TOP TEN IN GASTROENTEROLOGIA ISEO 13 14 MARZO 2015TOP TEN IN GASTROENTEROLOGIA - ISEO 13_14 MARZO 2015
Microbiota intestinale:Microbiota intestinale: un decennio diun decennio di
conquisteconquistemarco candela@unibo [email protected]
HUMAN INTESTINAL MICROBIOTAwe are 90% bacteria (1013–1014) and our bacterial counterpart provideswe are 90% bacteria (10 10 ) and our bacterial counterpart provides
essential features we have not evolved
• enhancement of the digestive efficiency and modulation of energetic homeostasisenergetic homeostasis
• vitamin synthesis
titi b i i t l i ti /i i• competitive barrier against colonization/invasion
• development, education and function of the immune system• strengthening of the GIT epithelium impermeability
• detoxification of xenobiotics
• central nervous system modulation
• endocrine system modulationendocrine system modulation
WHAT IS MISSING IN GERM-FREE MICE
PHYLOGENETIC DIVERSITY
> 1000 species
6 (out of 100) bacterial phyla• Firmicutes, Bacteroidetes : 90%• Actinobacteria, Proteobacteria, Fusobacteria
and Verrucomicrobia : 10%and Verrucomicrobia : 10%
GUT METAGENOME FUNCTIONAL DIVERSITYDIVERSITY
MICROBIOME 106 GENES
58% KNOWN 42% UNKNOWN58% KNOWN 42% UNKNOWN • carbohydrate metabolism (CAZymes)• energy metabolisme e gy e abo s• amino acid metabolism• biosynthesis of secondary metabolites• metabolism of cofactors and vitamins• metabolism of cofactors and vitamins
SUBSTRATES OF THE GM CAZymes ARSENALthousands of enzymes while we possess only 17thousands of enzymes while we possess only 17
El Kaoutary et al., Nature Rev. 2013
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
WE ARE BORN STERILE IN A MICROBIAL WORLDWORLD
environmental microorganisms
vaginal flora (mother)
fecal flora (mother / father) Lactobacillaceae
Gut microbiota Proteobacteria
skin flora (mother / father)-Streptococcus-Staphylococcus
Streptococcus, Staphylococcus
Proteobacteria
mother’s milkmicroorganisms
mouth flora (mother / father)p y
-Lachnospiraceae-Ruminococcaceae-Bacteroidaceae-Bifidobacteriaceae
Streptococcus, Staphylococcus, Proteobacteria, Actinobacteria, Bacteroidetes
INFANT MICROBIOTAGE
NO
ME - low diversity
- highly dynamic- Bifidobacterium-dominated
f b
mother’s milk-Bifidobacteriaceae-Proteobacteria (dead)
INFANT MICROBIOTA
VID
UA
L G
WEANING - presence of aerobes - Bacteroidetes and Veillonella as minor components
ADULT INDIVIDUAL MICROBIOTA
IND
I p
(from 1st year to all life)
there is a strong selection towards a readily changeable individual microbiome profilechangeable individual microbiome profile
ECOSYSTEM PLASTICITY UNIQUENESS OF OUR HISTORY, PHYSIOLOGY AND LIFESTYLEPHYSIOLOGY 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
The gut microbiota is a multistable systemCandela M Biagi E Maccaferri S Turroni S and Brigidi P Intestinal microbiota is a plastic factor responding to environmentalCandela M., Biagi E., Maccaferri S., Turroni S. and Brigidi P. Intestinal microbiota is a plastic factor responding to environmental
changes. Trends Microbiol. 2012 Aug; 20(8): 385‐91.
MUTUALISM
n different compositional layoutsn different compositional layouts
OPTIMIZATION OF SUPERORGANISM’S METABOLIC AND IMMUNOLOGICAL PERFORMANCESIMMUNOLOGICAL PERFORMANCES
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. 2014
PERIOD OF STATIONARY GM DYNAMICS
di di t b t l idlmedian distance between samples rapidly reaches the asymptoterapid 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):nation (A), Salmonella infection (B):
A) reversible environmental disturbanceB) 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
TEMPORAL VARIABILITY IS A PERSONALIZED MICROBIOME FEATURE 85 adults, weekly sampling, 3 months, recording of lifestyle and dietary habits
Flores et al., Genome Biol. 2014
INDIVIDUAL VARIATION IN THE DEGREE OF GM TEMPORAL
VARIABILITYVARIABILITY
INDIVIDUALS WITH MOREINDIVIDUALS WITH MORE STABLE GM COMPOSITION
ARE INDIVIDUALS WITH MORE DIVERSE COMMUNITY
BACTEROIDACEAE WERE THE OS SMOST ABUNDANT IN STABLE
INDIVIDUALS, CLOSTRIDIACEAE AND LACTOBACILLACEAE INLACTOBACILLACEAE IN VARIABLE INDIVIDUALS
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 i bi t C iti l R i i Mi bi l 2013 S t O li bli h dmicrobiota. Critical Reviews in Microbiology, 2013. 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
CONVENTIONALIZATION OF GERM-FREE MICE
CONVENTIONALIZATION OF GERM-FREE MICE ALLOWS THE RECOVERY OF THE LOST MICROBIOTA-DEPENDENT ECOLOGICAL
SERVICESSERVICES
SPECIFIC TIME WINDOW ENTIRE LIFE SPAN
• IMMUNE FUNCTION (INFANCY)• REGULATION OF CENTRAL NERVOUS
S S O ( C )
• NUTRITION• PROTECTIONSYSTEM AND BEHAVIOR (INFANCY)
• REGULATION OF SEX HORMONES(PUBERTY)
PROTECTION• GIT STRUCTURE
Infant‐type microbiota: Bifidobacterium‐dominated, simple and readily changeablesimple and readily changeable
INFANT‐TYPE MICROBIOTA IS STRUCTURED TOCOPE WITH INFLAMMATION, BEING CO‐EVOLVEDTO PRIME THE EARLY IMMUNE SYSTEM IN THETO PRIME THE EARLY IMMUNE SYSTEM IN THECONTEXT OF TRANSIENT INFLAMMATORYRESPONSES
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 pro‐
inflammatory stimulus. PLoS ONE. 2013 Nov; 8(11): e81762.
Adult‐type microbiota: complex and adaptable ecosystem dominated by Firmicutes and Bacteroidetesdominated 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 SUBSTRATESINDIGESTIBLE DIETARY AND HOST SUBSTRATES
RANGE OF METABOLIC ENDPOINTS WITH THE POTENTIAL TO MODULATE AND REGULATE SEVERAL ASPECTS OF OUR PHYSIOLOGY
ENERGETIC HOMEOSTASIS IMMUNE HOMEOSTASIS
HOST POLYSACCHARIDES STARCH AMINO ACIDSPLANT CELL WALL
cellulose
RuminococciSOLUBLE CELL WALLPOLYSACCHARIDES
hemicellulose, xylan, pectin, mannans,inulin, fructans ACETATE
Bacteroidetes Clostridium clustersIV and XIVa
proteolyticclostridia and
low CO2 IV and XIVaFaecalibacterium prausnitzii,
Butyrrivibrio, Roseburia, Eubacterium rectale
Bacteroidetes(Alistipes) ACETATE
SUCCINATE
low CO2
PROPIONATE BUTYRATE
SUCCINATE
SCFA
acetogensmethanogens
PROPIONATE
H2BCFA
PHENOLIC AND INDOLICacetogens
Blautia hydrogenotrophicamethanogens
Methanobrevibacter smithii
sulfate-reducing bacteriaCH4
METHYLAMINES
INDOLIC METABOLITES
ACETATEbacteria Bilophila wadsworthia
H2S
CH4 ACETATE
IMPACT OF DIETARY FAT ON THE GUT MICROBIAL COMMUNITIESCOMMUNITIES
DIETARY FATS BILE SECRETION
BILE ACIDSIN THE GUT
MICROBIOTA
EnterobacteriaceaeFirmicutesClostridia, Erysipelotrichi
MAKE-UP
sulfate-reducing Bacteroidetes
H2SSECONDARY BILE ACIDS
bacteria Bilophila wadsworthia
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 ofpeptide 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
COLONOCYTESintestinal gluconeogenesis activation (5): favors glucose control
expression of fasting-induced adipose factor (6): favors fat storageexpression of fasting-induced adipose factor (6): favors fat storage
suppression of insulin signaling in adipose tissue (4)
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 hematopoiesisregulation of bone marrow hematopoiesis
regulation of dendritic cell function
Immune homeostasis
GM PLASTIC RESPONSE TO DIET
DIFFERENT GM COMPONENTS SHOW A DIFFERENT PERFORMANCE IN THE DEGRADATION OF DIETARY SUBSTRATES
substrate selection for the better metabolizers
GM-HOST CO-METABOLIC LAYOUTS
diets regulates microbiota composition and metabolic output with a final g p pimpact on host physiology
amino acids animal fatcomplexSACCHAROLYTIC
METABOLISMPROTEOLYTIC METABOLISM
FATADAPTATION
amino acids animal fatcomplex polysaccharides
highly diverse community of low diverse community selection of a low diverse polysaccharide-degrading
Bacteroidetes andClostridia establishing
yenriched in specialized
proteolytic Alistipes and Clostridia
community made of bile resistantErysipelotrichi,
Bilophila wadsworthia, syntrophy in the gut Enterobacteriaceae
SCFA PHENOLIC AND
H2SSECONDARY BILE ACIDS
SCFA PHENOLIC AND INDOLIC
METABOLITESSCFACH4SUCCINATE
BCFAMETHYLAMINESHealth
promotingDisease
associatedp g associated
THE GM-HOST MUTUALISTIC AGREEMENT
THE GM-HOST MUTUALISTIC AGREEMENT INVOLVES THE CONSTANT CONSUMPTION OF PLANT FOODS WITH AN
OCC S O CO S O O OO SOCCASIONAL CONSUMPTION OF ANIMAL FOODS
PALEOLITHIC AND NEOLITHIC DIETSPALEOLITHIC 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 homeostasisfrom diet and regulates energy homeostasis
THE GM OF HADZA HUNTER-GATHERERSA mirable example of GM-host adaptive co-evolution in p p
response to diet
FORAGING SUBSISTENCE
- direct interface with the natural environmentdirect interface with the natural environment, deriving their wild food
- no cultivation or domestication of plants and animals minimal agricultural products fromanimals, minimal agricultural products from external sources, < 5% calories
HEAVY PLANT BASED DIETHEAVY 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;
Schnorr SL.†, Candela M.†, Rampelli S., CentanniM., Consolandi C., Basaglia G., Turroni S., Biagi E.,Peano C., Severgnini M., Fiori J., Gotti R., De BellisG., Luiselli D., Brigidi P., Mabulla A., Marlowe F.,protein while lean in fat;
- wild foods: tubers, leafy green foliage, baobab fruit, berry, honey and meat
Crittenden A.N., Henry A.G. Gut microbiome fromthe Hadza hunter-gatherers. Nature Communication.2014 Apr; 5: 3654.
HADZA POSSESS A UNIQUE CONFIGURATION OF THEIR GM THAT CAN BE LINKED TO THEIR FORAGING LIFESTYLEGM THAT CAN BE LINKED TO THEIR FORAGING LIFESTYLE
HADZA GM IS ADAPTED TO THEIR FORAGING LIFESTYLELIFESTYLE
GM FEATURE HOST NEEDS IN HADZA LAND
ENRICHMENT IN FIBROLYTIC BACTERIA
HIGH BACTERIAL DIVERSITY HARD DIGESTIBLE FOOD
HEAVY PLANT BASED DIETENRICHMENT IN FIBROLYTIC BACTERIA high abundance in xylan-degrading Prevotella, Treponema, unclassified Bacteroidetes and Clostridiales
SEX-RELATED DIVERGENCE IN GM STRUCTURE hi h T i H d
SEX DIFFERENCES IN DIET COMPOSITION (higher consumption
f l t f d i )higher Treponema in Hadza women
ABSENCE OF BIFIDOBACTERIUM
of plant foods in women)
ABSENCE OF AGRO-PASTORAL-DERIVED FOODS
ENRICHMENT OF OPPORTUNISTIC BACTERIA
IMMUNE EDUCATION TO THE DIRECT INTERFACE WITH NATURAL ENVIRONMENTProteobacteria and Spirochaetes NATURAL ENVIRONMENT
MUTUALISM INTERRUPTION
MUTUALISM
Switch-like behavior, making sudden jumps from different steady states
ABNORMAL IMMUNE
DEREGULATIONDIETARY INTAKE
INFLAMMATIONINFECTIONANTIBIOTIC
INTAKE
RUPTURE OF THE GM-HOST MUTUALISTIC AGREEMENT AND COMPROMISED HOST ENERGY BALANCE AND IMMUNE
HOMEOSTASISHOMEOSTASIS
AN INCREASE IN CALORIC INTAKE (HIGH FAT – HIGH SUGAR DIET) SELECTS FOR OBESOGENIC GMDIET) SELECTS FOR OBESOGENIC GM
HIGH FERMENTATIVE INCREASE OF ENERGY HIGH FERMENTATIVE CAPACITY
HIGH BILE ACID
HARVEST FROM FOOD
MODULATION OF DIETARY METABOLISM
OVERALL INFLAMMATORY POTENTIAL
FAT ABSORPTION
METABOLIC ENDOTOXEMIAPOTENTIAL ENDOTOXEMIA
GUT MICROBIOTA DYSBIOSES IN T2D Biagi E., Candela M., Soverini M., Quercia S., Consolandi C., Severgnini M., Fallucca F., Pianesi M., Pozzilli P.,
S S f 2Rampelli S., Turroni S., Brigidi P. Modulation of gut microbiota dysbioses in type 2 diabetic patients by macrobioticMa-Pi 2 diet. IHMC. Luxembourg 2015
Depletion in health-promoting SCFA producers
Reduced production of arginine (insulinogenic) and higher alanine (associated with BMI and cholesterol level)
Higher load of pro-inflammatory Enterobacteriaceae and Collinsella
level)
Higher load of functions involved in immuno-escaping processesEnterobacteriaceae and Collinsella immuno escaping processes
GUT MICROBIOTA IN INFLAMMATORY DISEASES
VERY RECENT NATURE COMMENT
Microbial Ecology of Health UNITDept Pharmacy and Biotechnology University of Bologna ItalyDept. Pharmacy and Biotechnology, University of Bologna, Italy
Marco Candela
Silvia Turroni
Sara Quercia
Prof. Patrizia
Matteo Simone
QuerciaBrigidi
Matteo Soverini
Simone Rampelli
Elena Biagi