HUMAN GUT MICROBIOTA

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1 HUMAN GUT MICROBIOTA Patrizia Brigidi Department of Pharmaceutical Sciences, University of Bologna, Italy The Gut-Liver axis: a bidirectional relation in health and disease Bologna, Palazzo Re Enzo, October 4 th -5 th, 2012

2 HUMAN INTESTINAL MICROBIOTA we are 90% bacteria ( ) our bacterial counterpart provides essential features we have not evolved: enhancement of the digestive efficiency vitamin synthesis competitive barrier against colonization/invasion development, education and function of the immune system strengthening of GIT epithelium impermeability detoxification of xenobiotics gut-brain axis (brain development and function)

3 PERVASIVE SYSTEMIC PHYSIOPATHOLOGICAL INFLUENCE OF GM Gut Microbiota Gut Immune System INFLAMMATION Liver Immune System AdiposeTissue Muscle Brain

4 METACOMMUNITY STRUCTURE PHYLOGENETIC STRUCTURE > 1000 species 6 (out of 100) bacterial phyla Firmicutes (65%), Bacteroidetes (25%) Actinobacteria (5%), Proteobacteria (<8%), Fusobacteria (1%) and Verrucomicrobia (1%)

5 METACOMMUNITY STRUCTURE FUNCTIONAL DIVERSITY MICROBIOME (collective genome of the microbiota) 10 6 GENES 58% KNOWN 42% UNKNOWN carbohydrate metabolism (CAZymes) energy metabolism amino acid metabolism biosynthesis of secondary metabolites metabolism of cofactors and vitamins WE ARE FAR TO COMPREHEND THE DEGREE OF FUNCTIONAL COMPLEXITY

6 INDIVIDUAL MICROBIOTA EACH HEALTHY SUBJECT POSSESSES A SPECIFIC AND DYNAMIC SUBSET OF HUNDREDS OF SPECIES 70% of species phylotypes are subject specific no phylotype is present at more than 0.5% of abundance in all subjects THE INDIVIDUAL MICROBIOTA SHOWS AN ASTONISHING LEVEL OF SPECIFICITY AT PHYLOGENETC LEVEL MICROBIAL FINGERPRINT

7 FUNCTIONAL SPECIFICITY 25% OF THE MICROBIOME CODES FOR A PECULIAR SET OF INDIVIDUAL-SPECIFIC FUNCTIONAL GENES 25% VARIABLE 75% CONSTANT THIS INDIVIDUAL METAGENOME SPECIFICITY PROVIDES AN EXPANDED AND DYNAMIC VIEW OF THE HUMAN INTERPERSONAL GENETIC VARIATION

8 CORE MICROBIOTA CONSTANT AND SHARED FRACTION OF HUMAN MICROBIOTA AND MICROBIOME BELIEVED AS FUNDAMENTAL TO SUPPORT HUMAN HEALTH PHYLOGENETIC CORE: 2% of microbial species of an individual is shared by at least 50% of the population FUNCTIONAL CORE: 38% of the assigned bacterial genes are shared by at least 50% of the population Phylogenetic and functional core are too subtle to support the supposed strategic role in mutualism individual specificity and plasticity must be essential microbiota features

9 WE WERE BORN STERILE IN A MICROBIAL WORLD vaginal flora (mother) environmental microorganisms fecal flora (mother) food microorganisms skin flora (mother) mother milk INDIVIDUAL GENOME INFANT MICROBIOTA WEANING ADULT INDIVIDUAL MICROBIOTA (from 3 rd year to all life) GENERAL FEATURES OF THE INFANT TYPE MICROBIOTA -highly dynamic -high interpersonal variation -low complexity -Bifidobacterium dominated -presence of environmental aerobes

10 MICROBIOTA PLASTICITY THE INDIVIDUAL MICROBIOTA COMPOSITION CONTINUOUSLY CHANGES IN RESPONSE TO EXTRINSIC AND INTRINSIC VARIABLES DIET ENV. FACTORS (env. microbes-geography-climate sanitization-medication) MICROBIOTA MAKE-UP GIT ENVIRONMENT (inflammation-disease) HOST GENETICS AGE

11 NORMAL TEMPORAL VARIATION EXTEND OF THE MICROBIOTA DYNAMICS - 14 FREE LIVING PEOPLE- 120 DAYS MICROBIOTA MAKE-UP 163 PHYLOTYPES 2205 IDENTIFIED GENES DEGREE OF PLASTICITY 74.6% PHYLOTYPES AND 36% GENES WERE VARIABLE McNulty et al., Sci.Transl.Med., 2011

12 DIET AND MICROBIOTA DYNAMICS THE MOST REMARKABLE EXAMPLE OF MICROBIOTA PLASTICITY IS ITS CAPACITY TO RAPIDLY RESPOND TO DIETARY CHANGES PROTEINS TYPE OF INGESTED FERMENTABLE CARBOHYDRATES MICROBIOTA MAKE-UP CARBOHYDRATES FAT

13 HOW MICROBIOTA RESPONDS TO DIET DIET SHAPES THE MICROBIOTA AND ITS VAST COLLECTION OF GENES IN A DRAMATIC AND REPRODUCIBLE WAY FAST: dietary changes occur and reverse in 1-3 days INDIVIDUAL MICROBIOTA SPECIFIC: response to dietary changes is influenced by the initial species composition of the individual microbiota SHORT-TERM AND LONG-TERM RESPONDERS: while some bacterial groups respond rapidly to diet, others are modulated exclusively by long-term dietary changes (enterotypes) THE INTESTINAL MICROBIOTA CONFIGURES ITS PHYLOGENETIC PROFILE TO OPTIMIZE ITS CAPACITY TO METABOLIZE DIETARY COMPONENTS Caporaso et al., Genome Biol., 2011

14 THE METAORGANISM PERFORMANCES THE METABOLISM OF DIETARY COMPOUNDS BY GUT MICROORGANISMS IS A KEY PROCESS FOR THE HOST TO MAXIMIZE THE EXTRACTION OF ENERGY FROM DIET indigestible plant polysaccharides SCFAs 5-15% of the total energy required THE MICROBIOTA FLUCTUATIONS IN RESPONSE TO DIET PROVIDE THE HOST WITH THE CAPABILITY TO READILY ADAPT TO DIETARY CHANGES, OPTIMIZING THE NUTRIENT METABOLISM

15 WESTERN-AFRICAN DIETS WESTERN DIET HIGH FAT HIGH PROTEIN HIGH SUGAR FOOD PROCESSING FOOD STORING RURAL AFRICAN DIET LOW FAT STARCH AND PLANT POLYSACCHARIDE-RICH CONTAMINATED HOMEMADE PROMPTLY CONSUMED LOCALLY PRODUCED MICROBIOTA MAKE-UP + Firmicutes + Proteobacteria LOW FUNCTIONAL AND PHYLOGENETIC DIVERSITY + Bacteroidetes + Actinobacteria HIGH FUNCTIONAL AND PHYLOGENETIC DIVERSITY De Filippo et al., PNAS, 2010

16 ENVIRONMENTAL MICROBES AND MICROBIOTA DYNAMICS THE INTESTINAL MICROBIOTA SHOWS A SECOND DEGREE OF PLASTICITY IN RESPONSE TO ENVIRONMENTAL BACTERIA FOOD MICROBES MICROBES FROM LIVESTOCK MICROBIOTA MAKE-UP MICROBES FROM DOMESTIC ANIMALS MICROBES FROM SOIL/WATER INFECTIONS BY PATHOGENS

17 OLD FRIEND HYPOTHESIS CONTAMINATED FOOD PERINATAL PERIOD FECES OLD FRIENDS LIVESTOCK - SFB (Cl related) - C. leptum (Cl IV) - C. coccoides (Cl XIV) MICROBIOTA MAKE-UP THE EXPOSURE TO THE OLD FRIENDS IS ESSENTIAL FOR THE FINE TUNING OF OUR IMMUNOLOGICAL ASSET FROM THE EARLIEST STAGES OF LIFE

18 AGE-DEPENDENT VARIATION THE INTESTINAL MICROBIOTA SHOWS A DEVELOPMENT TRAJECTORY IN THE COURSE OF HUMAN LIFE SPECIFIC NUTRITIONAL AND IMMUNOLOGICAL NEEDS OF THE HUMAN BEING AT DIFFERENT STAGES OF DEVELOPMENT INFANT-TYPE enriched in genes involved in folate biosynthesis and milk digestion; enriched in immunomodulating Bifidobacteria and virulent Proteobacteria ADULT-TYPE enriched in genes involved in vitamin B7 and B1 biosynthesis; higher phylogenetic and functional diversity to cope with a higher dietary complexity ELDERLY????

19 ADAPTABILITY AND RESILIENCE IN A MUTUALISTIC CONTEXT, THE PLASTICITY OF THE HUMAN INTESTINAL MICROBIOTA GUARANTEES A RAPID ADAPTATION OF THE SUPER-ORGANISM IN RESPONSE TO DIET, AGE AND, AT THE SAME TIME, REPRESENTS AN ESSENTIAL PREREQUISITE TO EDUCATE OUR IMMUNE SYSTEM TO HOMEOSTASIS THE MICROBIOTA CAN BE REGARDED AS AN EPIGENETIC FACTOR THAT, SHAPED BY THE ENVIRONMENT, CONFERS ADAPTABILITY (LAMARCKIAN) AND RESILIENCE TO THE HUMAN METAORGANISM

20 MUTUALISM BREAKDOWN Candela et al., Trends Microbiol 2012

21 OBESOGENIC MICROBIOTA Candela et al., Trends Microbiol 2012

22 IBD MICROBIOTA DECREASED BIODIVERSITY + Proteobacteria (Enterobacteria), Fusobacteria - Clostridium cluster XIVa and IV (Faecalibacterium prausnitzii) - Ruminococcaceae

23 OPEN QUESTIONS AND CONCLUSIONS WHAT IS THE REAL EXTENSION AND THE FUNCTION OF THE BIOLOGICAL DARK MATTER OF THE HUMAN MICROBIOME? WHAT ARE THE LIMITS OF THE «NORMAL VARIABILITY» OF THE HUMAN MICROBIOTA IN THE COURSE OF HUMAN LIFE? WHAT ARE THE MECHANISMS THAT FORCE THE RUPTURE OF THE MUTUALISTIC SYMBIOTIC RELATIONSHIP? Implement dietary strategies to preserve mutualism over time or to support habitat restoration for recovering the microbiota ecosystem services strategic for our health

24 THANK YOU FOR YOUR ATTENTION