GASBARRINI A. Nutrizione Clinica e Gastroenterologia. ASMaD 2017

Nutrizione clinica e
Gastroenterologia
Antonio Gasbarrini
Medicina Interna
Gastroenterologia e Malattie del Fegato
Area Gastroenterologia
Fondazione Policlinico Universitario Gemelli
Universita’ Cattolica, Roma
Il presente e il futuro della Nutrizione Clinica
Roma, 24 marzo 2017

22
La Nutrizione per il Gastroenterologo
La Gastroenterologia per il Nutrizionista
• Achalasia
• GastroEsophageal Reflux Disease (GERD)
• Helicobacter pylori and Gastritis
• Coeliac Disease and Malabsorption
• Irritable bowel syndrome (IBS)
• Inflammatory Bowel Diseases (IBD)
• Diverticulosis
• Liver diseases (NAFLD, ALCOHOL, Cirrhosis)
• Acute and chronic pancreatitis
• GI neoplasms
• Oesophageal cancer
• Gastric cancer
• Colon cancer
• Liver Cancer
• Pancreatic cancer

3
…It is like looking into a mirror
Achalasia Impaired relaxation of the lower esophageal sphincter
(LES) and loss of esophageal peristalsis
Dysphagia to both solids and liquids
Dyspepsia
Wheight loss
Regurgitation
Malnutrition
Krill JT, Clinical and Experimental Gastroenterology 2016
Patel DA, Orphanet Journal of Rare Diseases 2015

4
GERD
Abnormal backward flow of gastric contents into
the esophagus
Eructation
Nausea
Chest pain
Obesity and
Metabolic Syndrome
• Metabolic syndrome is associated with a higher risk of
reflux esophagitis (Odds ratio [OR]: 1.76, 95CI: 1.27 - 2.44,
P = 0.001)
• Alcohol consumption, higher levels of LDL-C and TG, led
to an increasing prevalence of erosive esophagitis (P < 0.05
for all)
• Increased WC (P < 0.01) and insulin resistance (P = 0.02)
are independent risk factors of erosive esophagitis
• Prevalence of Metabolic Syndrome in patients with reflux
esophagitis was significantly higher than in those without
reflux esophagitis (26.9% vs. 18.5%, P < 0.001)
• Metabolic syndrome could increase the risk of reflux
esophagitis after a multivariate analysis (OR: 1.42, 95% CI:
1.26 - 1.60, P < 0.001).
Mohammadi M, Iran Red Crescent Med J.2016

5
Eosinophilic Esophagitis Eosinophil-predominant inflammation of esophagus
Eructation
Nausea
Chest pain
Role of food antigens as trigger
Role of elimination diet in remission
• Food antigen-driven hypersensitivity
• Elevated food-specific IgE
• Immune dysregulation secondary to allergic
sensitization to dietary and/or aeroallergens.
• Isolated milk elimination had success rates of 65%
for complete or partial histologic remission
• Elemental diet reduces eosinophilic inflammation
and induces clinical remission in adult patients with
eosinophilic oesophagitis
Wechsler and Bryce, Gastroenterol Clin North Am 2015
Kagalwalla AF, J of pediatric gastr and nutrition. 2012
Warners MJ, Aliment Pharmacol Ther 2017

6
Coeliac Disease
A chronic immune-mediated gluten dependent
enteropathy induced by ingestion of gluten
Malabsorption and
Malnutrition
Vici G, Clin Nutr 2016
Abenavoli L, Eur Rev Med and Pharm Sci 2015
Gluten Free Diet Pitfalls
Deficiencies
GF-diet is poor in:
Alimentary fiber
Vitamins
(Vit. D, Vit. B12 and folate)
Micronutrients
(Iron, Zinc, Magnesium,
Calcium)
High content of
GF-diet is rich in
Saturated and
hydrogenated fatty acids
High glycemic index
High glycemic load meals
• Malnutrition by malabsorption
• Deficiencies of vitamin D,
• calcium, iron, folic acid, and
vitamin B12.
• Up to 70% of CD is significantly
associated with reduced bone
mineral density

7
IBD
Inflammatory bowel disease (IBD) is a collection of
chronic inflammatory disorders of the
gastrointestinal tract, including ulcerative colitis (UC)
and Crohn’s disease (CD), which is characterized by
periods of remission and flare-up of the disease
Anorexia
Hypercatabolism
Food associated pain
Malnutrition
• Up to 75% of patients with an active phase of IBD suffer
from wheight loss and hypoalbuminemia.
• Anemia and vitamin deficiences (especially vit. D and
B12) are also described
• Loss of lean body mass is more frequent in CD than UC
• Complications as short bowel, high output fistula or
severe stenosis reduce food intake
Hebuterne X, Gastroenterol Clin Biol 2009
Hartmann C, World J Gastroenterol 2009
Growth retardation
Protein energy
malnutrition

8
Acute
Pancreatitis
Rinninella E, Eur Rev Med and Pharm Sci, 2017
Oral or Enteral early nutrition in AP reduce:
- Complications,
- Sepsis
- Overall mortality
- Lenght of hospital stay

9
Liver
diseases
NAFLD
Obesity, insulin resistance,
metabolic syndrome, diabetes type II
Alcoholic liver
disease
Malabsorption,
Vitamin deficiencies (Vit. B1 -
B9 – B12, Vit. D)
Zinc, Selenium deficiencies
Cirrhosis Hepatic glicogen stores depletion
Protein energy malnutrition
Lean body mass loss
Vitamin and micronutrient
deficiences
Notably, in low grade encephalopaty (I-
II grade) an adequate protein supply (1.6
g/kg/day) is not a controindication, while
many clinician use a low protein diets!
ESPEN Textbook, Basics in clinical Nutrition, 2011, Galen Edition

10
Pancreatic
cancer
Gupta D, British Journal of Nutrition 2004
• Progressive weight loss and nutritional deterioration are commonly found in patients with pancreatic
cancer and a majority of patients are already in a state of malnutrition on admission
• Nutritional status measured with phase angle is a strong prognostic indicator in advanced
pancreatic cancer
• Patients with phase angle <5·08 had a median survival time of 6·3 (95% CI 3·5, 9·2) months (n 29),
while those with phase angle .5·08 had a median survival time of 10·2 (95% CI 9·6, 10·8) months (n
29); this difference was statistically significant (P<0·02).
phA: cut off 5,08

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

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

Balfour Sartor, Gastroenterology 2008
Each tract of the GUT owns a
specific Microbiota

Acquired
and
Innate
immunity
Vascular and lymphatic
systems
Neuroenteric system
Digestive enzymes
Mucosal
Barrier
Epithelial
barrier
Endocrine
system
Virus/phages Bacteria
Yeast
GUT Microbiota has many components
Helminth
ParasiteArchea
Protozoa
Micro-eukaryotes

Acquired
and
Innate
immunity
systems
Neuroenteric system
Digestive enzymes
Mucosal
Barrier
Epithelial
barrier
Endocrine
system
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%)

Acquired
and
Innate
immunity
systems
Neuroenteric system
Digestive enzymes
Mucosal
Barrier
Epithelial
barrier
Endocrine
system
Yeast
Other components of the Microbiota
Helminth
ParasiteArchea
Protozoa
Micro-eukaryotes

The gut is home to >50 genera of fungi with Candida,
Saccharomyces and Cladosporium species being particularly
common
Commensal fungal populations are more
variable than those of bacteria and may be
influenced by fungi in the environment (less
abundant and less robust?)
Diet can affect the fungal microbiota: plant-
based diet ↑Candida species, animal-based diet
↑ Penicillium species
Dollive S, et al. Genome Biol 2014
Cui et al. Genome Med 2014
HUMAN GUT MYCOME
Fungal microbiome
Bacterial microbiome
MUCUS
Gut microbiome
Bacteria
Fungi
Huffnagle GB et al. Trends Microbiol 2014

HUMANE GUT VIROME
Berg Miller et al, Environ Microbiol 2011
• In the gut have been isolated >30.000 different viral
genotypes. Majority (∼78%) of sequences did
not match any previously described virus
• Some are human, most are bacterial virus or
bacteriophages (caudovirales, corticoviridae,
• myoviridae, microviridae, siphoviridae..)
• Metabolic profiling revealed an enrichment
of sequences with putative functional roles in DNA,
protein and carbohydrate metabolism
• Phage have a main role in bacteriome adaptation to
perturbations (diet, antibiotics..)
• Pro phages outnumbered lytic phages: 2:1

Correlation network analysis between relative abundance
of bacterial phylotypes, yeast and bacteriophage-matching
reads

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

Shenderov AB et al. Anaerobe 2011 Schauder S et al. Genes & Development
How Bacteria Talk to Each Other?
Highly specific as well as universal QUORUM
SENSING languages exist: METABIOTICS!
Regardless of the type of signal used, QS allows
coordinated regulation of behavior
QS enables a group of bacteria to act in a
concerted manner, and thus acquire some of
the characteristics of multicellular
organisms, becoming similar to eukaryotes
Bacterial behaviors are regulated by QUORUM SENSING,
including symbiotic features, virulence, biofilm
formation, genes expression and epigenetic regulation,
apoptosis

 Some of the neurological diseases are associated with
an altered microbiota composition, such as autism
 In this study three chemically diverse quorum sensing
peptides were investigated for their brain influx (multiple
time regression technique) and efflux properties in an in
vivo mouse model (ICR-CD-1) to determine blood-brain
transfer properties
Evelien Wynendaele et al., PLoS One 2015

 3 main chemically diverse clusters distinguished
 One peptide from each cluster was selected, resulting in 3
chemically diverse molecules:
Quorumpeps ID 102 (BIP-2, GLWEDLLYNINRYAHYIT)
Quorumpeps ID 186 (PhrANTH2, SKDYN)
Quorumpeps ID 206 (PhrCACET1, SYPGWSW)
 BIP-2, or bacteriocin-inducing peptide 2, synthesized by
Streptococcus pneumonia (commensal of the human nasopharynx)
PhrANTH2 produced by Bacillus anthracis
PhrCACET1 formed by Clostridium acetobutylicum the
predominant presence of Clostridium spp. in the human gut is
associated with autism in children. It is able to pass the HH barrier.
Evelien Wynendaele et al., PLoS One 2015

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

Stecher B et al. Nat Rev Microbiol 2013
EUBIOSIS vs DYSBIOSIS

Vogt SL et al. Anaerobes 2015
Eubiotic bacterial interaction

INDIVIDUAL
HUMAN GUT
ENTEROTYPE

MICROBIAL
ENTEROTYPE
DETERMINANTS
(INFLUENCERS)

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

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..)

Verdu – Nat Rev Gastro Hepatol 2015
Early determinants of
GUT Microbiota composition

Backhed et al. Cell Host & Microbe, 2014
..an early programming with long-term effects

• 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

Ianiro, Tilg, Gasbarrini– Gut 2016 Cox et al – Nat Rev Endocr 2015
In a body of large
population-based
studies, early
antibiotic exposure
(0–24 months of life)
is associated with
higher risk of
overweight/obesity,
weight gain later in
childhood
Antibiotics in early life and obesity

Dysbiosis is a consequence of life events
Adult

• Diet
– Composition (calories, fat, vegetable, meat..)
– Cooking
– Natural food additives (safrolo..)
– Artificial chemical food additives:
• Preservatives (benzoic acid, sodium benzoate,
nitrite/nitrate, sulfur dioxide/sulfite..)
• Sweeteners, emulsifiers and stabilizers, flavors,
thickeners, antifoaming, anticaking, bulking,
antioxidants..)
• Others (titanium dioxide..)
• Exercise
• Sleep
• Stress
• Drugs

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…

David LA et al. Nature. 2014 January 23; 505(7484): 559–563
The animal-based diet
increases the abundance
of bile-tolerant
microorganisms
(Alistipes, Bilophila, and
Bacteroides) and
decreases the levels of
Firmicutes that
metabolize dietary plant
polysaccharides
(Roseburia, Eubacterium
rectale, and
Ruminococcus bromii )
The human gut microbiome can rapidly switch between herbivorous and
carnivorous functional profiles. It may reflect past selective pressures during
human evolution.
The short-term modification of diet alters
microbial community structure and microbial gene expression
Diet & Gut microbiota

 Non caloric artificial sweeteners (NAS: SACHARIN, SUCRALOSE,
ASPARTAME) drive development of glucose intolerance through
induction of compositional and functional alterations of gut
microbiota
 NAS-mediated effects can be abrogated by antibiotic treatment
 NAS-mediated effects are fully transferrable to germ free mice upon
transplantation of microbiota from NAS consuming mice or of
microbiota anaerobically incubated in presence of NAS
Suez et al, Nature 2014
CALLING FOR A REASSESSMENT OF
MASSIVE SWEETENERS USAGE
Non caloric artificial sweeteners

• At week 12,
exercise changed
the levels of phyla
of bacteria:
Bacteroidetes
Firmicutes
Proteoacteria
Evans – Plos One 2014
Exercise

Poroiko – Sci Rep 2016
Chronic sleep disruption
Chronic Sleep Disruption Alters Gut Microbiota
Mice were exposed to Sleep Fragmentation (SF) for 4 w and then allowed to recover
for 2 w
Firmicutes
Lachnospiraceae
Ruminococcaceae
Bacteroidetes
Bifidobacteriaceae
Lactobacillaceae
Reversible gut microbiota
changes after SF

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.

Cavenini E et al. Currt Pharm Des 2010

367 Japanese individuals: 6 centenarians (100-104 years old) and 7 individuals >95 years
Metagenomics seems associated with longevity: accentuated age-related
microbiota features in the 90 and 100 years old subjects

Young adults (30 years old in average) vs. “young elderly” (aged 65-75 years) vs. long-living subjects, subdivided
into a group of 15 centenarians (99-104 years old) and a group of 24 semi-supercentenarians (105-109 years old),
all enrolled in a restricted geographic area in Italy
Typical signs of an elderly gut
microbiota: decrease in saccharolytic
butyrate producers (Faecalibacterium,
Coprococcus, Roseburia), increase in
possibly opportunistic bacteria
(Enterobacteriaceae,
Desulfovibrionaceae)
Centenarians and semi-
supercentenarians showed an
increase in bacteria possibly linked
to good immunological and
metabolic health, such as
Christensenellaceae,
Akkermansia, Bifidobacterium

Bifidobacterium minimum
Bifidobacterium saecular
Bifidobacterium pullorum
Bifidobacterium gallinarum
Bifidobacterium mongoliense
were found in centenarians
but were absent in the
younger elderlies
Centenarians tend to have more complex fecal Bifidobacterium
species than young elderlies from different regions
Bama
centenarians
Nanning
elderlies
Bama
Younger
elderlies

Hollister EB et al. Gastroenterology 2014
GUT BARRIER INTEGRITY

Gut Barrier disfunction
Intestinal permeability: Leaky gut

Shimizu M, Biosci Biotechnol Biochem 2010
FOOD affects Intestinal Permeability
Food factors
Internal factors
Medium chain fatty acids
OPEN CLOSE
Diterpene
glycoside
(sweet pepper)
Beta-casein-derived
peptide
Beta-lactoglobulin
Gamma-linolenic acid, EPA
Piperin (pepper)
Polycation (protamine)
Saponin

Farhadi A, J Gast Hepatol 2003
STRESS affects Intestinal Permeability

DYSBIOSIS
OUTGROWTHOVERGROWTH
DOWNGROWTH
LEAKY GUT

DYSBIOSIS
REDUCTION OF ABUNDANCE OF SPECIES
LEAKY GUT
THE FRAGILE
MICROBIOTA

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…

SMALL INTESTINE BACTERIAL OVERGROWTH
is associated with IBS symptoms (bloating,
diarrhea/constipation, pain) and food intolerance
Lin, JAMA 2004Fermentation and gas production

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

Junjie Qin et al. Nature 2010;464(7285):59-65
IBD pts are DYSBIOTIC
1. Reduction of bacterial abundance

Daniel N. Frank et al., PNAS 2007;104(34):13780-5
IBD pts are DYSBIOTIC
2. Different bacterial variety

Sanchez. Appl Environ Microbiol 2013
Untreated CD VS GFD-CD VS Controls
Proteobacteria (11 vs 2%)
Enterobacteriaceae
(15 vs 5%)
Staphylococcaceae
(22 vs 10%)
Firmicutes (73 vs 92%)
Bacterial Microbiota dysbiosis
in Celiac Disease

 Breastfed/vaginally delivered infants with first-degree CD relative
 HLA-DQ2 VS non-HLA-DQ2/8 carriers
 16S rRNA gene Pyrosequencing + qRT PCR
DQ2 vs Non DQ2/8 - Genus level
Bifidobacterium
Unclassified Bifidobacteriaceae
Corynebacterium; Gemella
Clostridium sensu stricto,
Unclassified Clostridiaceae
Unclassified Enterobacteriaceae
Raoultella
Olivares. Gut 2015;64(3):406-17

De Palma. Br J Nutr 2009;102(8):1154-60
30 days of GFD in healthy people
Bifidobacterium
C. lituseburense
F. prausnitzii
Bifidobacterium
Lactobacillus
Enterobacteriaceae
E.coli
FISH
qPCR
Gluten Free Diet causes dysbiosis
in not Celiacs subjects

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

Microbiota in anticancer immunotherapy
Antibodies targeting CTLA-4 have been successfully
used as cancer immunotherapy. Their effect depends on
the presence of microbiota.
Vétizou et al. Science 2015
Tumors in antibiotic-treated or germ-free mice did
not respond to CTLA blockade.

The antitumor effects of CTLA-4 blockade
depend on distinct Bacteroides species.
In mice and patients,
T cell responses
specific for B.
thetaiotaomicron or
B. fragilis were
associated with the
efficacy of CTLA-4
blockade.
Microbiota in anticancer immunotherapy
Vétizou et al. Science 2015

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

Microbiota transmits Obesity phenotype
Ridaura et al. Science 2013, 341 (6150)
TRANSFERRED INTO THE
INTESTINES
OF GERM-FREE MICE
(Ob) twin + mice = adiposity
(Ln) twin + mice =  adiposity
Fecal microbiota from 4 human female twin pairs discordant for obesity
COHOUSING
(Ob) twin transplanted mice +
(Ln) twin transplanted mice =
(Ob) mice became LEAN
(Ln) mice remain LEAN
TRANSMISSIBILITY
OF INTESTINAL MICROBES
AND ADIPOSITY PHENOTYPE
ARE TIGHTLY LINKED

Which changes in Gut
Microbiota composition in
Obesity and Metabolic
disorders?

Obesity is associated
with:
• Reduced bacterial
diversity
• Phylum-level
changes
• Altered
representation of
bacterial genes and
metabolic pathways
Turnbaugh – Nature 2009
obesecontrol
Gut microbiota in obese humans
BACTEROIDETES/
FIRMICUTES
Adiposity index

Changes in gut microbial ecology
• Low bacterial richness (Low gene count)
• Microbiotal phenotype
• Higher rate of systemic inflammation
Bacterial alteration
Reduction in F. prausnitzii, A. muciniphila, Alistipes…
Proinflammatory bacteria dominate (Ruminococcus gnavus.)
Consequences
• Reduction in butyrate production and increased mucus degradation
• Increased oxidative stress and metainflammation
Tilg and Moschen , Gut 2014
obesecontrol
Gut microbiota in obese humans

Akkermansia muciniphila
Microbiota fingerprint of obesity?
Everard – PNAS 2013
Akkermansia muciniphila
is a mucin-degrading
bacteria that resides in the
mucus layer
Lower abundance of A.
muciniphila in leptin-
deficient obese than in lean
mice
100-fold decrease of A.
muciniphila in high-fat-fed
mice

GUT MICROBIOTA in T2D: West
Shotgun sequencing to assess the faecal metagenome of 145 70yo
European women with normal, impaired or diabetic glucose control (NGT
VS IGT VS T2D)
Species model VS microbial gene clusters (MCGs) model
Karlsson – Nature 2013
T2D vs Controls
• Increases in the abundance
of 4 Lactobacillus species
• Decreases in the abundance
of 5 Clostridium species

Metformine and diabetes
A microbiota-dependent pathway?
Meta-analysis of metagenomic data from 199 T2D patients, from whom information on antidiabetic
treatment was available, and 554 non-diabetic controls, comprising Swedish, Danish and Chinese
individuals
Metformin changes gut microbiota in T2D patients
Forslund et al – Nature 2015
Metformin-treated T2D pts
Intestinibacter spp abundance
Escherichia spp abundance

Gut microbiota Mucosal immune system
Muco-epithelial barrier
Vascular pathway Neuroendocrine/
Neuroenteric
Systems
How to mantain an
Eubiotic gut barrier?

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)

Fermentation
Intestinal bacteria and dietary fibres are a close entity
Bacteria are involved in
• fibre breakdown and production of SCFA
• Salvage energy from nutrients that escape digestion and absorption in
the small bowel (5% of total energy needs of the body)
Right Colon
Saccharolytic fermentation
• SCFA
– Butyrate (15%)
– Acetate (60%)
– Propionate (25%)
• Lactate
• Gas
• Bacterial growth
(bifidobacteria, lactobacilli)
End-products of fermentation are essential to mantain normal
composition and number of bacteria
Left Colon
Proteolytic fermentation
(putrefaction)
• Less SCFA
• Toxic substrates
– Ammonia
– Amines
– Phenols
– Thiols
– Indoles
• Less bacterial growth
Guarner F, Lancet 2003

Dietary fibres:classification
Dietary Fibre Solubility Fermentability Colonic metabolism
Structural polysaccharides
Cellulose None <50% Moderate
Hemicellulose A Good 70% Moderate
Hemicellulose B Poor 30% Moderate
Structural non-polysaccarides
Lignin None 5% None
Non structural polysaccarides
Pectin Very good 100% Extensive
Gum Very good 100% Extensive
Mucilages Good 100% Extensive
Oligosaccharides
Inulin Good 100% Extensive
Fructo-oligosaccharides (FOS) Good 100% Extensive
Galacto-oligosaccarides (GOS) Good 100% Extensive
Resistant starch Poor 100% Moderate
FUNCTIONAL FIBRES

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

Spencer M et al. J Neurogastroenterol Motil 2016
FODMAPs: poorly absorbed short-chain
carbohydrates including fructose (in excess of
glucose), lactose, polyols, fructans,
and galacto-oligosaccharides

Greenhalgh K et al. Environment Microbiol 2016

Diet composition (fibers/high glicemic index/saturated fatty
acids…)
Intervention
Antibiotics

Lactobacillus spp
• casei spp (Rhamnosus, DN..)
• reuteri
• acidophilus
• shirota
• delbrueckii, sp. Bulgaricus
• brevis
• plantarum
Bifidobacterium spp
• bifidum
• infantum
• longum
• thermophilum
• lactis
Which PROBIOTIC?
Cocci gram-positive
• Streptococcus thermophilus
• Enterococcus faecium
• Streptococcus intermedieus
• Streptococcus alfa-emoliticus
Bacillus gram-negative
• Escherichia coli Nissle (1917)
Guarino A. Bruzzese E. 2001; FAO/WHO, 2001
Bacillus gram-positive
• Bacillus clausii
Yeast
• Saccharomyces boulardii

Needs for a Subspecie
(Strain)-specific Microbial
Therapy
Different action for each Probiotic:
Knowledge of micro-organism functions and host
genetic modulation by different Species/Strain is
crucial

Probiotics has to be
choosen according to level
of evidence
Strain-specific Microbial
Therapy

LACTOBACILLUS CASEI sp RHAMNOSUS
Reduction of Antibiotic-associated Diarrhea
Prevention and treatment of Infectious Diarrhea
Adjuvant for H. pylori and C. difficile treatment
Treatment of Necrotizing enterocolitis
Treatment of Sugar Intolerance
Prevention and treatment of Pouchitis
Maintenance of remission in Ulcerative Colitis
Treatment of IBS
Practice guidelines on Probiotics usage
World Gastroenterology Organization (2011)

LACTOBACILLUS REUTERII
Adjuvant for H. pylori and C. difficile treatment
Maintenance of remission in Ulcerative Colitis
Treatment of IBS

ESCHERICHIA COLI sp NISSLE 1917
Adjuvant for H. pylori treatment
Maintenance of remission of Ulcerative Colitis
Treatment of IBS

BACILLUS COAGULANS GBI-30, 6086
Adjuvant for H. pylori treatment
Treatment and maintenance of remission of Ulcerative
Colitis
Treatment of IBS

Multistrains combination VSL 3
Treatment and maintenance of remission of Ulcerative
Colitis
Treatment of IBS

SACCHAROMYCES CEREVISAE sp BOULARDII
Adjuvant for H. pylori and C. Difficile treatment
Treatment of Traveller’s diarrhea
Maintenance of remission in IBD
Treatment of IBS

..waiting NEXT GENERATION
PROBIOTICS
1.Faecalibacterium Prausnitzii
2.Akkermansia Muciniphila
3.Eubacterium halii
4.…

Diet composition (meat, cheese, fibers, high glicemic index,
saturated fatty acids, ethanol, sweeteners…)
Intervention
Fecal Microbial Transplantation
Antibiotics

Antibiotics
Gut-specificSystemic

Time a vs Time b P.Value adj.P.Val
f__Rikenellaceae 0,0001 0,002 <
f__Streptococcaceae 0,002 0,026 <
f__Lactobacillaceae 0,005 0,039 >
Time a vs Time c P.Value adj.P.Val
f__Rikenellaceae 0,0002 0,002 >
f__Enterobacteriaceae 0,007 0,057 >
f__Streptococcaceae 0,011 0,06 <
Time b vs Time c P.Value adj.P.Val
f__Streptococcaceae 0,0003 0,007 >
f__Rikenellaceae 0,003 0,028 >
f__Enterobacteriaceae 0,008 0,048 >
Time a (baseline) vs time b (stop Rifa)
Time a (baseline) vs time c (1 month after Rifa)
Time b (stop Rifa) vs time c (1 month after Rifa)
Gasbarrini et al, Dig Dis 2016
EUBIOTIC EFFECT OF RIFAXIMIN

• Faecalibacterium prausnitzii (from 5.6% at T0 to 8.5% at T14)
• Roseburia inulinivorans (from 2.4% at T0 to 1.9% at T56)
• Streptococcus salivarius (from 1% at T0 to 0.4% at T14
• Blautia luti (from 1.6% at T0 to 0.7% at T14)
Soldi, Gasbarrini et al. Clin Exp Gastroenterol 2015
EUBIOTIC EFFECT OF RIFAXIMIN IN IBS

Diet composition (meat, cheese, fibers, high glicemic index,
saturated fatty acids, ethanol, sweeteners…)
Intervention
Fecal Microbial Transplantation
Biotherapy (prebiotics, probiotis, symbiotics, postbiotics)
Antibiotics

FMT: therapeutical applications
• C Difficile* and other antibiotic resistant GI
infection
• IBD and IBS
• Other inflammatory/autoimmune conditions
• NAFLD and other liver diseases
• Diabetes, Metabolic Syndrome, Obesity
• GI cancer
• Oncohematology
• Neurological and psichiatric disorders
*Approved

Drekonja et al. – Ann Intern Med 2015
 35 studies of FMT for CDI were identified
(only 2 RCTs): 516 patients
 Across all studies for recurrent CDI,
symptom resolution without recurrence was
seen in 85% of cases
 In 7 case-series studies of patients with
refractory CDI, symptom resolution ranged
from 0% to 100%
 Among 7 patients treated with FMT for
initial CDI, results were mixed

 Short vanco+FMT vs Short
vanco+bowel prep vs Standard vanco
 Study stop after an interim analysis
 Resolution of CDAD
 Mild diarrhea and abdominal
cramping in the FMT group on the
infusion day
• FMT group (n=16): 81%1 FMT, 94% >1 FMT
• Vancomycin group (n=13): 31%
• Bowel prep (n=13): 23%
Van Nood et al – NEJM 2013
RCT: FMT nasoduodenal tube

 Short vanco+FMT vs Standard vanco
 Study stop after a 1-year interim
analysis
 Resolution of CDAD
 5/7 pts with severe disease (PMC):
progressive disappearance of PMC and
resolution of CDAD after multiple FMT
 No significant adverse events
RCT: FMT colonoscopy
• FMT group (n=20): 90%
• Vancomycin group (n=19): 26%
Cammarota et al – APT 2015

FMT for recurrent C. Diff entered
in the European Guidelines
 FMT is strongly
suggested in
combination with
antibiotics for multiple
recurrent CDI
SoR: A
QoE: 1
Debast et al – Clin Microbiol Infect 2014

Youngster – JAMA 2014
 20 pts with rCDI received 15 FMT capsules by healthy
volunteers on 2 consecutive days and were followed up for
symptom resolution and adverse events for up to 6 months
 Resolution of diarrhea in 14 patients (70%; 95%CI, 47%-
85%) after a single capsule-based FMT
 All 6 non-responders were re-treated; 4 had resolution of
diarrhea, resulting in an overall 90% rate of clinical
resolution of diarrhea (18/20)
 No serious adverse events attributed to FMT

Moayeddi et al Gastroenterology 2015, 16-5085 (15) 451-5
FMT induces remission of UC
 Parallel study of UC patients
 FMT vs placebo
 50 ml via Enema from anonymous donors
 FMT once weekly for 6 weeks
 Primary end points: remission (Mayo score <2) and
endoscopic Mayo score of 0 at week 7
 Trial stopped for futility
 24% of FMT reached remission vs 5% of controls
 No differences in adverse events
 7 out of 9 pts in remission received FMT from a
single donor THE MAGIC POOP!

Stripling et al – Open Forum Infect Dis 2015
Wei et al – BMC Infect Dis 2015
FMT for multi-resistant enteric pathogens
Methicillin-resistant Staphylococcus aureus (MRSA) Enterocolitis
•5 patients with MRSA enteritis received vancomycin 2 g/o.i.d. for 3 days and FMT
for 3 consecutive days
•All patients experienced clinical response, as symptoms disappeared and and
MRSA in stools eliminated clearly
•The microbiota profile in feces of the patients also regained balance
Vancomycin-resistant Enterococcus (VRE)
• A case of FMT in a patient with C. difficile infection, recurrent VRE infections, and
vancomycin-resistant Enterococcus (VRE) fecal dominance, has been recently
reported
• FMT resulted in the reconstruction of a diverse microbiota with (1) reduced
relative abundance of C difficile and VRE and (2) positive clinical outcome

FMT x Autistic Spectrum Disorders
• Late-onset autism is commonly preceded by massive
antibiotic treatment
• Oral vancomycin has shown some efficacy in reducing
autistic symptoms
• In mice, B. fragilis improved autism-related behavioral
abnormalities
• FMT improved specific autistic symptoms in some case
reports
Bolte – Med Hypoth 1998; Brandt – unpublished;
Hsiao – Cell 2013; Sandler – J Child neurol 2000

Kang et al. Microbiome (2017)
• Small open-label clinical trial evaluating the impact of FMT on gut microbiota
composition and GI and ASD symptoms of 18 ASD-diagnosed children
• MTT involved a 2-week antibiotic treatment, a bowel cleanse, and then FMT using a high
initial dose followed by daily and lower maintenance doses for 7–8 weeks

• Similarly, behavioral
ASD symptoms
improved
significantly and
remained improved
8 weeks after
treatment ended
• The Gastrointestinal Symptom
Rating Scale revealed an
approximately 80% reduction of GI
symptoms at the end of treatment
(significant improvements in
constipation, diarrhea, indigestion,
and abdominal pain)
• Improvements persisted 8 weeks
after treatment

• Bacterial and phage deep sequencing
analyses revealed successful partial
engraftment of donor microbiota and
beneficial changes in the gut environment
• Overall bacterial diversity and the
abundance of Bifidobacterium, Prevotella,
and Desulfovibrio among other taxa
increased following FMT
• These changes persisted after treatment
stopped (followed for 8 weeks)

Painting the landascape
of Gut Microbiota in Obesity and
Metabolic disorders
Take Home Message

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

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…

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

GASBARRINI A. Nutrizione Clinica e Gastroenterologia. ASMaD 2017

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