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Alimenti, microbiota e
meccanismi di malattia
infiammatoria
intestinale
immunomediata
Salvatore Cucchiara
CROSS-TALK BETWEEN HOST CELLS, RESIDENT MICROBIOTA AND ENVIRONMENT
Diet, microbes and host genetics:
the perfect storm in inflammatory bowel disease
The microbiota and host genetic and
environmental factors contribute to
pathogenesis of Crohn’s disease
PRO-INFLAMMATORY EFFECTS OF GUT BACTERIA IN IBD
PRO-INFLAMMATORY EFFECTS OF GUT BACTERIA IN IBD
AIEC INFECTION AND LOOP OF COLONIZATION AND INFLAMMATION
Early phase CD
development
Gastroenterology 2011;140:1720-8
2012
CHARACTERIZATION OF ADHERENT-INVASIVE ESCHERICHIA COLI ISOLATED FROM PEDIATRIC
PATIENTS WITH INFLAMMATORY BOWEL DISEASE. Inflammatory Bowel Disease 2012;18:912
EC10, EC15 survival within macrophages
CHARACTERIZATION OF ADHERENT-INVASIVE ESCHERICHIA COLI ISOLATED FROM PEDIATRIC
PATIENTS WITH INFLAMMATORY BOWEL DISEASE. Inflammatory Bowel Disease 2012;18:912
CEACAM6 protein expression in the ileum of IBD patients and healthy controls
CHARACTERIZATION OF ADHERENT-INVASIVE ESCHERICHIA COLI ISOLATED FROM PEDIATRIC
PATIENTS WITH INFLAMMATORY BOWEL DISEASE. Inflammatory Bowel Disease 2012;18:912
CEACAM6 inducible in vitro and in
cultured
mucosa
by
proinflammatory cytokines. Caco2 cells
treated with TNF-α and INFγ for 6,
24 and 48 hrs
A
CEACAM6 mRNA expression was
analyzed by real-time PCR (A).
Same experiment repeated in
mucosa explants cultured for 6 and
24 hrs (B).
Fold of activation: ratio between
CEACAM6 expression level in
treated and untreated cells.
B
CHARACTERIZATION OF ADHERENT-INVASIVE ESCHERICHIA COLI ISOLATED FROM PEDIATRIC
PATIENTS WITH INFLAMMATORY BOWEL DISEASE. Inflammatory Bowel Disease 2012;18:912
EC10 and EC15 reduce the epithelial barrier function and cause morphological alterations
uninfected
EC10
EC10
EC10
Intestinal epithelium is a large surface
area of about 100m2 lined by a single
layer of columnar IECs performing
several functions:
 processing and absorbing dietary nutrients
 secreting compounds influencing microbial composition
 sampling of the intestinal microenvironments
 sensing both beneficial and harmful microbes
 inducing and modulating immune responses
To fulfil these functions, IECs comprise several
specialized
a cell types with distinctive functions
STEM CELL
Apical
junctional complex
Mucus
Unstirred
Columnar cells: (the most abundant) absorbe nutrients
bylayer
apical villi;
Intraepithelial
lymphocyt e
Epithelial cells
Goblet
Goblet cells: produce and secrete mucins
in cell
order to form a
protective luminal mucus layer;Basement
membrane
Neuroendocrine cells: release hormones in an endocrine
and paracrine fashion;
Paneth cells: secrete antimicrobial peptides
Plasma cell
Lamina propria
lymphocyt e
b
SCHEMATIC REPRESENTATION OF THE ZONULIN MECHANISM OF ACTION
BARRIER DEFECTS ASSOCIATED WITH INTESTINAL DISEASES
A “LEAKY GUT” has a pivotal role in the pathogenesis
of gastrointestinal and systemic diseases
What do we know?
Intestinal barrier function is modulated by:
 the immune system, including the TH1-cytokine IFN-γ, the TH2 cytokines
IL-4 and IL-13, TNF-α, T cells, mast cells, and eosinophils;
 the gut microflora
Altered intestinal barrier function and increased intestinal permeability is
associated with:
 food allergies
 IBD
 celiac disease
 type I diabetes
IECs function as a part of a coordinated response to signals provided by
the commensal microbiota and immune cells
SEVERE CROHN’S DISEASE IN A BOY
H
E
I
G
H
T
DRUG THERAPY
NUTRITIONAL
THERAPY
W
E
I
G
H
T
GRUPPO
STEROIDI
ELEMENTARE
SEMIELEMENTARE
POLIMERICA
p
NUMERO
10
11
14
12
<0.05
SESSO
3M
5M
8M
8M
<0.05
ETA’ (anni)
12.62.4
12.9 2.4
11.9 2.5
11.2 1.6
<0.05
PCDAI
27.15
28
33
24
<0.05
Short- and long-term therapeutic efficacy of nutritional therapy and
corticosteroids in pediatric Crohn’s disease. Cucchiara S et al.
Digestive and Liver Disease 2006; 38:381-7
Short- and long-term therapeutic efficacy of nutritional therapy and
corticosteroids in pediatric Crohn’s disease. Cucchiara S et al.
Digestive and Liver Disease 2006; 38:381-7
BACTERIAL
PENETRATION
CYCLE
CHANGE IN
CONSUMPTION
OF FOOD OR
ADDITIVES
If disease
susceptibility genes
PENETRATIONREPLICATION
WITHIN
EPITHELIAL
CELLS, DCs,
MACROPHAGES
IMPAIRMENT
OF BARRIER
FUNCTION
OF GUT
EPITHELIUM
ADHERENCEINVASION
OF NON
PATHOGENIC
BACTERIA
CONTINUOUS
TRIGGERING OF THE
ADAPTIVE IMMUNE
SYSTEM
INFLAMMATION
Examples for effects of dietary components on intestinal permeability and
translocation of bacteria
Environment and pathogenesis of Crohn’s Disease: bacterial penetration cycle
hypothesis
DIETARY ROADS TO COLITIS
rats with TBNS-induced colitis
ASSOCIATION OF THE MICROBIOTA WITH HUMANS
MICROBIAL IMPACT ON
HOST PHYSIOLOGY
Immuno-mediated diseases known to be associated with microbial dysbalance
blue: autoimmune - black: inducible disease
GUT MICROBIOTA AFFECTS EXTRA-INTESTINAL AUTOIMMUNE DISEASES
Microbiota-gut-brain axis. Direct and indirect pathways support the bidirectional
interactions between the gut microbiota and the central nervous system (CNS), involving
endocrine, immune and neural pathways.
Possible mechanisms linking gut microbiota to obesity
and nonalcoholic metabolic liver disease
(fasting-induced adipose factor)
(lipopolysaccharide)
(lipoprotein lipase)
% Sequences
How does community composition
impact function?
Hypothesis: Gut microbial communities
can impact risk for obesity
Different gut microbial
community structure in
obese mice
Firmicutes
Bacteroidetes
Mice that receive a fecal transplant from obese donors not
only become obese, but do so while eating less food…
Conventionalized mice (CONV-D) are formerly germ-free (GF) recipients of a
gut microbiota transplant from conventionally-raised (CONV-R) donors
Microbiota fecal transplantation
Conventionally
raised donors
Germ-free
Wild type
recipients
ob
wt
wt
wt
Donor
Turnbaugh et al., Nature 444: 1027-1031
THE GUT MICROBIOTA, GUT BARRIER FUNCTION AND
THE ONSET OF METABOLIC ENDOTOXEMIA
LINKING INTESTINAL HOMEOSTASIS AND LIVER DISEASE
ROMA - Con i suoi 621.253,75 euro annui, non c'è capo della Polizia più pagato di quello italiano
FRANCIA. Il capo della Polizia, attualmente Frederic Pechenard, ha "esattamente lo stesso stipendio
degli altri prefetti, intorno ai 6mila-7mila euro al mese”: si tratta di un trattamento economico "da
funzionario pubblico, rigidamente regolamentato da una griglia salariale".
GRAN BRETAGNA. Bernard Hogan-Howe, attuale capo della Metropolitan Police, ovvero la polizia di
Londra comunemente chiamata Scotland Yard, ha uno stipendio annuo di circa 253mila sterline .
GERMANIA. Secondo il tariffario valido dal gennaio del 2012, ai capi della Polizia nazionale spettano
9.668,56 euro mensili,
SPAGNA. Lo stipendio base del direttore generale della Polizia, che dal gennaio scorso è Ignacio
Cosidò Gutierrez, è equiparato a quello di un sottosegretario, 71mila euro all'anno.
USA. Lo stipendio base del capo dell'Fbi è pari a 155mila dollari (intorno ai 116mila euro). A questi
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