES MAY DO SO THROUGH EPIGENETIC MECHANISMS THAT MAY AFFECT EXPRESSION OF THESE PARTICULAR GENES. THE POSSIBLE INVOLVEMENT OF EPIGENETIC REGULATION IN PAIN AND PSYCHIATRIC DISORDERS SUGGESTS THAT TREATMENTS TARGETING EPIGENETIC MECHANISMS THAT MEDIATE ADVERSE LIFE EVENTS SHOULD BE CONSIDERED. 2015 14 5927 31 TARGETING EPIGENETIC MECHANISMS FOR CHRONIC VISCERAL PAIN: A VALID APPROACH FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. BACKGROUND: CHRONIC VISCERAL PAIN IS PERSISTENT PAIN EMANATING FROM THORACIC, PELVIC, OR ABDOMINAL ORIGIN THAT IS POORLY LOCALIZED WITH REGARD TO THE SPECIFIC ORGAN AFFECTED. THE PREVALENCE CAN RANGE UP TO 25% IN THE ADULT POPULATION AS CHRONIC VISCERAL PAIN IS A COMMON FEATURE OF MANY VISCERAL DISORDERS, WHICH MAY OR MAY NOT BE ACCOMPANIED BY DISTINCT STRUCTURAL OR HISTOLOGICAL ABNORMALITIES WITHIN THE VISCERAL ORGANS. MOUNTING EVIDENCE SUGGESTS THAT CHANGES IN EPIGENETIC MECHANISMS ARE INVOLVED IN THE TOP-DOWN OR BOTTOM-UP SENSITIZATION OF PAIN PATHWAYS AND THE DEVELOPMENT OF CHRONIC PAIN. EPIGENETIC CHANGES CAN LEAD TO LONG-TERM ALTERATIONS IN GENE EXPRESSION PROFILES OF NEURONS AND CONSEQUENTLY ALTER FUNCTIONALITY OF PERIPHERAL NEURONS, DORSAL ROOT GANGLIA, SPINAL CORD, AND BRAIN NEURONS. HOWEVER, EPIGENETIC MODIFICATIONS ARE DYNAMIC, AND THUS, DETRIMENTAL CHANGES MAY BE REVERSIBLE. HENCE, EXTERNAL FACTORS/THERAPEUTIC INTERVENTIONS MAY BE CAPABLE OF MODULATING THE EPIGENOME AND RESTORE NORMAL GENE EXPRESSION FOR EXTENDED PERIODS OF TIME. PURPOSE: THE GOAL OF THIS REVIEW IS TO HIGHLIGHT THE LATEST DISCOVERIES MADE TOWARD UNDERSTANDING THE EPIGENETIC MECHANISMS THAT ARE INVOLVED IN THE DEVELOPMENT OR MAINTENANCE OF CHRONIC VISCERAL PAIN. FURTHERMORE, THIS REVIEW WILL PROVIDE EVIDENCE SUPPORTING THAT TARGETING THESE EPIGENETIC MECHANISMS MAY REPRESENT A NOVEL APPROACH TO TREAT CHRONIC VISCERAL PAIN. 2019 15 1329 29 DEPRESSION ASSOCIATED WITH DIABETES: FROM PATHOPHYSIOLOGY TO TREATMENT. DIABETES IS A CHRONIC AND PROGRESSIVE SYNDROME COMMONLY ASSOCIATED WITH SEVERAL NEUROPSYCHIATRIC COMORBITIES, OF WHICH DEPRESSION IS THE MOST STUDIED. THE PREVALENCE OF DEPRESSION IS ABOUT TWO OR THREE TIMES HIGHER IN DIABETIC PATIENTS COMPARED TO THE GENERAL POPULATION. IT IS BELIEVED THAT THE DIABETES - DEPRESSION RELATION MAY BE BIDIRECTIONAL, I.E., THE DEPRESSION CAN LEAD TO DIABETES AND CONVERSELY DIABETES COULD FACILITATE THE EMERGENCE OF DEPRESSION. DEPRESSION IS ONE OF THE MOST NEGLECTED SYMPTOMS IN DIABETIC PATIENTS AND IS DIRECTLY LINKED WITH LOWERING OF QUALITY OF LIFE. THE TREATMENT OF DEPRESSION IN THESE PATIENTS IS STILL QUITE INEFFECTIVE AND IN MANY CASES TREATMENTREFRACTORY. FURTHERMORE, SOME OF THE FIRST CHOICE DRUGS USED TO TREAT THE DEPRESSION AFFECT THE BLOOD GLUCOSE CONTROL, AGGRAVATING THE HYPERGLYCEMIC STATE. THESE ISSUES UNDERSCORE THE URGENCY IN STUDIES SEARCHING FOR NEW PHARMACOLOGICAL TARGETS FOR THE TREATMENT OF DEPRESSION ASSOCIATED WITH DIABETES. FOR THIS, A BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT RELATES THIS COMORBIDITY BECOMES CRITICAL. IN THIS RESPECT, THIS REVIEW WILL FOCUS ON SOME HYPOTHESES THAT HAVE BEEN PROPOSED TO EXPLAIN THE MECHANISMS UNDERLYING DEPRESSION ASSOCIATED WITH DIABETES, HIGHLIGHTING THE TREATMENT OPTIONS CURRENTLY AVAILABLE AND THEIR LIMITATIONS. AMONG THESE HYPOTHESES, WE WILL POINT OUT THE HYPERGLYCEMIA AS A PRIMARY METABOLIC CAUSE OF THE DEPRESSION DEVELOPMENT, THE INVOLVEMENT OF THE DYSREGULATION OF HYPOTHALAMIC PITUITARY-ADRENAL (HPA) AXIS AND OF NEUROTRANSMITTER SYSTEMS, SPECIALLY MONOAMINERGIC SYSTEM. BESIDES, THE ROLE OF OXIDATIVE STRESS, NEUROINFLAMMATION AND CELL DEATH, ESPECIALLY IN HIPPOCAMPUS AND PREFRONTAL CORTEX, BRAIN AREAS IMPORTANT FOR THE MEDIATION AND MODULATION OF EMOTIONAL BEHAVIOR WILL ALSO BE DISCUSSED. FINALLY, WE WILL BRING UP THE INFLUENCE OF THE EPIGENETIC REGULATION WITH RESPECT TO NEUROPSYCHIATRIC DISORDERS. 2016 16 1314 30 DELINEATING CONDITIONS AND SUBTYPES IN CHRONIC PAIN USING NEUROIMAGING. DIFFERENTIATING SUBTYPES OF CHRONIC PAIN STILL REMAINS A CHALLENGE-BOTH FROM A SUBJECTIVE AND OBJECTIVE POINT OF VIEW. PERSONALIZED MEDICINE IS THE CURRENT GOAL OF MODERN MEDICAL CARE AND IS LIMITED BY THE SUBJECTIVE NATURE OF PATIENT SELF-REPORTING OF SYMPTOMS AND BEHAVIORAL EVALUATION. PHYSIOLOGY-FOCUSED TECHNIQUES SUCH AS GENOME AND EPIGENETIC ANALYSES INFORM THE DELINEATION OF PAIN GROUPS; HOWEVER, EXCEPT UNDER RARE CIRCUMSTANCES, THEY HAVE DILUTED EFFECTS THAT AGAIN, SHARE A COMMON RELIANCE ON BEHAVIORAL EVALUATION. THE APPLICATION OF STRUCTURAL NEUROIMAGING TOWARDS DISTINGUISHING PAIN SUBTYPES IS A GROWING FIELD AND MAY INFORM PAIN-GROUP CLASSIFICATION THROUGH THE ANALYSIS OF BRAIN REGIONS SHOWING HYPERTROPHIC AND ATROPHIC CHANGES IN THE PRESENCE OF PAIN. ANALYTICAL TECHNIQUES SUCH AS MACHINE-LEARNING CLASSIFIERS HAVE THE CAPACITY TO PROCESS LARGE VOLUMES OF DATA AND DELINEATE DIAGNOSTICALLY RELEVANT INFORMATION FROM NEUROIMAGING ANALYSIS. THE ISSUE OF DEFINING A "BRAIN TYPE" IS AN EMERGING FIELD AIMED AT INTERPRETING OBSERVED BRAIN CHANGES AND DELINEATING THEIR CLINICAL IDENTITY/SIGNIFICANCE. IN THIS REVIEW, 2 CHRONIC PAIN CONDITIONS (MIGRAINE AND IRRITABLE BOWEL SYNDROME) WITH SIMILAR CLINICAL PHENOTYPES ARE COMPARED IN TERMS OF THEIR STRUCTURAL NEUROIMAGING FINDINGS. INDEPENDENT INVESTIGATIONS ARE COMPARED WITH FINDINGS FROM APPLICATION OF MACHINE-LEARNING ALGORITHMS. FINDINGS ARE DISCUSSED IN TERMS OF DIFFERENTIATING PATIENT SUBGROUPS USING NEUROIMAGING DATA IN PATIENTS WITH CHRONIC PAIN AND HOW THEY MAY BE APPLIED TOWARDS DEFINING A PERSONALIZED PAIN SIGNATURE THAT HELPS SEGREGATE PATIENT SUBGROUPS (EG, MIGRAINE WITH AND WITHOUT AURA, WITH OR WITHOUT NAUSEA; IRRITABLE BOWEL SYNDROME VS OTHER FUNCTIONAL GASTROINTESTINAL DISORDERS). 2019 17 5637 34 SEROTONIN TRANSPORTER GENE POLYMORPHISMS IN SOUTHWESTERN IRANIAN PATIENTS WITH IRRITABLE BOWEL SYNDROME. BACKGROUND AND STUDY AIMS: IRRITABLE BOWEL SYNDROME IS A COMMON CHRONIC FUNCTIONAL GASTROINTESTINAL DISORDER OF UNKNOWN ETIOLOGY. SEROTONIN IS AN IMPORTANT FACTOR IN SENSORY SIGNALING IN THE BRAIN-GUT AXIS, WHICH PLAYS A KEY ROLE IN INTESTINAL MOTILITY AND SECRETION. SEROTONIN CLEARANCE IS MEDIATED BY A SPECIFIC PROTEIN CALLED THE SEROTONIN REUPTAKE TRANSPORTER. TRANSCRIPTION ACTIVITY OF THE SEROTONIN TRANSPORTER GENE IS AFFECTED BY SOME POLYMORPHISMS IN THIS GENE. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE RELATIONSHIP BETWEEN SEROTONIN TRANSPORTER GENE POLYMORPHISMS AND IRRITABLE BOWEL SYNDROME. PATIENTS/MATERIAL AND METHODS: THE 5-HTTLPR, RS25531 AND STIN2VNTR POLYMORPHISMS OF THE SEROTONIN TRANSPORTER GENE WERE ANALYZED BY PCR-BASED METHODS IN 50 PATIENTS WITH IRRITABLE BOWEL SYNDROME AND 100 HEALTHY CONTROLS. RESULTS: SEROTONIN TRANSPORTER POLYMORPHISMS WERE SIMILAR IN PATIENTS AND HEALTHY CONTROLS. THERE WERE NO SIGNIFICANT DIFFERENCES IN ALLELE OR GENOTYPE FREQUENCIES BETWEEN THE TWO GROUPS. CONCLUSION: OUR FINDINGS SUGGEST THAT POLYMORPHISMS IN THE GENE ENCODING FOR THE SEROTONIN TRANSPORTER ARE NOT ASSOCIATED WITH IRRITABLE BOWEL SYNDROME. INTERACTIONS BETWEEN ENVIRONMENTAL FACTORS AND PREDISPOSING GENETIC FACTORS ARE IMPORTANT IN THE PATHOPHYSIOLOGY OF IRRITABLE BOWEL SYNDROME, AND FURTHER GENETIC AND EPIGENETIC RESEARCH MAY PROVIDE NOVEL INSIGHTS INTO THE MECHANISMS CONTRIBUTING TO THIS DISEASE. 2013 18 6228 24 THE LINKS BETWEEN STRESS AND DEPRESSION: PSYCHONEUROENDOCRINOLOGICAL, GENETIC, AND ENVIRONMENTAL INTERACTIONS. THE ROLE OF STRESS IN THE ORIGIN AND DEVELOPMENT OF DEPRESSION MAY BE CONCEIVED AS THE RESULT OF MULTIPLE CONVERGING FACTORS, INCLUDING THE CHRONIC EFFECT OF ENVIRONMENTAL STRESSORS AND THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES DURING CHILDHOOD, ALL OF WHICH MAY INDUCE PERSISTENT HYPERACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. THESE CHANGES, INCLUDING INCREASED AVAILABILITY OF CORTICOTROPIN-RELEASING FACTOR AND CORTISOL, ARE ALSO ASSOCIATED WITH HYPERACTIVITY OF THE AMYGDALA, HYPOACTIVITY OF THE HIPPOCAMPUS, AND DECREASED SEROTONERGIC NEUROTRANSMISSION, WHICH TOGETHER RESULT IN INCREASED VULNERABILITY TO STRESS. THE ROLE OF OTHER MONOAMINERGIC NEUROTRANSMITTERS, GENETIC POLYMORPHISMS, EPIGENETIC MECHANISMS, INFLAMMATORY PROCESSES, AND ALTERED COGNITIVE PROCESSING HAS ALSO BEEN CONSIDERED IN THE DEVELOPMENT OF A COMPREHENSIVE MODEL OF THE INTERACTIONS BETWEEN DIFFERENT FACTORS OF VULNERABILITY. FURTHER UNDERSTANDING OF THE UNDERLYING MECHANISMS THAT LINK THESE FACTORS MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND PREVENTIVE STRATEGIES IN THE INTERFACE BETWEEN STRESS AND MOOD DISORDERS. 2016 19 2520 25 EPIGENETICS AND THE GLUCOCORTICOID RECEPTOR: A REVIEW OF THE IMPLICATIONS IN DEPRESSION. DEPRESSION IS A SERIOUS PSYCHIATRIC DISORDER THAT EFFECTS AT LEAST 350 MILLION PEOPLE WORLDWIDE TODAY. DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS (HPAA) IS A ROBUST FINDING IN THE PATHOPHYSIOLOGY OF DEPRESSION. THIS DYSREGULATION IS HYPOTHESIZED TO RESULT FROM ALTERED CENTRAL GLUCOCORTICOID RECEPTOR (GR) LEVELS AND/OR FUNCTION AS A CONSEQUENCE OF CHRONIC GLUCOCORTICOID (GC) RELEASE, LEADING TO RECEPTOR RESISTANCE. PIVOTAL ANIMAL AND HUMAN RESEARCH TO DATE HAS IDENTIFIED THAT EARLY LIFE EXPOSURE TO PROLONGED LEVELS OF GCS, STRESS AND/OR DEPRESSION, CAN INDUCE EPIGENETIC MODIFICATIONS AT KEY REGIONS ON THE GR GENE THAT LEAD TO ALTERATIONS IN GR EXPRESSION AND FUNCTION. EPIGENETICS PROVIDES AN ATTRACTIVE MECHANISM TO EXPLAIN HOW ONES' GENES AND ENVIRONMENT CAN INTERACT TO PRODUCE DIFFERENT DISEASE PHENOTYPES. THIS REVIEW AIMS TO COMPILE THE INFORMATION THAT HAS BEEN COLLECTED TO DATE AND TO IDENTIFY KEY AREAS FOR FURTHER INVESTIGATION. 2016 20 632 26 BIOLOGICAL CORRELATES OF EARLY LIFE STRESSFUL EVENTS IN MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD) IS THE MOST COMMON PSYCHIATRIC DISORDER AND RESPONDS FOR IMPORTANT PSYCHOSOCIAL CONSEQUENCES. STRESSFUL LIFE EVENTS, ESPECIALLY EARLY LIFE STRESS (ELS), CONTRIBUTE TO AN INCREASED PROBABILITY TO DEVELOP MDD, LEADING IN PARTICULAR TO SEVERE AND CHRONIC MANIFESTATION AND UNFAVORABLE TREATMENT OUTCOME. THE ASSOCIATION BETWEEN ELS AND MDD SEEMS TO HAVE BIOLOGICAL BASES, CONSISTING IN DYSREGULATIONS OCCURRING AT DIFFERENT LEVELS. THE AIM OF THIS NARRATIVE REVIEW IS TO PROPOSE AN OVERVIEW OF THE LITERATURE RANGING FROM GENETIC, EPIGENETIC, EXPRESSION AND PROTEIN TO NEUROIMAGING CORRELATES UNDERLYING THIS RELATIONSHIP. A SEARCH ON PUBMED OF STUDIES ASSESSING BIOLOGICAL CORRELATES OF ELS IN MDD DEVELOPMENT, FOCUSING ON HUMAN STUDIES CONDUCTED IN BOTH PERIPHERAL AND BRAIN TISSUES, WAS PERFORMED. EVIDENCE INDICATED THAT THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND THE SEROTONERGIC, DOPAMINERGIC, NEUROTROPHIN AND OXYTOCIN SYSTEMS MIGHT PLAY A ROLE IN THE MEDIATION BETWEEN ELS AND MDD. THE MOST CONSISTENT RESULTS WERE FOUND FOR GENETIC AND EPIGENETIC STUDIES AND INDICATED A JOINT INVOLVEMENT OF THE SYSTEMS MENTIONED. EXPRESSION STUDIES ARE LESS NUMEROUS AND POINT TO AN INVOLVEMENT OF STRESS-RELATED SYSTEMS. CONCERNING PROTEIN STUDIES, THE MAIN MEDIATORS ARE MARKERS RELATED TO THE INFLAMMATORY AND IMMUNE SYSTEMS. NEUROIMAGING STUDIES AIMING AT EVALUATING BRAIN ALTERATIONS CONNECTING ELS AND MDD IN RELATION TO BIOMARKERS INDICATED THE HIPPOCAMPUS, THE AMYGDALA AND THE FRONTAL CORTEX AS IMPORTANT ANATOMICAL MEDIATORS. THESE FINDINGS CAN BUILD THE BASES FOR FUTURE RESEARCH AND CLINICAL INTERVENTIONS; INDEED, THE CLARIFICATION OF BIOLOGICAL MECHANISMS MEDIATING THE RELATIONSHIP BETWEEN ELS AND MDD CAN LEAD TO NEW AND INDIVIDUALIZED PREVENTIVE AND THERAPEUTIC POSSIBILITIES. 2021