1 3536 104 IMMUNE CHROMATIN READER SP140 REGULATES MICROBIOTA AND RISK FOR INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASE (IBD) IS DRIVEN BY HOST GENETICS AND ENVIRONMENTAL FACTORS, INCLUDING COMMENSAL MICROORGANISMS. SPECKLED PROTEIN 140 (SP140) IS AN IMMUNE-RESTRICTED CHROMATIN "READER" THAT IS ASSOCIATED WITH CROHN'S DISEASE (CD), MULTIPLE SCLEROSIS (MS), AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). HOWEVER, THE DISEASE-CAUSING MECHANISMS OF SP140 REMAIN UNDEFINED. HERE, WE IDENTIFY AN IMMUNE-INTRINSIC ROLE FOR SP140 IN REGULATING PHAGOCYTIC DEFENSE RESPONSES TO PREVENT THE EXPANSION OF INFLAMMATORY BACTERIA. MICE HARBORING ALTERED MICROBIOTA DUE TO HEMATOPOIETIC SP140 DEFICIENCY EXHIBITED SEVERE COLITIS THAT WAS TRANSMISSIBLE UPON COHOUSING AND AMELIORATED WITH ANTIBIOTICS. LOSS OF SP140 RESULTS IN BLOOMS OF PROTEOBACTERIA, INCLUDING HELICOBACTER IN SP140(-/-) MICE AND ENTEROBACTERIACEAE IN HUMANS BEARING THE CD-ASSOCIATED SP140 LOSS-OF-FUNCTION VARIANT. PHAGOCYTES FROM PATIENTS WITH THE SP140 LOSS-OF-FUNCTION VARIANT AND SP140(-/-) MICE EXHIBITED ALTERED ANTIMICROBIAL DEFENSE PROGRAMS REQUIRED FOR CONTROL OF PATHOBIONTS. THUS, MUTATIONS WITHIN THIS EPIGENETIC READER MAY CONSTITUTE A PREDISPOSING EVENT IN HUMAN DISEASES PROVOKED BY MICROBIOTA. 2022 2 4269 28 MICROBIAL DYSBIOSIS AND LACK OF SCFA PRODUCTION IN A SPANISH COHORT OF PATIENTS WITH MULTIPLE SCLEROSIS. BACKGROUND: MULTIPLE SCLEROSIS (MS) IS A CHRONIC, DEMYELINATING, AND IMMUNE-MEDIATED DISEASE OF THE CENTRAL NERVOUS SYSTEM CAUSED BY A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. THE INCIDENCE OF MS HAS INCREASED IN THE PAST SEVERAL DECADES, SUGGESTING CHANGES IN THE ENVIRONMENTAL RISK FACTORS. MUCH EFFORT HAS BEEN MADE IN THE DESCRIPTION OF THE GUT MICROBIOTA IN MS; HOWEVER, LITTLE IS KNOWN ABOUT THE DYSBIOSIS ON ITS FUNCTION. THE MICROBIOTA PRODUCES THOUSANDS OF BIOLOGICALLY ACTIVE SUBSTANCES AMONG WHICH ARE NOTABLE THE SHORT-CHAIN FATTY ACID (SCFA) EXCRETION. OBJECTIVES: ANALYZE THE INTERACTION BETWEEN MICROBIOTA, SCFAS, DIET, AND MS. METHODS: 16S, NUTRITIONAL QUESTIONNAIRES, AND SCFAS QUANTIFICATION HAVE BEEN RECOVERED FROM MS PATIENTS AND CONTROLS. RESULTS: OUR RESULTS REVEALED AN INCREMENT IN THE PHYLUM PROTEOBACTERIA, ESPECIALLY THE FAMILY ENTEROBACTERIACEAE, A LACK IN TOTAL SCFA EXCRETION, AND AN ALTERED PROFILE OF SCFAS IN A SPANISH COHORT OF MS PATIENTS. THESE ALTERATIONS ARE MORE EVIDENT IN PATIENTS WITH HIGHER DISABILITY. CONCLUSIONS: THE ABUNDANCE OF PROTEOBACTERIA AND ACETATE AND THE LOW EXCRETION OF TOTAL SCFAS, ESPECIALLY BUTYRATE, ARE COMMON CHARACTERISTICS OF MS PATIENTS, AND BESIDES, BOTH ARE ASSOCIATED WITH A WORSE PROGNOSIS OF THE DISEASE. 2022 3 2271 48 EPIGENETIC READER SP140 LOSS OF FUNCTION DRIVES CROHN'S DISEASE DUE TO UNCONTROLLED MACROPHAGE TOPOISOMERASES. HOW MIS-REGULATED CHROMATIN DIRECTLY IMPACTS HUMAN IMMUNE DISORDERS IS POORLY UNDERSTOOD. SPECKLED PROTEIN 140 (SP140) IS AN IMMUNE-RESTRICTED PHD AND BROMODOMAIN-CONTAINING EPIGENETIC "READER," AND SP140 LOSS-OF-FUNCTION MUTATIONS ASSOCIATE WITH CROHN'S DISEASE (CD), MULTIPLE SCLEROSIS (MS), AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). HOWEVER, THE RELEVANCE OF THESE MUTATIONS AND MECHANISMS UNDERLYING SP140-DRIVEN PATHOGENICITY REMAINS UNEXPLORED. USING A GLOBAL PROTEOMIC STRATEGY, WE IDENTIFIED SP140 AS A REPRESSOR OF TOPOISOMERASES (TOPS) THAT MAINTAINS HETEROCHROMATIN AND MACROPHAGE FATE. IN HUMANS AND MICE, SP140 LOSS RESULTED IN UNLEASHED TOP ACTIVITY, DE-REPRESSION OF DEVELOPMENTALLY SILENCED GENES, AND ULTIMATELY DEFECTIVE MICROBE-INDUCIBLE MACROPHAGE TRANSCRIPTIONAL PROGRAMS AND BACTERIAL KILLING THAT DRIVE INTESTINAL PATHOLOGY. PHARMACOLOGICAL INHIBITION OF TOP1/2 RESCUED THESE DEFECTS. FURTHERMORE, EXACERBATED COLITIS WAS RESTORED WITH TOP1/2 INHIBITORS IN SP140(-/-) MICE, BUT NOT WILD-TYPE MICE, IN VIVO. COLLECTIVELY, WE IDENTIFY SP140 AS A TOP REPRESSOR AND REVEAL REPURPOSING OF TOP INHIBITION TO REVERSE IMMUNE DISEASES DRIVEN BY SP140 LOSS. 2022 4 5842 25 STRUCTURE OF HUMAN SP140 PHD FINGER: AN ATYPICAL FOLD INTERACTING WITH PIN1. SP140 IS A NUCLEAR LEUKOCYTE-SPECIFIC PROTEIN INVOLVED IN PRIMARY BILIARY CIRRHOSIS AND A RISK FACTOR IN CHRONIC LYMPHOCYTIC LEUKEMIA. THE PRESENCE OF SEVERAL CHROMATIN RELATED MODULES SUCH AS PLANT HOMEODOMAIN (PHD), BROMODOMAIN AND SAND DOMAIN SUGGESTS A ROLE IN CHROMATIN-MEDIATED REGULATION OF GENE EXPRESSION; HOWEVER, ITS REAL FUNCTION IS STILL ELUSIVE. HEREIN WE PRESENT THE SOLUTION STRUCTURE OF SP140-PHD FINGER AND INVESTIGATE ITS ROLE AS EPIGENETIC READER IN VITRO. SP140-PHD PRESENTS AN ATYPICAL PHD FINGER FOLD WHICH DOES NOT BIND TO HISTONE H3 TAILS BUT IS RECOGNIZED BY PEPTIDYLPROLYL ISOMERASE PIN1. PIN1 SPECIFICALLY BINDS TO A PHOSPHOPEPTIDE CORRESPONDING TO THE L3 LOOP OF SP140-PHD AND CATALYZES CIS-TRANS ISOMERIZATION OF A PTHR-PRO BOND. MOREOVER CO-IMMUNOPRECIPITATION EXPERIMENTS DEMONSTRATE FLAG-SP140 INTERACTION WITH ENDOGENOUS PIN1 IN VIVO. OVERALL THESE DATA INCLUDE SP140 IN THE LIST OF THE INCREASING NUMBER OF PIN1 BINDERS AND EXPAND THE REGULATORY POTENTIAL OF PHD FINGERS AS VERSATILE STRUCTURAL PLATFORMS FOR DIVERSIFIED INTERACTIONS. 2014 5 4271 30 MICROBIAL DYSBIOSIS-INDUCED OBESITY: ROLE OF GUT MICROBIOTA IN HOMOEOSTASIS OF ENERGY METABOLISM. THE GLOBAL OBESITY EPIDEMIC HAS NECESSITATED THE SEARCH FOR BETTER INTERVENTION STRATEGIES INCLUDING THE EXPLOITATION OF THE HEALTH BENEFITS OF SOME GUT MICROBIOTA AND THEIR METABOLIC PRODUCTS. THEREFORE, WE EXAMINED THE GUT MICROBIAL COMPOSITION AND MECHANISMS OF INTERACTION WITH THE HOST IN RELATION TO HOMOEOSTATIC ENERGY METABOLISM AND PATHOPHYSIOLOGY OF DYSBIOSIS-INDUCED METABOLIC INFLAMMATION AND OBESITY. WE ALSO DISCUSSED THE EUBIOTIC, HEALTH-PROMOTING EFFECTS OF PROBIOTICS AND PREBIOTICS AS WELL AS EPIGENETIC MODIFICATIONS ASSOCIATED WITH GUT MICROBIAL DYSBIOSIS AND RISK OF OBESITY. HIGH-FAT/CARBOHYDRATE DIET PROGRAMMES THE GUT MICROBIOTA TO ONE PREDOMINATED BY FIRMICUTES (CLOSTRIDIUM), PREVOTELLA AND METHANOBREVIBACTER BUT DEFICIENT IN BENEFICIAL GENERA/SPECIES SUCH AS BACTEROIDES, BIFIDOBACTERIUM, LACTOBACILLUS AND AKKERMANSIA. ALTERED GUT MICROBIOTA IS ASSOCIATED WITH DECREASED EXPRESSION OF SCFA THAT MAINTAIN INTESTINAL EPITHELIAL BARRIER INTEGRITY, REDUCE BACTERIAL TRANSLOCATION AND INFLAMMATION AND INCREASE EXPRESSION OF HUNGER-SUPPRESSING HORMONES. REDUCED AMOUNTS OF BENEFICIAL MICRO-ORGANISMS ALSO INHIBIT FASTING-INDUCED ADIPOCYTE FACTOR EXPRESSION LEADING TO DYSLIPIDAEMIA. A LOW-GRADE CHRONIC INFLAMMATION (METABOLIC ENDOTOXAEMIA) ENSUES WHICH CULMINATES IN OBESITY AND ITS CO-MORBIDITIES. THE SYNERGY OF HIGH-FAT DIET AND DYSBIOTIC GUT MICROBIOTA INITIATES A RECIPE THAT EPIGENETICALLY PROGRAMMES THE HOST FOR INCREASED ADIPOSITY AND POOR GLYCAEMIC CONTROL. INTERESTINGLY, THESE OBESOGENIC MECHANISTIC PATHWAYS THAT ARE TRANSMITTABLE FROM ONE GENERATION TO ANOTHER CAN BE MODULATED THROUGH THE ADMINISTRATION OF PROBIOTICS, PREBIOTICS AND SYNBIOTICS. THOUGH THE INFLUENCE OF GUT MICROBIOTA ON THE RISK OF OBESITY AND SEVERAL INTERVENTION STRATEGIES HAVE BEEN EXTENSIVELY DEMONSTRATED IN ANIMAL MODELS, APPLICATION IN HUMANS STILL REQUIRES FURTHER ROBUST INVESTIGATION. 2020 6 1797 24 EFFECT OF HELICOBACTER PYLORI ERADICATION ON GASTRIC PRECANCEROUS LESIONS: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND: THE QUESTION OF WHETHER ERADICATION OF HELICOBACTER PYLORI (HP) CAN REVERSE GASTRIC PRECANCEROUS LESIONS, INCLUDING INTESTINAL METAPLASIA, REMAINS UNCERTAIN, LEADING TO ONGOING DEBATE. THEREFORE, A META-ANALYSIS WAS PERFORMED TO EVALUATE THE EFFECT OF HP ERADICATION ON GASTRIC PRECANCEROUS LESIONS. MATERIALS AND METHODS: PUBMED, EMBASE, COCHRANE LIBRARY, WEB OF SCIENCE, SCOPUS DATABASE, AND CLINICALTRIALS.GOV WERE SYSTEMATICALLY SEARCHED FROM INCEPTION TO APRIL 2023 FOR STUDIES THAT EXPLORED THE IMPACT OF HP ERADICATION ON GASTRIC PRECANCEROUS LESIONS. RISK RATIOS (RRS) AND THEIR 95% CONFIDENCE INTERVALS (95% CIS) WERE SELECTED AS THE EFFECT SIZE. WE USED THE RANDOM-EFFECTS MODEL TO ASSESS POOLED DATA. WE ALSO PERFORMED QUALITY ASSESSMENTS, SUBGROUP ANALYSES, AND SENSITIVITY ANALYSES. RESULTS: FIFTEEN STUDIES WERE INCLUDED. COMPARED WITH PLACEBO, HP ERADICATION COULD SIGNIFICANTLY PREVENT THE PROGRESSION OF GASTRIC PRECANCEROUS LESIONS (RR = 0.87, 95% CI: 0.81-0.94, P < 0.01) AND REVERSE THEM (RR = 1.32, 95% CI: 1.17-1.50, P < 0.01). THEN, SPECIFIC PRECANCEROUS LESIONS WERE FURTHER EXPLORED. THE PROGRESSION OF INTESTINAL METAPLASIA WAS SIGNIFICANTLY PREVENTED BY HP ERADICATION COMPARED TO PLACEBO OR NO TREATMENT (RR = 0.80, 95% CI: 0.69-0.94, P < 0.01). MOREOVER, COMPARED WITH PLACEBO OR NO TREATMENT, HP ERADICATION ALSO IMPROVED CHRONIC ATROPHIC GASTRITIS (RR = 1.84, 95% CI: 1.30-2.61, P < 0.01) AND INTESTINAL METAPLASIA (RR = 1.41, 95% CI: 1.15-1.73, P < 0.01). HOWEVER, IN TERMS OF PREVENTING DYSPLASIA PROGRESSION (RR = 0.86, 95% CI: 0.37-2.00) AND IMPROVING DYSPLASIA (RR = 0.89, 95% CI: 0.47-1.70), HP ERADICATION HAD NO ADVANTAGE COMPARED TO PLACEBO OR NO TREATMENT. CONCLUSIONS: HP ERADICATION THERAPY COULD PREVENT THE PROGRESSION OF GASTRIC PRECANCEROUS LESIONS AND REVERSE THEM. NOTABLY, INTESTINAL METAPLASIA CAN BE REVERSED, BUT THIS MAY ONLY BE APPROPRIATE FOR PATIENTS WITH EPIGENETIC ALTERATIONS AND MILDER LESIONS. 2023 7 3446 31 HYPERMETHYLATION OF MIR21 IN CD4+ T CELLS FROM PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS ASSOCIATES WITH LOWER MIRNA-21 LEVELS AND CONCOMITANT UP-REGULATION OF ITS TARGET GENES. BACKGROUND: MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM CAUSED BY GENETIC AND ENVIRONMENTAL FACTORS. DNA METHYLATION, AN EPIGENETIC MECHANISM THAT CONTROLS GENOME ACTIVITY, MAY PROVIDE A LINK BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS. OBJECTIVE: WE SOUGHT TO IDENTIFY DNA METHYLATION CHANGES IN CD4+ T CELLS IN PATIENTS WITH RELAPSING-REMITTING (RR-MS) AND SECONDARY-PROGRESSIVE (SP-MS) DISEASE AND HEALTHY CONTROLS (HC). METHODS: WE PERFORMED DNA METHYLATION ANALYSIS IN CD4+ T CELLS FROM RR-MS, SP-MS, AND HC AND ASSOCIATED IDENTIFIED CHANGES WITH THE NEARBY RISK ALLELE, SMOKING, AGE, AND GENE EXPRESSION. RESULTS: WE OBSERVED SIGNIFICANT METHYLATION DIFFERENCES IN THE VMP1/MIR21 LOCUS, WITH RR-MS DISPLAYING HIGHER METHYLATION COMPARED TO SP-MS AND HC. VMP1/MIR21 METHYLATION DID NOT CORRELATE WITH A KNOWN MS RISK VARIANT IN VMP1 OR SMOKING BUT DISPLAYED A SIGNIFICANT NEGATIVE CORRELATION WITH AGE AND THE LEVELS OF MATURE MIR-21 IN CD4+ T CELLS. ACCORDINGLY, RR-MS DISPLAYED LOWER LEVELS OF MIR-21 COMPARED TO SP-MS, WHICH MIGHT REFLECT DIFFERENCES IN AGE BETWEEN THE GROUPS, AND HEALTHY INDIVIDUALS AND A SIGNIFICANT ENRICHMENT OF UP-REGULATED MIR-21 TARGET GENES. CONCLUSION: DISEASE-RELATED CHANGES IN EPIGENETIC MARKING OF MIR21 IN RR-MS LEAD TO DIFFERENCES IN MIR-21 EXPRESSION WITH A CONSEQUENCE ON MIR-21 TARGET GENES. 2018 8 6043 26 THE COMBINED PROGNOSTIC SIGNIFICANCE OF ALKALINE PHOSPHATASE AND INTRACRANIAL ARTERIAL CALCIFICATIONS IN HEMODIALYSIS PATIENTS. INTRODUCTION: THE PREVALENCE OF INTRACRANIAL ARTERIAL CALCIFICATION (ICAC) IN MAINTENANCE HEMODIALYSIS (MHD) PATIENTS IS ABOUT 90%, AND ITS SEVERITY IS CORRELATED WITH AGE, HEMODIALYSIS VINTAGE, AND MINERAL BONE DISEASE. ELEVATED CONCENTRATIONS OF CALCIUM AND PHOSPHORUS ARE NOT SUFFICIENT FOR MEDIAL CALCIFICATION BECAUSE OF INHIBITION BY PYROPHOSPHATE. ALKALINE PHOSPHATASE (ALP) PROMOTES CALCIFICATION BY HYDROLYZING EXTRACELLULAR PYROPHOSPHATE. EPIGENETIC MECHANISMS INVOLVING ALP INHIBITION BY APABETALONE WERE INVESTIGATED AS A POTENTIAL TARGET FOR PREVENTING VASCULAR CALCIFICATIONS (VCS). THIS STUDY ASSESSED THE COMBINED IMPACT OF VCS AND ELEVATED SERUM ALP ON MORTALITY AMONG CHRONIC HD PATIENTS. METHODS: VCS REPRESENTED BY ICAC WERE MEASURED SIMULTANEOUSLY WITH MINERAL BONE DISEASE PARAMETERS INCLUDING SERUM ALP OF MHD PATIENTS WHO UNDERWENT NONCONTRAST BRAIN COMPUTED TOMOGRAPHY FROM 2015 TO 2018 IN OUR INSTITUTION. RESULTS: THIS RETROSPECTIVE STUDY INCLUDED 150 MHD PATIENTS (MEAN AGE 71.3 +/- 12.1 YEARS, 60.1% MALE). OF THE TOTAL COHORT, 12 (7.8%) HAD NO BRAIN CALCIFICATIONS AND 69 (45.1%) HAD MULTIPLE INTRACRANIAL CALCIFICATIONS. CONSIDERING THE PATIENTS WITH NORMAL ALP AND NO CALCIFICATION AS THE REFERENCE GROUP YIELDED ADJUSTED ODDS RATIOS FOR ALL-CAUSE MORTALITY OF 4.6 (95% CI: 1.7-12.7) AMONG PATIENTS WITH BRAIN CALCIFICATIONS AND NORMAL ALP (P = 0.003) AND ODDS RATIOS FOR ALL-CAUSE MORTALITY OF 6.1 (95% CI: 2.1-17.7) AMONG PATIENTS WITH BRAIN CALCIFICATIONS AND ELEVATED ALP (P= 0.001). CONCLUSION: WE FOUND AN INDEPENDENT ASSOCIATION BETWEEN ICAC AND THE RISK OF DEATH AMONG MHD PATIENTS. THE COMBINED EFFECT OF ICAC AND ELEVATED ALP WAS ASSOCIATED WITH A HIGHER ODDS RATIO FOR ALL-CAUSE MORTALITY IN MHD PATIENTS AND MAY CONTRIBUTE TO THE RISK STRATIFICATION OF THESE PATIENTS. 2021 9 312 28 ALCOHOL FEEDING IN MICE PROMOTES COLONIC HYPERPERMEABILITY AND CHANGES IN COLONIC ORGANOID STEM CELL FATE. BACKGROUND: ALCOHOL INCREASES INTESTINAL PERMEABILITY TO PROINFLAMMATORY MICROBIAL PRODUCTS THAT PROMOTE LIVER DISEASE, EVEN AFTER A PERIOD OF SOBRIETY. WE SOUGHT TO TEST THE HYPOTHESIS THAT ALCOHOL AFFECTS INTESTINAL STEM CELLS USING AN IN VIVO MODEL AND EX VIVO ORGANOIDS GENERATED FROM JEJUNUM AND COLON FROM MICE FED CHRONIC ALCOHOL. METHODS: MICE WERE FED A CONTROL OR AN ALCOHOL DIET. INTESTINAL PERMEABILITY, LIVER STEATOSIS-INFLAMMATION, AND STOOL SHORT-CHAIN FATTY ACIDS (SCFAS) WERE MEASURED. JEJUNUM AND COLONIC ORGANOIDS AND TISSUE WERE STAINED FOR STEM CELL, CELL LINEAGE, AND APICAL JUNCTION MARKERS WITH ASSESSMENT OF MRNA BY PCR AND RNA-SEQ. CHIP-PCR ANALYSIS WAS CARRIED OUT FOR NOTCH1 USING AN ANTIBODY SPECIFIC FOR ACETYLATED HISTONE 3. RESULTS: ALCOHOL-FED MICE EXHIBITED COLONIC (BUT NOT SMALL INTESTINAL) HYPERPERMEABILITY, STEATOHEPATITIS, AND DECREASED BUTYRATE/TOTAL SCFA RATIO IN STOOL. STEM CELL, CELL LINEAGE, AND APICAL JUNCTION MARKER STAINING IN TISSUE OR ORGANOIDS FROM JEJUNUM TISSUE WERE NOT IMPACTED BY ALCOHOL. ONLY CHROMOGRANIN A (CHGA) WAS INCREASED IN JEJUNUM ORGANOIDS BY QPCR. HOWEVER, COLONIC TISSUE AND ORGANOID STAINING EXHIBITED AN ALCOHOL-INDUCED SIGNIFICANT DECREASE IN CYTOKERATIN 20+ (KRT20+) ABSORPTIVE LINEAGE ENTEROCYTES, A DECREASE IN OCCLUDIN AND E-CADHERIN APICAL JUNCTION PROTEINS, AN INCREASE IN CHGA, AND AN INCREASE IN THE LGR5 STEM CELL MARKER. QPCR REVEALED AN ALCOHOL-INDUCED DECREASE IN COLONIC ORGANOID AND TISSUE NOTCH1, HES1, AND KRT20 AND INCREASED CHGA, SUPPORTING AN ALTERATION IN STEM CELL FATE DUE TO DECREASED NOTCH1 EXPRESSION. COLONIC TISSUE CHIP-PCR REVEALED ALCOHOL FEEDING SUPPRESSED NOTCH1 MRNA EXPRESSION (VIA DEACETYLATION OF HISTONE H3) AND DECREASED NOTCH1 TISSUE STAINING. CONCLUSIONS: DATA SUPPORT A MODEL FOR ALCOHOL-INDUCED COLONIC HYPERPERMEABILITY VIA EPIGENETIC EFFECTS ON NOTCH1, AND THUS HES1, SUPPRESSION THROUGH A MECHANISM INVOLVING HISTONE H3 DEACETYLATION AT THE NOTCH1 LOCUS. THIS DECREASED ENTEROCYTE AND INCREASED ENTEROENDOCRINE CELL COLONIC STEM CELL FATE AND DECREASED APICAL JUNCTIONAL PROTEINS LEADING TO HYPERPERMEABILITY. 2017 10 3804 24 INTESTINAL MICROBIOTA, CHRONIC INFLAMMATION, AND COLORECTAL CANCER. IN ADDITION TO GENETIC AND EPIGENETIC FACTORS, VARIOUS ENVIRONMENTAL FACTORS, INCLUDING DIET, PLAY IMPORTANT ROLES IN THE DEVELOPMENT OF COLORECTAL CANCER (CRC). RECENTLY, THERE IS INCREASING INTEREST IN THE INTESTINAL MICROBIOTA AS AN ENVIRONMENTAL RISK FACTOR FOR CRC, BECAUSE DIET ALSO INFLUENCES THE COMPOSITION OF THE INTESTINAL MICROBIOTA. THE HUMAN INTESTINAL MICROBIOTA COMPRISES ABOUT 100 TRILLION MICROBES. THIS MICROBIOME THRIVES ON UNDIGESTED DIETARY RESIDUES IN THE INTESTINAL LUMEN AND PRODUCES VARIOUS METABOLITES. IT IS WELL KNOWN THAT THE DIETARY RISK FACTORS FOR CRC ARE MEDIATED BY DYSBIOSIS OF THE INTESTINAL MICROBIOTA AND THEIR METABOLITES. IN THIS REVIEW, WE DESCRIBE THE BACTERIAL TAXA ASSOCIATED WITH CRC, INCLUDING FUSOBACTERIUM NUCLEATUM, ENTEROTOXIGENIC BACTEROIDES FRAGILIS, ESCHERICHIA COLI, AND BUTYRATE-PRODUCING BACTERIA. WE ALSO DISCUSS THE HOST-DIET INTERACTION IN COLORECTAL CARCINOGENESIS. 2018 11 1137 31 COMPREHENSIVE PHENOTYPING IN INFLAMMATORY BOWEL DISEASE: SEARCH FOR BIOMARKER ALGORITHMS IN THE TRANSKINGDOM INTERACTIONS CONTEXT. INFLAMMATORY BOWEL DISEASE (IBD) IS THE MOST COMMON FORM OF INTESTINAL INFLAMMATION ASSOCIATED WITH A DYSREGULATED IMMUNE SYSTEM RESPONSE TO THE COMMENSAL MICROBIOTA IN A GENETICALLY SUSCEPTIBLE HOST. IBD INCLUDES ULCERATIVE COLITIS (UC) AND CROHN'S DISEASE (CD), BOTH OF WHICH ARE REMARKABLY HETEROGENEOUS IN THEIR CLINICAL PRESENTATION AND RESPONSE TO TREATMENT. THIS TRANSLATES INTO A NOTABLE DIAGNOSTIC CHALLENGE, ESPECIALLY IN UNDERDEVELOPED COUNTRIES WHERE IBD IS ON THE RISE AND ACCESS TO DIAGNOSIS OR TREATMENT IS NOT ALWAYS ACCESSIBLE FOR CHRONIC DISEASES. THE PRESENT WORK CHARACTERIZED, FOR THE FIRST TIME IN OUR REGION, EPIGENETIC BIOMARKERS AND GUT MICROBIAL PROFILES ASSOCIATED WITH UC AND CD PATIENTS IN THE BUENOS AIRES METROPOLITAN AREA AND REVEALED DIFFERENCES BETWEEN NON-IBD CONTROLS AND IBD PATIENTS. GENERAL METABOLIC FUNCTIONS ASSOCIATED WITH THE GUT MICROBIOTA, AS WELL AS CORE MICROORGANISMS WITHIN GROUPS, WERE ALSO ANALYZED. ADDITIONALLY, THE GUT MICROBIOTA ANALYSIS WAS INTEGRATED WITH RELEVANT CLINICAL, BIOCHEMICAL AND EPIGENETIC MARKERS CONSIDERED IN THE FOLLOW-UP OF PATIENTS WITH IBD, WITH THE AIM OF GENERATING MORE POWERFUL DIAGNOSTIC TOOLS TO DISCRIMINATE PHENOTYPES. OVERALL, OUR STUDY PROVIDES NEW INSIGHTS INTO DATA ANALYSIS ALGORITHMS TO PROMOTE COMPREHENSIVE PHENOTYPING TOOLS USING QUANTITATIVE AND QUALITATIVE ANALYSIS IN A TRANSKINGDOM INTERACTIONS NETWORK CONTEXT. 2022 12 1707 36 DYSBIOTIC 1-CARBON METABOLISM IN CARDIAC MUSCLE REMODELING. UNLESS THERE IS A GENETIC DEFECT/MUTATION/DELETION IN A GENE, THE CAUSATION OF A GIVEN DISEASE IS CHRONIC DYSREGULATION OF GUT METABOLISM. MOST OF THE TIME, IF NOT ALWAYS, STARTS WITHIN THE GUT; THAT IS WHAT WE EAT. RECENT RESEARCH SHOWS THAT THE IMBALANCE BETWEEN GOOD VERSUS BAD MICROBIAL POPULATION, ESPECIALLY IN THE GUT, CAUSES SYSTEMIC DISEASES. THUS, AN APPROPRIATE BALANCE OF THE GUT MICROBIOTA (EUBIOSIS OVER DYSBIOSIS) NEEDS TO BE MAINTAINED FOR NORMAL HEALTH (VEERANKI AND TYAGI, 2017, JOURNAL OF CELLULAR PHYSIOLOGY, 232, 2929-2930). HOWEVER, DURING VARIOUS DISEASES SUCH AS METABOLIC SYNDROME, INFLAMMATORY BOWEL DISEASE, DIABETES, OBESITY, AND HYPERTENSION THE DYSBIOTIC GUT ENVIRONMENT TENDS TO PREVAIL. OUR RESEARCH FOCUSES ON HOMOCYSTEINE (HCY) METABOLISM THAT OCCUPIES A CENTER-STAGE IN MANY BIOCHEMICALLY RELEVANT EPIGENETIC MECHANISMS. FOR EXAMPLE, DYSBIOTIC BACTERIA METHYLATE PROMOTERS TO INHIBIT GENE ACTIVITIES. INTERESTINGLY, THE PRODUCT OF THE 1-CARBON METABOLISM IS HCY, UNEQUIVOCALLY. EMERGING STUDIES SHOW THAT HOST RESISTANCE TO VARIOUS ANTIBIOTICS OCCURS DUE TO INVERTON PROMOTER INHIBITION, PRESUMABLY BECAUSE OF PROMOTER METHYLATION. THIS RESULTS FROM MODIFICATION OF HOST PROMOTERS BY BACTERIAL PRODUCTS LEADING TO LOSS OF HOST'S ABILITY TO DRUG COMPATIBILITY AND SYSTEM SENSITIVITY. IN THIS STUDY, WE FOCUS ON THE ROLE OF HIGH METHIONINE DIET (HMD), AN INGREDIENT RICH IN RED MEAT AND MEASURE THE EFFECTS OF A PROBIOTIC ON CARDIAC MUSCLE REMODELING AND ITS FUNCTIONS. WE EMPLOYED WILD TYPE (WT) AND CYSTATHIONINE BETA-SYNTHASE HETEROZYGOTE KNOCKOUT (CBS(+/-) ) MICE WITH AND WITHOUT HMD AND WITH AND WITHOUT A PROBIOTIC; PB (LACTOBACILLUS) IN DRINKING WATER FOR 16 WEEKS. RESULTS INDICATE THAT MATRIX METALLOPROTEINASE-2 (MMP-2) ACTIVITY WAS ROBUST IN CBS(+/-) FED WITH HMD AND THAT IT WAS SUCCESSFULLY ATTENUATED BY THE PB TREATMENT. CARDIOMYOCYTE CONTRACTILITY AND ECHO DATA REVEALED MITIGATION OF THE CARDIAC DYSFUNCTION IN CBS(+/-) + HMD MICE TREATED WITH PB. IN CONCLUSION, OUR DATA SUGGEST THAT PROBIOTICS CAN POTENTIALLY REVERSE THE HCY-MEDITATED CARDIAC DYSFUNCTION. 2020 13 2731 19 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 14 447 21 APABETALONE LOWERS SERUM ALKALINE PHOSPHATASE AND IMPROVES CARDIOVASCULAR RISK IN PATIENTS WITH CARDIOVASCULAR DISEASE. BACKGROUND AND AIMS: IN PATIENTS WITH CARDIOVASCULAR DISEASE, CONSIDERABLE RESIDUAL RISK REMAINS DESPITE EVIDENCE-BASED SECONDARY PREVENTION MEASURES. ALKALINE PHOSPHATASE (ALP) HAS BEEN SUGGESTED AS A MODIFIABLE CARDIOVASCULAR RISK FACTOR. WE SOUGHT TO DETERMINE WHETHER CARDIOVASCULAR RISK REDUCTION BY THE BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEIN INHIBITOR APABETALONE IS ASSOCIATED WITH THE CONCOMITANT LOWERING OF SERUM ALP. METHODS: IN A POST-HOC ANALYSIS OF 795 PATIENTS WITH ESTABLISHED CORONARY HEART DISEASE AND STATIN TREATMENT, WHO PARTICIPATED IN PHASE 2 PLACEBO-CONTROLLED TRIALS OF APABETALONE, WE DETERMINED THE EFFECT OF ASSIGNED TREATMENT FOR UP TO 24 WEEKS ON THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) AND SERUM ALP. RESULTS: BASELINE ALP (MEDIAN 72 U/L) PREDICTED MACE (DEATH, NON-FATAL MYOCARDIAL INFARCTION, CORONARY REVASCULARIZATION, OR HOSPITALIZATION FOR CARDIOVASCULAR CAUSES), INDEPENDENT OF HIGH-SENSITIVITY C-REACTIVE PROTEIN (HSCRP), SEX, AGE, RACE, STUDY, CARDIOVASCULAR RISK FACTORS, CHRONIC KIDNEY DISEASE (CKD), LIVER FUNCTION MARKERS AND TREATMENT ALLOCATION (HAZARD RATIO [HR] PER STANDARD DEVIATION [SD] 1.6, 95% CI 1.19-2.16, P = 0.002). MEAN PLACEBO-CORRECTED DECREASES IN ALP FROM BASELINE WERE 9.2% (P < 0.001) AFTER 12-14 WEEKS AND 7.7% (P < 0.001) AFTER 24-26 WEEKS OF APABETALONE TREATMENT. IN THE APABETALONE GROUP, A 1-SD REDUCTION IN ALP WAS ASSOCIATED WITH A HR FOR MACE OF 0.64 (95% CI 0.46-0.90, P = 0.009). CONCLUSIONS: SERUM ALP PREDICTS RESIDUAL CARDIOVASCULAR RISK, INDEPENDENT OF HSCRP, ESTABLISHED CARDIOVASCULAR RISK FACTORS AND CKD, IN PATIENTS WITH CARDIOVASCULAR DISEASE ON STATIN TREATMENT. APABETALONE LOWERS SERUM ALP, WHICH WAS ASSOCIATED WITH A LOWER RISK OF CARDIOVASCULAR EVENTS. WHETHER THE BENEFICIAL CARDIOVASCULAR EFFECTS OF APABETALONE ARE CAUSALLY RELATED TO ALP REDUCTION REMAINS UNDETERMINED. 2019 15 725 21 CAN THE BLOOD TRYPTASE BE AN INDICATOR OF THE SEVERITY OF ATOPIC DERMATITIS? ATOPIC DERMATITIS (AD - ATOPIC ECZEMA) IS A CHRONIC INFLAMMATORY DERMATOSIS RESULTING FROM COMPLEX GENETIC, EPIGENETIC AND ENVIRONMENTAL INTERACTIONS WITH AN OVERLAPPING DEFECT IN THE EPIDERMAL BARRIER.AD IS ONE OF THE MOST COMMON INFLAMMATORY DERMATOSES IN CHILDREN AND ADULTS. AIM: THE AIM OF THE STUDY WAS TO ASSESS THE RELATIONSHIP BETWEEN SERUM BASAL TRYPTASE (SBT) AND TOTAL IGE (TIGE) LEVEL IN BLOOD SERUM AND THE SEVERITY OF LESIONS (SCORAD; SCORING ATOPIC DERMATITIS). MATERIALS AND METHODS: THE STUDY WAS PERFORMED IN THE GROUP OF ADULT PATIENTS (57 PEOPLE, F/M: 30/27; AVERAGE AGE: 37.5 YEARS) AND IN THE CONTROL GROUP (10 PEOPLE, K/M: 6/4; AVERAGE AGE: 44 YEARS). DIAGNOSIS OF ATOPIC DERMATITIS WAS ESTABLISHED BY A DERMATOLOGIST-ALLERGIST SPECIALIST BASED ON THE CRITERIA OF HANIFIN AND RAJKA. THE SEVERITY OF LESIONS WAS DETERMINED ON THE SCORAD SCALE (SCORING ATOPIC DERMATITIS). RESULTS: THE DISTRIBUTION OF TRYPTASE CONCENTRATION DID NOT DIFFER STATISTICALLY SIGNIFICANTLY BETWEEN PATIENTS WITH VARIOUS DISEASE SEVERITY AND THE CONTROL GROUP ALSO THE SEVERITY OF SKIN LESIONS WAS SIGNIFICANTLY HIGHER (P<0.001) IN PATIENTS WHOSE TIGE LEVEL EXCEEDED 3500 IU / ML. CONCLUSION. SBT DID NOT PROVE TO BE A USEFUL BIOMARKER IN ASSESSING. CONCLUSIONS: SBT DID NOT PROVE TO BE A USEFUL BIOMARKER IN ASSESSING SEVERITY OF AD. THE PRESENT STUDY DEMONSTRATED THAT IN THE PATIENTS WITH ATOPIC DERMATITIS THE CONCENTRATION OF TOTAL IGE WAS CORRELATED WITH SEVERITY OF THE DISEASE SYMPTOMS. 2020 16 6871 20 [PATHOGENETIC IMPORTANCE OF HELICOBACTER PYLORI INFECTION]. H. PYLORI ARE ETIOLOGICAL FACTOR OF HUMAN ACUTE AND CHRONIC GASTRITIS. DEPENDING ON PATHOGENIC FACTORS OF MICROORGANISM AND POLYMORPHISM OF HUMAN GENES, CHRONIC GASTRITIS CAN BE A CAUSE FOR ULCERATIVE ENTERITIS OF THE DUODENUM OR STOMACH, GASTRIC ADENOCARCINOMA AND MALT-LYMPHOMA DEVELOPMENT. WE REVEALED GENETIC FEATURES OF BACTERIA, DETERMINED THE INTENSITY OF INFLAMMATION, SUCH AS PATHOGENIC FACTORS--CAG, PLASTIC REGION OF THE GENOME AND ADHESIN CODING GENES. EPIGENETIC CHANGES, FOR EXAMPLE THE METHYLATION OF E-CADHERIN GENE ASSOCIATED WITH H PYLORI, ARE CRUCIAL FOR CARCINOGENESIS. THEREBY, PREDISPOSITION OF CHRONIC GASTRITIS ASSOCIATED WITH H. PYLORI TO ULCERATIVE ENTERITIS OF THE DUODENUM, ULCERATIVE STOMACH DISEASE OR GASTRIC ADENOCARCINOMA DEPENDS ON TOPOGRAPHY, THE INTENSITY OF INFLAMMATION AND CHANGES OF ACID PRODUCTION IN THE STOMACH. 2012 17 4272 30 MICROBIOME AND BEHCET'S DISEASE: A SYSTEMATIC REVIEW. THE AIM OF THIS REVIEW WAS TO DESCRIBE THE CHANGES IN THE MICROBIOTA OF PATIENTS WITH BEHCET'S DISEASE (BD) AND THE MECHANISMS INVOLVED IN THE RELATIONSHIP BETWEEN THE MICROBIOME AND IMMUNITY IN BD. A SYSTEMATIC SEARCH FOR RELEVANT ARTICLES WAS MADE ON PUBMED AND THE COCHRANE LIBRARY DATABASE USING THE FOLLOWING TERMS: "MICROBIOTA AND BEHCET'S DISEASE" OR "MICROBIOME AND BEHCET'S DISEASE". SIXTEEN ARTICLES WERE INCLUDED IN A QUALITATIVE SYNTHESIS. THIS SYSTEMATIC REVIEW ON THE MICROBIOME AND BEHCET'S DISEASE UNDERLINES THE PRESENCE OF GUT DYSBIOSIS IN BD PATIENTS. THIS DYSBIOSIS IS MARKED BY (I) A DECREASE IN BUTYRATE-PRODUCING BACTERIA, WHICH COULD AFFECT T CELL DIFFERENTIATION AND EPIGENETIC REGULATION OF IMMUNE-RELATED GENES, (II) A MODIFICATION OF TRYPTOPHAN-METABOLISING BACTERIA, WHICH COULD BE LINKED TO DYSREGULATED IL-22 SECRETION, AND (III) A DECREASE IN BACTERIA KNOWN TO HAVE ANTI-INFLAMMATORY PROPERTIES. REGARDING ORAL MICROBIOTA, THIS REVIEW UNDERLINES THE POSSIBLE ROLE OF STREPTOCOCCUS SANGUINIS THROUGH MOLECULAR MIMICRY AND NETOSIS. CLINICAL STUDIES OF BD HAVE SHOWN THAT (I) NEED FOR DENTISTRY IS ASSOCIATED WITH A MORE SEVERE COURSE IN BD, AND (II) ANTIBIOTIC-SUPPLEMENTED MOUTHWASH REDUCES PAIN AND ULCERS. FECAL TRANSPLANTATION OF BD PATIENTS' MICROBIOTA INTO MOUSE MODELS LED TO DECREASED SCFA PRODUCTION, NEUTROPHIL ACTIVATION, AND TH1/TH17 RESPONSES.RECIPIENT MICE SHOWED EXACERBATED EXPERIMENTAL AUTOIMMUNE UVEITIS (EAU) AND EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE). IN HERPES VIRUS SIMPLEX-1 (HSV-1) INFECTED MICE MIMICKING BD, ADMINISTRATION OF BUTYRATEPRODUCING BACTERIA IMPROVED SYMPTOMS AND IMMUNE VARIABLES. THE MICROBIOME MAY THUS BE INVOLVED IN BD THROUGH IMMUNITY REGULATION AND EPIGENETIC MODIFICATIONS. 2023 18 99 29 A PUTATIVE "HEPITYPE" IN THE ATM GENE ASSOCIATED WITH CHRONIC LYMPHOCYTIC LEUKEMIA RISK. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS ARE CHARACTERIZED BY SEVERAL CHROMOSOMAL LESIONS. SOME OF THESE ABERRATIONS IMPLY CHROMOSOME BREAKS AS A RESULT OF UNREPAIRED DOUBLE STRAND BREAKS (DSBS) IN THE DNA. THE ATM (ATAXIA TELANGIECTASIA-MUTATED) PROTEIN IS THE PRINCIPAL INTEGRATOR OF CELLULAR RESPONSES TO DSBS. ATM DELETION IS ALSO AN ADVERSE PROGNOSTIC FACTOR IN CLL. TAKING THIS INTO ACCOUNT, WE EVALUATED IF GENETIC AND/OR EPIGENETIC VARIATION IN THE ATM GENE MAY MODULATE THE INDIVIDUAL SUSCEPTIBILITY TO DEVELOP CLL. OUR CASE-CONTROL ASSOCIATION STUDY WAS PERFORMED IN A LARGE SPANISH POPULATION OF 1,503 INDIVIDUALS, INCLUDING 742 PATIENTS WITH CLL AND 761 CONTROLS. WE IDENTIFIED ONE HAPLOTYPE WITHIN THE ATM GENE THAT CONFERS AN INCREASED RISK OF CLL DEVELOPMENT (OR = 1.33; 95% CI: 1.10-1.60). TWO POLYMORPHISMS OF THIS ATM HAPLOTYPE ELIMINATED ONE CPG SITE EACH IN INTRONS 15 AND 61, CAUSING CHANGES IN DNA METHYLATION PATTERN. THESE DATA PROVIDE THE FIRST EVIDENCE FOR THE EXISTENCE OF A PUTATIVE "HEPITYPE" IN THE ATM GENE ASSOCIATED WITH CLL RISK. 2011 19 1395 34 DIET AND MICROBIOME IN THE BEGINNING OF THE SEQUENCE OF GUT INFLAMMATION. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC INFLAMMATORY CONDITION OF THE GASTROINTESTINAL TRACT DUE, AT LEAST PARTIALLY, TO AN ABERRANT AND EXCESSIVE MUCOSAL IMMUNE RESPONSE TO GUT BACTERIA IN GENETICALLY-PREDISPOSED INDIVIDUALS UNDER CERTAIN ENVIRONMENTAL FACTORS. THE INCIDENCE OF IBD IS RISING IN WESTERN AND NEWLY INDUSTRIALIZED COUNTRIES, PARALLELING THE INCREASE OF WESTERNIZED DIETARY PATTERNS, THROUGH NEW ANTIGENS, EPITHELIAL FUNCTION AND PERMEABILITY, EPIGENETIC MECHANISMS (E.G., DNA METHYLATION), AND ALTERATION OF THE GUT MICROBIOME. ALTERATION IN THE COMPOSITION AND FUNCTIONALITY OF THE GUT MICROBIOME (INCLUDING BACTERIA, VIRUSES AND FUNGI) SEEMS TO BE A NUCLEAR PATHOGENIC FACTOR. THE MICROBIOME ITSELF IS DYNAMIC, AND THE CHANGES IN FOOD QUALITY, DIETARY HABITS, LIVING CONDITIONS AND HYGIENE OF THESE WESTERN SOCIETIES, COULD INTERACT IN A COMPLEX MANNER AS MODULATORS OF DYSBIOSIS, THEREBY INFLUENCING THE ACTIVATION OF IMMUNE CELLS' PROMOTING INFLAMMATION. THE MICROBIOME PRODUCES DIVERSE SMALL MOLECULES VIA SEVERAL METABOLIC WAYS, WITH THE FIBER-DERIVED SHORT-CHAIN FATTY ACIDS (I.E., BUTYRATE) AS MAIN ELEMENTS AND HAVING ANTI-INFLAMMATORY EFFECTS. THESE METABOLITES AND SOME MICRONUTRIENTS OF THE DIET (I.E., VITAMINS, FOLIC ACID, BETA CAROTENE AND TRACE ELEMENTS) ARE REGULATORS OF INNATE AND ADAPTIVE INTESTINAL IMMUNE HOMEOSTASIS. AN EXCESSIVE AND UNHEALTHY CONSUMPTION OF SUGAR, ANIMAL FAT AND A LOW-VEGETABLE AND -FIBER DIET ARE RISK FACTORS FOR IBD APPEARANCE. FURTHERMORE, METABOLISM OF NUTRIENTS IN INTESTINAL EPITHELIUM AND IN GUT MICROBIOTA IS ALTERED BY INFLAMMATION, CHANGING THE DEMAND FOR NUTRIENTS NEEDED FOR HOMEOSTASIS. THIS ROLE OF FOOD AND A REDUCED GUT MICROBIAL DIVERSITY IN CAUSING IBD MIGHT ALSO HAVE A PROPHYLACTIC OR THERAPEUTIC ROLE FOR IBD. THE RELATIONSHIP BETWEEN DIETARY INTAKE, SYMPTOMS, AND BOWEL INFLAMMATION COULD LEAD TO DIETARY AND LIFESTYLE RECOMMENDATIONS, INCLUDING DIETS WITH ABUNDANT FRUITS, VEGETABLES, OLIVE OIL AND OILY FISH, WHICH HAVE ANTI-INFLAMMATORY EFFECTS AND COULD PREVENT DYSBIOSIS AND IBD. DIETARY MODULATION AND APPROPRIATE EXCLUSION DIETS MIGHT BE A NEW COMPLEMENTARY MANAGEMENT FOR TREATMENT AT DISEASE FLARES AND IN REFRACTORY PATIENTS, EVEN REDUCING COMPLICATIONS, HOSPITALIZATIONS AND SURGERY, THROUGH MODIFYING THE LUMINAL INTESTINAL ENVIRONMENT. 2021 20 4274 34 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