HUMAN INTESTINAL MICROBIOTA

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1 TOP TEN IN GASTROENTEROLOGIA - ISEO 13_14 14 MARZO 2015 Microbiota intestinale: un decennio di conquiste marco.candela@unibo.it candela@unibo it

2 HUMAN INTESTINAL MICROBIOTA we are 90% bacteria ( ) and our bacterial counterpart provides essential features we have not evolved enhancement of the digestive efficiency and modulation of energetic homeostasis vitamin synthesis competitive barrier against colonization/invasion i development, education and function of the immune system strengthening of the GIT epithelium impermeability detoxification of xenobiotics central nervous system modulation endocrine system modulation

3 WHAT IS MISSING IN GERM-FREE MICE

4 PHYLOGENETIC DIVERSITY > 1000 species 6 (out of 100) bacterial phyla Firmicutes, Bacteroidetes : 90% Actinobacteria, Proteobacteria, Fusobacteria and Verrucomicrobia : 10%

5 GUT METAGENOME FUNCTIONAL DIVERSITY MICROBIOME 10 6 GENES 58% KNOWN 42% UNKNOWN carbohydrate metabolism (CAZymes) energy e metabolism amino acid metabolism biosynthesis of secondary metabolites metabolism of cofactors and vitamins

6 SUBSTRATES OF THE GM CAZymes ARSENAL thousands of enzymes while we possess only 17 El Kaoutary et al., Nature Rev not accessible to the human glycobiome! The GM possesses a broad glycobiome complexity, complementing the limited diversity of the human glycobiome and enhancing the superorganism capacity to metabolize complex polysaccharides

7 WE ARE BORN STERILE IN A MICROBIAL WORLD environmental microorganisms Proteobacteria -Streptococcus -Staphylococcusp y -Lachnospiraceae -Ruminococcaceae -Bacteroidaceae -Bifidobacteriaceae -Proteobacteria (dead) mother s milk microorganisms mother s milk vaginal flora (mother) Lactobacillaceae VIDUAL GENOME INDI fecal flora (mother / father) Gut microbiota skin flora (mother / father) Streptococcus, Staphylococcus mouth flora (mother / father) Streptococcus, Staphylococcus, Proteobacteria, Actinobacteria, Bacteroidetes INFANT MICROBIOTA WEANING ADULT INDIVIDUAL MICROBIOTA (from 1 st year to all life) - low diversity - highly dynamic - Bifidobacterium-dominated - presence of aerobes - Bacteroidetes and Veillonella as minor components

8 there is a strong selection towards a readily changeable individual microbiome profile ECOSYSTEM PLASTICITY UNIQUENESS OF OUR HISTORY, PHYSIOLOGY AND LIFESTYLE peculiar structure and temporal dynamics of the individual intestinal microbiota provide microbiota ecosystem services in the face of personalized physiology, immune system, environmental or dietary exposure and lifestyle

9 The gut microbiota is a multistable system Candela M., Biagi E., Maccaferri S., Turroni S. and Brigidi P. Intestinal microbiota is a plastic factor responding to environmental changes. Trends Microbiol Aug; 20(8): MUTUALISM n different compositional layouts OPTIMIZATION OF SUPERORGANISM S METABOLIC AND IMMUNOLOGICAL PERFORMANCES

10 LIFESTYLE IMPACTS THE GM ON A DAILY TIMESCALE two subjects, everyday sampling, ios App to record everyday lifestyle and dietary habits David et al., Genome Biol PERIOD OF STATIONARY GM DYNAMICS median distance between samples rapidly reaches the asymptote rapid variation in niche size due to daily fluctuation in diet ABRUPT CHANGES IN GM CONFIGURATION disruptive windows resulting in broad community disturbance: travel to developing nation (A), Salmonella infection (B): A) reversible environmental disturbance B) non-reversible community disturbance gut microbiome variation involves changes in relative abundance of already present bacteria (allocative efficiency), colonization of new species (dynamic efficiency) is relatively rare

11 TEMPORAL VARIABILITY IS A PERSONALIZED MICROBIOME FEATURE 85 adults, weekly sampling, 3 months, recording of lifestyle and dietary habits Flores et al., Genome Biol INDIVIDUAL VARIATION IN THE DEGREE OF GM TEMPORAL VARIABILITY INDIVIDUALS WITH MORE STABLE GM COMPOSITION ARE INDIVIDUALS WITH MORE DIVERSE COMMUNITY BACTEROIDACEAE WERE THE MOST ABUNDANT IN STABLE INDIVIDUALS, CLOSTRIDIACEAE AND LACTOBACILLACEAE IN VARIABLE INDIVIDUALS

12 The gut microbiota describes an adaptive trajectory along human aging Candela M., Biagi E., Turroni S., Maccaferri S., Figini P., Brigidi P. Dynamic efficiency of the human intestinal microbiota. Citi Critical lreviews in Microbiology, Sept, Online published. GUT MICROBIOTA CHANGES ITS PHYLOGENETIC AND FUNCTIONAL PROFILE FROM INFANCY TO ELDERLY PROVIDING THE HOST WITH ECOLOGICAL SERVICES CALIBRATED FOR EACH STAGE OF LIFE

13 CONVENTIONALIZATION OF GERM-FREE MICE CONVENTIONALIZATION OF GERM-FREE MICE ALLOWS THE RECOVERY OF THE LOST MICROBIOTA-DEPENDENT ECOLOGICAL SERVICES SPECIFIC TIME WINDOW ENTIRE LIFE SPAN IMMUNE FUNCTION (INFANCY) REGULATION OF CENTRAL NERVOUS SYSTEMS AND BEHAVIOR (INFANCY) REGULATION OF SEX HORMONES (PUBERTY) NUTRITION PROTECTION GIT STRUCTURE

14 Infant type microbiota: Bifidobacterium dominated, simple and readily changeable INFANT TYPE MICROBIOTA IS STRUCTURED TO COPE WITH INFLAMMATION, BEING CO EVOLVED TO PRIME THE EARLY IMMUNE SYSTEM IN THE CONTEXT OF TRANSIENT INFLAMMATORY RESPONSES Centanni M., Turroni S., Consolandi C., Rampelli S., Peano C., Severgnini M., Biagi E., Caredda G., De Bellis G., Brigidi P., Candela M. The enterocyte associated intestinal microbiota of breast fed infants and adults responds differently to a TNF α mediated proinflammatory stimulus. PLoS ONE Nov; 8(11): e81762.

15 Adult type microbiota: complex and adaptable ecosystem dominated by Firmicutes and Bacteroidetes HIGHLY DIVERSE, THE ADULT-TYPE GM IS AN ADAPTIVE COMMUNITY FUNCTIONALLY STRUCTURED TO DEGRADE A VAST RANGE OF INDIGESTIBLE DIETARY AND HOST SUBSTRATES RANGE OF METABOLIC ENDPOINTS WITH THE POTENTIAL TO MODULATE AND REGULATE SEVERAL ASPECTS OF OUR PHYSIOLOGY ENERGETIC HOMEOSTASIS IMMUNE HOMEOSTASIS

16 HOST POLYSACCHARIDES STARCH PLANT CELL WALL cellulose AMINO ACIDS Ruminococci SOLUBLE CELL WALL POLYSACCHARIDES hemicellulose, xylan, pectin, mannans, inulin, fructans ACETATE Bacteroidetes ACETATE low CO 2 Clostridium clusters IV and XIVa Faecalibacterium prausnitzii, Butyrrivibrio, Roseburia, Eubacterium rectale proteolytic clostridia and Bacteroidetes (Alistipes) SUCCINATE PROPIONATE BUTYRATE methanogens Methanobrevibacter smithii CH 4 H 2 sulfate-reducing bacteria Bilophila wadsworthia acetogens Blautia hydrogenotrophica ACETATE SCFA BCFA PHENOLIC AND INDOLIC METABOLITES METHYLAMINES H 2 S

17 IMPACT OF DIETARY FAT ON THE GUT MICROBIAL COMMUNITIES DIETARY FATS BILE SECRETION BILE ACIDS IN THE GUT Firmicutes Clostridia, Erysipelotrichi SECONDARY BILE ACIDS Bacteroidetes Enterobacteriaceae MICROBIOTA MAKE-UP sulfate-reducing bacteria Bilophila wadsworthia H 2 S

18 SCFA POSSESS A KEY MULTIFACTORIAL ROLE IN HUMAN BIOLOGY, METABOLIC HOMEOSTASIS Tilg et al., Gut 2014 peptide Pyy expression (2): inhibition of gut motility; increase of intestinal transit rate; reduction of energy harvest from diet glucagon-like peptide 1 expression (3): increase of insulin sensitivity ENERGY SOURCE FOR COLONOCYTES intestinal gluconeogenesis activation (5): favors glucose control expression of fasting-induced adipose factor (6): favors fat storage suppression of insulin signaling in adipose tissue (4)

19 SCFA POSSESS A KEY MULTIFACTORIAL ROLE IN HUMAN BIOLOGY, REGULATION OF THE HOST IMMUNE FUNCTION Tilg et al., Gut 2014 development of colonic and extrathymic Treg regulation of bone marrow hematopoiesis regulation of dendritic cell function Immune homeostasis

20 GM PLASTIC RESPONSE TO DIET DIFFERENT GM COMPONENTS SHOW A DIFFERENT PERFORMANCE IN THE DEGRADATION OF DIETARY SUBSTRATES substrate selection for the better metabolizers

21 GM-HOST CO-METABOLIC LAYOUTS diets regulates microbiota composition and metabolic output with a final impact on host physiology complex polysaccharides SACCHAROLYTIC METABOLISM amino acids PROTEOLYTIC METABOLISM animal fat FAT ADAPTATION highly diverse community of low diverse community selection of a low diverse polysaccharide-degrading Bacteroidetes and Clostridia establishing enriched in specialized proteolytic Alistipes and Clostridia community made of bile resistant Erysipelotrichi, Bilophila wadsworthia, syntrophy in the gut Enterobacteriaceae SUCCINATE SCFA CH4 SCFA PHENOLIC AND INDOLIC METABOLITES SECONDARY BILE ACIDS Health BCFA METHYLAMINES Disease promoting associated H 2 S

22 THE GM-HOST MUTUALISTIC AGREEMENT THE GM-HOST MUTUALISTIC AGREEMENT INVOLVES THE CONSTANT CONSUMPTION OF PLANT FOODS WITH AN OCCASIONAL O CONSUMPTION O OF ANIMAL FOODS PALEOLITHIC AND NEOLITHIC DIETS (99% of our evolutionary history) Providing the host with SCFA from indigestible plant polysaccharides GM allows the host to improve energy extraction from diet and regulates energy homeostasis

23 THE GM OF HADZA HUNTER-GATHERERS A mirable example of GM-host adaptive co-evolution in response to diet FORAGING SUBSISTENCE - direct interface with the natural environment, deriving their wild food - no cultivation or domestication of plants and animals, minimal agricultural products from external sources, < 5% calories HEAVY PLANT BASED DIET - 70% of kcal from plant foods; 30% from bird and animal meat (dry season); - diet rich in polysaccharides, starch and protein while lean in fat; - wild foods: tubers, leafy green foliage, baobab fruit, berry, honey and meat Schnorr SL., Candela M., Rampelli S., Centanni M., Consolandi C., Basaglia G., Turroni S., Biagi E., Peano C., Severgnini M., Fiori J., Gotti R., De Bellis G., Luiselli D., Brigidi P., Mabulla A., Marlowe F., Crittenden A.N., Henry A.G. Gut microbiome from the Hadza hunter-gatherers. Nature Communication Apr; 5: 3654.

24 HADZA POSSESS A UNIQUE CONFIGURATION OF THEIR GM THAT CAN BE LINKED TO THEIR FORAGING LIFESTYLE

25 HADZA GM IS ADAPTED TO THEIR FORAGING LIFESTYLE GM FEATURE HOST NEEDS IN HADZA LAND HIGH BACTERIAL DIVERSITY ENRICHMENT IN FIBROLYTIC BACTERIA high abundance in xylan-degrading Prevotella, Treponema, unclassified Bacteroidetes and Clostridiales SEX-RELATED DIVERGENCE IN GM STRUCTURE higher h Treponema in Hadza women ABSENCE OF BIFIDOBACTERIUM ENRICHMENT OF OPPORTUNISTIC BACTERIA Proteobacteria and Spirochaetes HARD DIGESTIBLE FOOD HEAVY PLANT BASED DIET SEX DIFFERENCES IN DIET COMPOSITION (higher consumption of plant foods in women) ABSENCE OF AGRO-PASTORAL- DERIVED FOODS IMMUNE EDUCATION TO THE DIRECT INTERFACE WITH NATURAL ENVIRONMENT

26 MUTUALISM INTERRUPTION MUTUALISM Switch-like behavior, making sudden jumps from different steady states ANTIBIOTIC INTAKE IMMUNE DEREGULATION ABNORMAL DIETARY INTAKE INFECTION INFLAMMATION RUPTURE OF THE GM-HOST MUTUALISTIC AGREEMENT AND COMPROMISED HOST ENERGY BALANCE AND IMMUNE HOMEOSTASIS

27 AN INCREASE IN CALORIC INTAKE (HIGH FAT HIGH SUGAR DIET) SELECTS FOR OBESOGENIC GM HIGH FERMENTATIVE CAPACITY HIGH BILE ACID METABOLISM OVERALL INFLAMMATORY POTENTIAL INCREASE OF ENERGY HARVEST FROM FOOD MODULATION OF DIETARY FAT ABSORPTION METABOLIC ENDOTOXEMIA

28 GUT MICROBIOTA DYSBIOSES IN T2D Biagi E., Candela M., Soverini M., Quercia S., Consolandi C., Severgnini M., Fallucca F., Pianesi M., Pozzilli P., Rampelli S., Turroni S., Brigidi P. Modulation of gut microbiota dysbioses in type 2 diabetic patients by macrobiotic Ma-Pi 2 diet. IHMC. Luxembourg 2015 Depletion in health-promoting SCFA producers Higher load of pro-inflammatory Enterobacteriaceae and Collinsella Reduced production of arginine (insulinogenic) and higher alanine (associated with BMI and cholesterol level) Higher load of functions involved in immuno-escaping processes

29 GUT MICROBIOTA IN INFLAMMATORY DISEASES

30 VERY RECENT NATURE COMMENT

31 Microbial Ecology of Health UNIT Dept. Pharmacy and Biotechnology, University of Bologna, Italy Marco Candela Silvia Turroni Prof. Patrizia Brigidi Sara Quercia Matteo Soverini Simone Rampelli Elena Biagi