Microbiota intestinale e Patologie Neurodegenerative

MICROBIOTA INTESTINALE E
PATOLOGIE NEURODEGENERATIVE
GIOVANNI GASBARRINI *
CAROLINA MOSONI
ANTONIO GASBARRINI
* PROFESSORE EMERITO DI MEDICINA INTERNA
FIMeG
Federazione Italiana Medicina Geriatrica
Roma 9 febbraio 2018

Yogurt. Per la legge è latte fermentato con due specifici batteri, il
Lattobacillus bulgaricus e lo Streptococcus thermophilus, il cui
compito è quello di fermentare il lattosio ad acido lattico (la cui
acidità fa coagulare il latte per la precipitazione della caseina) e
di dare gusto attraverso la trasformazione dei grassi e delle
proteine in sostanze aromatiche. Alla fine della fermentazione
lattica si registra anche un aumento dell’acido folico e della
niacina. Di norma il latte utilizzato è quello vaccino.
Latte fermentato. Questa denominazione viene riportata in
etichetta quando il latte è fermentato con microrganismi diversi
da quelli usati per lo yogurt.

NOVEL MICROBIOLOGICAL TOOLS
DIRECT
Colture-dipendent
Colture-indipendent
Molecular microbiology metagenomic
DGGEs16S
rRNA sequence analysis, quantitative PCR
FISH, microarray, pyrosequencing (NGS)
high resolution MR spectroscopy
gas/liquid chromatography
mass spectrometry
INDIRECT
Metabolic activity metabonomics
Breath testing
PAMPs traslocation
….

…specific effects in each tract!
GUT MICROBIOTA AND HOST HEALTH
Barrier effect
Immunocompetence
Synthesis
Food metabolism
Drug metabolism
…
Behavior conditioning

Acquired
and
Innate
immunity
Vascular and lymphatic
systems
Neuroenteric system
Digestive enzymes
Mucosal
Barrier
Epithelial
barrier
Endocrine
system
Virus/phages Bacteria
Yeast
Gut Bacteriome
Helminth
ParasiteArchea
Protozoa
Micro-eukaryotes

HUMAN GUT BACTERIOME
>9 phyla
>1000 species
>17.000 subspecies
800-1000 gr, >10.000.000 genes
Microbiome Metabolome
130-150 bacterial species
4-6 phyla
800-1200 subspecies
..HOWEVER, EACH INDIVIDUAL
800-1000 gr, 3.000.000 genes

Enterococcus
Dethlefsen et al., Nature, 2007 18;449(7164):811-8 Ley et al., Science, 2008, 20;320(5883):1647-51
Firmicutes
60 to 80 %
Clostridium coccoides
(cluster XIVa)
Clostridium leptum
(cluster IV)
Lactobacillales
Bacteroidetes
20 to 40 %
Faecalibacterium
prausnitzii
Lactobacillus
Bacteroides
thetaiotaomicron
Streptococcus
thermophilus
Bifidobacterium
Escherichia coli
Actinobacteria
Proteobacteria
Phylogenetic diversity of human gut Bacteriome
Helicobacter pylori
2 major phyla: Firmicutes and Bacteroidetes (>70%)

HOST-MICROBIAL INTERACTION
Microbial genome is the variable part of our
genome that makes possible human
adaptation to external perturbations (ie diet,
starvation, overfeeding, food preservatives,
antibiotics, stress, violence..)
Past selective pressures
during human evolution

EU= good BIOS= life
• Composition: Diversity
Richness
Relative Abundance
Our gut is a sophisticated ecosystem that is
regulated by the logic of RELATIONAL HARMONY
Microbiota and Host live in a COOPERATIVE
SYSTEMIC AGGREGATION MODEL
In a healthy Microbiota species
are in equilibrium: EUBIOSIS
How to define an
EUBIOTIC enterotype?

Kitamoto S et al. J Gastroenterol 2015
Microbiota “sensing”
Osmolarity
Bicarbonate
Oxygen pH
Fucose SCFAs
Bile
Viscosity
Attachment shear stress
Cell density
Unknown
Metabolic
sensing
Physico-chemical
sensing
Mechano
sensing
Quorum
sensing

The Microbiota revolution is causing
the falling of the Single Germ theory
• With the Microbiota revolution differences in
proportions of various bacteria in different
disease state are important rather than the
appearance of a single microrganism
• To understand disease pathogenesis the
emphasis has to be on the balance of different
microbes rather than a single pathological
microrganism

Microbiota revolution
• Classical infection theories are not reliable
anymore
• Single-germ Theory
• Koch’s postulates
• Microbes are fundamental for our health
• Microbes can be used to fight microbes

Failure of HOST-MICROBIOTA equilibrium
Quali-quantitative alterations of oral,
esophageal, gastric, small bowel and/or
colonic microbiota
DYSBIOSIS
Digestive and extradigestive diseases
EUBIOSIS

ENTEROTYPE
DETERMINANTS
(INFLUENCERS)

of peopleasleanor obesecanbemadesolelyonthebasisof their gut
microbiotawith90%accuracy46,47
,but theydonot separateintodistinct
microbiota-basedclustersoncommonlyusedprincipal coordinates
plots,whichareusedtoidentifystatistical differencesbetweengroups.
Thus,multiplestatistical techniquesareneededtoshowfullythediffer-
ncesin themicrobiotabetween different physiological states(Fig. 2).
Somedifferencesin themicrobiotacan contributedirectly to disease
tates.Gnotobioticmicethat wereraisedgerm-freethencolonizedwith
hemicrobiotafromanobesemousegainedfat morerapidlythanthose
olonizedwith themicrobiotaof alean mouse7,45
. A phenotypecan
emergefromdifferent compositional backgrounds,whichmayindicate
hat specificcomponentsof themicrobiotacanexert largeeffectsor that
many different changescan lead to thesamefunctional result.
Differencesinfaecal microbial communitydiversity,compositionand
unctionhavealsobeencorrelatedwithCrohn’sdisease9
,ulcerativecoli-
s10
, irritablebowel syndrome(IBS)48
,Clostridiumdifficile- associated
disease(CDAD)49
andacutediarrhoea50
.Sometimes,thenatureof the
microbiotadeviationfromhealthisconsistent acrossindividualswith
hesamedisease.For instance,atwinstudyof IBDfoundmarkedand
eproducibledeviationsin patientswith ileal Crohn’sdiseaserelativeto
hecontrols,andmoresubtle,but characteristic,changesinpatientswith
olonicCrohn’sdisease51
,andspecificfunctional differenceswerealso
observedfrommetabolicprofilingof thesamesamples24
.Other diseases
reassociated with marked deviationsfrom health that areinconsistent
crossindividuals. For instance, individualswith recurrent CDAD had
aphylum-level diversitythat wasverydifferent fromcontrolsbut not
milar toeachother49
.Manydiseasestudiesareconfoundedbyextensive
seof treatments,suchasantibiotics,that mayobscuretruedisease-asso-
iatedchanges,highlightingtheurgent needfor prospectivelongitudinal
udiesthat establish causeand effect.
Parallels between host physiological states
Studiesof themicrobiotaoften target onespecificdiseaseor state,
but comparisonsof themicrobiotaacrossmany diseasescan show
ommon changesin thegut environment. Disturbed mucouslay-
ersthat linetheintestinal cell wall and concomitant inflammation
re seen in individuals with I BD, coeliac disease, HI V enteropathy,
acutediarrhoea, diverticulosis, carcinomaand IBS52
. Given these
arallels, an increase or decrease in abundance of similar microbes
acrossdifferent disturbancesmight beexpected53
, but elucidation
Firm icutes
Phylum Function
Actinobacteria
Bacteroidetes
Proteobacteria
Fusobacteria
Tenericutes
Spirochaetes
Cyanobacteria
Verrucom icrobia
TM7
Central carbohydrate m etabolism
Cofactor and vitam in biosynthesis
Oligosaccharide and polyol transport system
Purine m etabolism
ATP synthesis
Phosphate and am ino acid-transport system
Am inoacyl transfer RNA
Pyrim idine m etabolism
Ribosom e
Arom atic am ino-acid m etabolism
Figure4 | Functional redundancy. Thefunctional redundancy in microbial
ecosystemsmay mirror that in macroecosystems. Asshown in theHMPdata
set14
, oral communities(top panels) and faecal communities(bottom panels)
analysed using 16SrRNA (coloured by microbial phyla, left panels) show
tremendousabundancediversity. Thesamesamplesanalysed by shotgun
REVIEW INSIGHT
Lozupone et al. Nature 2012
Phylum level diversity can have a marked
variation even across healthy adults in the
same population. Each individual has many
unique phylotypes not found in the other.
INDIVIDUAL ENTEROTYPE

Breastfeeding/
formula feeding
Fecal microbiota
(mother)
Koenig JE et al, PNAS 2010
During the weaning phase (first 2-3 years of age)
a Native CORE microbiota populates the
gut (early programming with life long-effects )
Mode of delivery (vaginal microbiota)
Other (e.g. antibiotcs)
Environment
(mother/father/parents/
babysitter/siblings/pets..)

Only the human species drinks milk in adulthood
and drinks milk of other species

The newborn takes probiotics (bifidobacters) of milk
by breast feeding.
However he has already a microbiota derived by placenta .

Dysbiosis is a consequence of life events
Ottmann N et al. Front Cell Infect Microb 2012
Weaning

• Existence of a critical window in early life, when the gut microbiota
can influence the development of persisting metabolic traits
• Recipients of penicillin altered microbiota had decreased
expression of intestinal immune-response genes, similar to their
donors Immunologic and metabolic changes are not caused
by direct effects of antibiotics but rather by derived changes in the
gut microbiota
• Currently there is no direct evidence for a causal relationship in
humans
Jess T., N Engl J Med. 2014
Microbiota influencers
Antibiotics

Cox – Cell 2014
• Mice receiving penicillin
during weaning gained
total mass and fat mass
in adult age
• Mice receiving penicillin-
altered microbiota
(transfer of the cecal
microbiota from 18 w-old
penicillin-treated mice to
3 w-old Germ Free mice)
gained total mass and fat
mass at a significantly
faster rate
Antibiotics in early life and obesity

Dysbiosis is a consequence of life events
Adult

Cavenini E et al. Currt Pharm Des 2010

Hollister EB et al. Gastroenterology 2014
GUT BARRIER INTEGRITY

Hollister EB et al. Gastroenterology 2014
THE ANATOMO-MICROBIOLOGICAL GUT BARRIER
CuriosityZein.net
BIOTIC SURFACE

Gasbarrini G et al., SEM, 1985
EFFECT OF THE MUCOLYTIC ACTIVITY OF BACTERIA ON THE
SURFACE OF ENTEROCYTES

Gut Barrier disfunction
Intestinal permeability: Leaky gut

…Host affects Microbiota
ANTIMICROBIAL
defensins or cryptdins by
Paneth cells, RegIII (a C-
type lectin) and
angiogenin
Reactive
oxygen species
(ROS)
by phagocyte
reaction to
both
pathogenic and
symbiotic
bacteria
Mucosal IgA
towards specific
and unspecific
bacterial antigens
Physiological inflammation

U.S. adults sampled >5 times up to 296 weeks apart revealed that they harbored
195±48 bacterial strains, representing 101 ± 27 species
..in stable conditions, microbiota is stable, with 60% of strains remaining over the course of
5 years: stable core of dominant species

David – Nature 2013
Each diet arm significantly
shifted subjects’
macronutrient intake
6 M, 4 F; 21-33 yo; one
lifetime vegetarian subject
 Plant-based diet VS animal-
based diet (same calories) for 5
days
Assessment of baseline and
washout period

DYSBIOSIS
OUTGROWTHOVERGROWTH
DOWNGROWTH
LEAKY GUT

But…specific effects in each GI tract!
EFFECTS OF GUT MICROBIOTA ON HOST
HEALTH
Barrier effect
Immunocompetence/Tolerance
Synthesis
Metabolic/Trophic function
Drug methabolism
Behavior conditioning

Almost any Digestive and extra-Digestive
Diseases have been associated to a
DYSBIOTIC and LEAKY GUT
• Gastrointestinal infections
• IBS and IBD
• SIBO and CBO
• Diverticulosis
• Gastro-intestinal Cancers
• Food Intolerance/Allergy
• Celiac disease
• Liver and Pancreatic diseases
• Obesity, Diabetes and Metabolic Syndrome
• Gynecological, Rheumatological,
Cardiovascular, Neuropsichiatric disorders…

TRUC mice, deficient
for Tbet and Rag
Colitic phenotype could be
transmitted vertically to progeny of
affected parents and horizontally to
unrelated animals
Microbiota transmits Colitic phenotype
Garrett, Cell 2007;131(1):33-45

ETOH NAFLD
HBV/HCV
HCC
Auto
immunity
Encephalopathy
Iron.. Portal
hypertension
HRS
Ascites/SBP
DYSBIOSIS
+
LEAKY GUT

HJ Flint et al. Nature Review Microbiol 2008
 Herbivores derive 70% of their energy intake from
microbial breakdown of dietary plant polysaccharides
GUT microbiota of ruminant has a
powerful metabolic action

‘‘NUTRIENT SENSOR PATHWAY’’
Tilg H, J Hepatology 2010

Human diet shapes bacteria ENTEROTYPES
Wu et al. Science 2011
biotin and riboflavin thiamine and folate
“feeding” our microbiota
Proteolytic bacteria:
Bacteroides, Streptococcus,
Staphylococcus, Proteus, Escherichia,
some species of Clostridium, Fusobacteria,
Bacillus, Propionibacterium…
Saccharolytic bacteria
Prevotella, Bifidobacterium, Lactobacillus,
Eubacterium, Propionibacterium,
Escherichia, Enterococcus,
Peptostreptococcus, Fusobacteria…

Fermentation
Prebiotic fibres: FOS, GOS and inulin
The highest level of butyrate are seen with prebiotic fibres: FOS, GOS and inulin
• Prebiotics fibres are totally fermented, producing SCFA
• FOS, GOS and inulin selctively
• Stimulate proliferation of bifidobacteria and lactobacilli
• Inhibition patogenic Gram + and Gram – bacteria
• Reduce intestinal permeability, LPS and metabolic
endotoxiemia
Bifidobacteria
Lactobacilli
E. Coli
Bacteroides sp.
Clostridium perfrigens
Salmonella sp.
Listeria sp.
Shigella sp.
Campylobacter
Vibrio Cholera
Duca FA, J Nutr Biochem 2013

From lifetime to evolution
Faecalibacterium (cyan)
Dialister (green)
Prevotella (orange)
Clostridiales_uncl (yellow)
Ruminococcaceae_ uncl (pink)
Blautia (violet)
Gut microbiome structure of modern populations with different lifestyles
mimics the evolution of the relationship between microbes and the
human host.
Adaptive functional changes of the GM accompanied the
evolutionary trajectory of human beings
Quercia S et al. Front Microbiol 2014; 5:1-9
children
adults
Paleolithic
Neolithic
Modern

Martinez I et al. Cell Press 2015
Asaro and Suasi (Papua Nuova Guinea populations):
-live in traditional settings
-no sewage, wastewater, or drinking water treatment facilities
exist, drinking water is derived primarily from rivers, streams,
or rainwater and is mainly consumed without boiling or any
other treatments
-both communities rely on subsistence agriculture for their
food supply, with households having their own gardens
-under-nutrition is rare in PNG, as carbohydrate sources are
generally available.
-staple foods are sweet potato, taro, and plantain, which are
traditionally cooked in open fires and meat-derived protein
(principally pork and fish) is consumed less frequently
-antibiotic use is high due to the high burden of infectious
diseases, poorly regulated administration, and the lack of
diagnostic capacity, which leads to empirical treatments.

Zobellia galactanivorans is a marine Bacteroidetes able to
metabolize the polysaccharide porphyran from marine red algae.
Metagenomics revealed that porphyranases were common in the
Japanese population but absent in North American individuals.
Heheann JH et al. Nature 2010
In Japan, the genome of the gut
bacterium Bacteroides plebeius revealed
presence of a porphyran utilization locus
upstream of genes for conjugative DNA
transfer, acquired by horizontal gene
transfer from sea-weed-associated
bacteria found in sushi.
“A special gift for sushi eaters”
Diet and gut bacteria

Dysbiosis is caused by several life events
Ageing

Community
Low-medium fat
High fruit/fiber diet
Long-stay
High fat
Low fiber diet
Overall
Microbiota composition in elderly people living
in long-stay residential care facilities was
different from that of the free living elderly,
within the same ethnogeographic region.

Alterations in intestinal microbiota composition are associated with several chronic
conditions. The microbiota of older people displays greater inter-individual variation
than that of the younger adults
RELATIONSHIP BEETWEEN DIET, MICROBIOTA AND HEALTH
STATUS
Analysis of the diet, residence and gut microbiota composition of 178 subjects, non-
antibiotic-treated, that have been stratified in four groups by community residence
setting:
1) community-dwelling : 83 subjects
2) attending an out-patient day hospital: 20 subjects
3) in short-term (<6 weeks) rehabilitation hospital care: 15 subjects
4) in long-term residential care: 60
Mean age: 78 years (with a range from 64 to 102 years)
Claesson MJ et al, Gut microbiota composition correlates with diet and health in the elderly, Nature. 2012 Aug 9;488(7410):178-
84. doi: 10.1038/nature11319

MICROBIOTA AND RESIDENCE
LOCATION
Community-dwelling
microbiota
• Phylum Bacterioidetes
• Parabacterioides
• Eubacterium
• Anaerotruncus
• Lactonifactor
• Coprobacillus
• Phylum Firmicutes
• Coprococcus
• Roseburia
Long-stay microbiota
84. doi: 10.1038/nature11319

84. doi: 10.1038/nature11319

CONCORDANCE OF DIET AND
MICROBIOTA
• A healthy, diverse diet promotes a more diverse gut microbiota
• Significant differences have been found between community and long-stay
subjects
• Examination of duration of care showed that the diet changed more quickly than
the microbiota did; both microbiota and diet moved in the direction away from
the community types
• Collectively the data indicate that the composition of the microbiota is determined
by composition and diversity of the diet.
84. doi: 10.1038/nature11319

GUT MICROBIOTA
•Parkinson’s disease (PD)
•Alzheimer’s disease (AD)
•Cerebrovascular diseases
•Affective disorders
•Alcohol addiction
•Autism spectrum disorders
•Multiple Sclerosis
NEUROLOGIC
DISEASES
Not typical of the
elderly
Sherwin E et al, Recent developments in understanding the role of the gut microbiota in brain health and disease. Ann N Y Acad
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

MICROBIOTA-GUT-BRAIN AXIS
•Neurotransmitters
synthesis
•Modulation of the
immune system
•Neuroactive
metabolites production
•Vagus pathway
•Modulation of key
dietary amino-acids
(TRP)
• Neuroinflammation
• Stress
• Neurotransmission
• Neurogenesis
• Modulation of complex
behaviors
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

MICROBIOTA-GUT-BRAIN AXIS
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

GI Cancers associated to DYSBIOSIS
• Oral cavity
• Esophagus
• Stomach
• Small Bowel
• Colon
• Liver
• Bile trat
• Pancreas
H. pylori
Gut microbiota

PARKINSON’S DISEASE
Degeneration of the pars compacta of the substantia nigra of the mid brain –
widespread neuroinflammation
• Parkinsonian patients often report depression, constipation and sleep
disturbance (suggestive of gastrointestinal dysfunction) before the
development of the motor symptoms
• Constipation, impaired gastric emptying and difficulties in defecation appear
following progression of the disease
• Alpha-synuclein, the hallmark of Parkinson’s disease in the brain, can also be
found in the mucosal and submucosal nerve fibers and ganglia of the enteric
nervous system of parkinsonian patients. There is some preclinical evidence
that alpha synuclein in the nerve can reach the brain via the vagus nerve.
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

GUT MICROBIOTA IN PARKINSONIAN PATIENTS
• Reduced abundance of Prevotella species, which produce
mucin increase in intestinal permeability and bacterial
transocation
• Increased Akkermansia muciniphila
• Lower levels of anti-inflammatory-associated bacteria (Blautia,
Roseburia)
• Lower levels of acetate, butyrate and propionate
• Small intestine bacterial overgrowth
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

PARKINSON’S DISEASE AND
HELICOBACTER PYLORI
• H. pylori may contribute to the developement of parkinsonian
symptoms through degeneratig dopaminergic neurons in the brain
• H. pylori eradication ehnances the onset time of levodopa and
improves tremor, rigidity and walking ability
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

Mucosa gastrica colonizzata da un grande
numero di H. pylori

ALZHEIMER’S DISEASE
• Higher levels of Shigella/Escherichia
• Increased of hematic IL-1β and CXCL2
• Higher levels of LPS and Escherichia coli K99 pilli protein in
brain parenchyma and blood vessels of Alzheimer’s patients
• LPS was found to colocalize with
Aβ 1-40 in amyloid plaques
• Molecular mimicry may also play a role in Alzheimer’s disease
neurodegeration
Accumulation of amyloid plaques, tau fibrils and neuroinflammation widespread
Systemic
inflammation
Bacterial
components
translocation
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

THE ROLE OF AMYLOID IN
NEURODEGENERATION
Friedland RP et al. The role of microbial amyloid in neurodegeneration. PLoS Pathog. 2017 Dec 21;13(12):e1006654. doi:
10.1371/journal.ppat.1006654. eCollection 2017 Dec.

NEURODEGENERATION
•The microbiota modulates immunological processes in
the CNS
•The microbiota may induce oxidative toxicity and
inflammation that contribute to neurodegeneration
•Metabolites produced by the microbiome may be
pathogenic or salutogenic (health sustaining)
•There is a complex interplay between the human host
and its resident microbiota

NEURODEGENERATION
• Why are the neurodegenerative disorders so closely related to
age?
The late onset of Alzheimer and Parkinson’s disease allows for
minute alterations in proteostasis and inflammation to have
cumulative effects
• What are the principal sources of microbial
amyloid in humans?

NEURODEGENERATION
What can be done in regard to prevention and therapy?
Prebiotics, probiotics, antibiotics, dietary interventions, fecal transplants.
Therapeutic approaches to neurodegenerative disease may someday include
adapting the gut bacteria to support salutogenic species and other means.
We must ask if disease phenotypes can be modulated in persons after the initiation of
disease.
Although prevention is generally easier than cure, we should not assume a priori that the
contribution of the microbiota to neurodegeneration cannot be repaired.

NEURODEGENERATION
10.1371/journal.ppat.1006654. e Collection 2017 Dec.

p=0.004
p=0.0002
p=0.52
Pasceri V et al, Circulation 1998
%
Ischemic Heart Disease and H. pylori

STROKE AND BRAIN INJURY
• Alterations to the human microbiota following stroke have been
observed, with specific decreases observed in the Bacteroides fragilis
group and increases in an Atopobium cluster noted
• Microbial metabolism was also affected by stroke, with decreases in
fecal concentration of acetic acide and increases in valeric acid and
isovaleric acid.
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

“Molecular Mimicry” Hypothesis
CagA-positive
strains
Anti-CagA
antibodies
Franceschi et al, Atherosclerosis, 2008

STROKE AND BRAIN INJURY – PRECLINICAL
DATA
•Depletion of gut bacteria through antibiotic
administration worsened the survival rate of mice
following the induction of ischemia
•In the middle cerebral artery occlusion, cerebral
ischemia is associated with a dysregulation of the
murine microbiota, with a reduction in bacterial α-
diversity, intestinal motility and intestinal barrier
dysfunction (=increased permeability)
•Microbial-derived metabolites may influence stroke
susceptibility through modulatinf platelet activation
and thrombosis.
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

STROKE AND BRAIN INJURY – PRECLINICAL
DATA
•The gut microbiota modulates immune signaling
and influences the pathological outcome during
stroke
•An increased activation of the sympathetic nervous
system may also influence dysregulation to the
microbiota following stroke
•The gut microbiota may influence the severity of
post-stroke infections, a complication associated
with stroke
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

DEPRESSION
Depressed patients usually have a dysregulated microbiota
(reduction in species richness and microbial diversity)
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.
Transplantation of these patients’ microbiota into microbiota-
depleted rats, they developed a depression behavioral
phenotype.
They also had an elevated kynurenne/tryptophan ratio, indicating
that perhaps the depressed microbiota facilitates the conversion
of tryptophan into kynurenine, a deleterious metabolite

ALCOHOL ADDICTION
• Chronic alcohol consumption can negatively affect the gut microbiota,
decreasing the relative abundance of Bacterioidetes and increasing the
abundance of Proteobacteria
• A subset off alcoholics had an increased intestinal permeability, with an
increased risk of bacterial translocation
• Alcoholics with an increased intestinal permeability have an increase in
the Bleutia and Megasphera genera, with decreased levels og the anti-
inflammatory Faecalibacterium prausnitzii, which inhibits the IL-8, an
pro-inflammatory cytokine, production.
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

Szabo G, Gastroenterology 2015
High prevalence of SIBO
↓ Bacteroidetes
↑ Proteobacteria and Fusobacteria
Microbiota and ethanol related liver disease
Hartmann et al. Alcohol Clin Exp Res 2015

ALCOHOL ADDICTION
The psychological status of alcoholics with increased intestinal
permeability was worse than that of controls and alcoholics with
regular intestinal permeability
Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.
A dysregulated microbiota-gut-brain axis
facilitates the psychological symptoms
observed in alcoholics

Delzenne et al., Nat Rev Endocrinol 2011
Leung DY et al. J Allergy Clin Immunol 2013
Schwabe RF et al. Gastroenterology 2012
Ponziani FR et al. Exp Rev Gastroenterol Hepatol 2015
↓ Satiety
↑ Energy harvest
↑ Lipogenesis
↑ Gluconeogenesis
↓ Hepatic VLDL secretion
↑ LPL ↓ beta-oxidation=
↑ FFA uptake in
liver/adipose tissue
HIGH
FAT DIET
Altered gut microbiota
(↑ Firmicutes/Bacteroidetes, ↓ diversity)
SIBO (50% of NASH pts)
↑ Intestinal permeability
Gut microbiota and NAFLD/NASH

Sci. 2017 Aug 2. doi: 10.1111/nyas.13416.

Nikoletopoulou V et al. Trend in Endocrinology and Metabolism 2014
There is no chronological threshold or age
at which the composition of the microbiota suddenly alters;
rather, changes occur gradually with time…

Loosely
adherent
mucus layer
Firmly adherent
mucus layer
Bad
bacteria
Bile
acids
Lumen
Recettori
ionici
Water
Stomach Duodenum
and
Jejunum
Ileum Colon
Adhesions molecules
Immune
cells
Food
antigens
Endothelium
And fibroblasts
Nerve and miocytes
Non-Immune
cells
Food
antigens
Good
bacteria

Lumen
Immune
cells
Endothelium
And fibroblasts
Nerve and miocytes
Non-Immune
cells
SEVERE LEAKY GUT AND DYSBIOSIS
GASBARRINI A, UNPUBLISHED

Dysbiosis
p
i
DIET
PREBIOTICS
ANTIBIOTICS
MICROBIOTA
TRANSPLANTATION
POSTBIOTICS
METFORMINE
SLEEP
EXERCISE

How to modulate Gut Microbiota?
Diet and Nutritional Support
Caloric amount, minerals, vitamins..
Diet composition (fibers/high glicemic index/saturated fatty
acids…)
Removal of predisposing conditions
Treat diabetes, endocrine, other motility disorders..
Surgery or prokinetics when indicated
Stop PPI or other antiacid, NSAIDs, antibiotic,
immunosoppressant, antidepressant….
Intervention
Antibiotics Fecal Microbiota Transplantation
Biotherapy (prebiotics, probiotics, symbiotics, postbiotics)

Development of Gut Microbiota
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