The document discusses the human microbiome and its role in various gastrointestinal diseases. It begins by noting that the microbiome contains over 1000 bacterial species and 1 million genes, far more than the human genome. It then discusses how the microbiome is established during birth and early life, and how it varies over time and geography. The document also explores how dysbiosis, or imbalance of the microbiome, is associated with diseases like IBD, IBS, diverticular disease, obesity and metabolic syndrome. It presents evidence that fecal microbiota transplantation can treat diseases like C. difficile infection and metabolic syndrome. Finally, it discusses potential therapeutic approaches like prebiotics, probiotics, antibiotics and diet to treat dysbiosis

1. Patologie digestive, extra-digestive
e microbiota
Giovanni Barbara
Dipartimento di Scienze Mediche e Chirurgiche
Università di Bologna
(1088 – 2018)

2. The Human Microbiome
Lee YK, and Mazmanian SK. Science 2010;330:1768-73
Microbiome
1.000.000+ genes
• Number of microbiota genes outnumber number of human genes
• >1000 bacterial species in each individual
• “A silent organ” with high metabolic activity (biomass ≈ liver)
Human genome
23.000 genes

3. In Utero Environment is Not Sterile
• Placental microbiome: commensal phyla (Firmicutes,
Tenericutes, Proteobacteria, Bacteroidetes and
Fusobacteria)
• Most akin to oral microbiome (dissimilarity <0.3)
Aagaard K et al., Science 2014;6:237ra65

4. Type of delivery imprints gut microbiota
• Each point corresponds to a
community colored according to
the mother’s body habitat or the
newborn’s delivery mode
Dominguez-Bello et al. PNAS 2010;107:11971–11975

5. Gut Microbiota Distribution
Simren, Barbara et al., Gut 2013;62:159-76
Mucosa Mucus layer Lumen/faeces
(60% fecal mass)
The majority of
bacteria reside
in the gut

6. Gut Ecosystem
Qin J, Li R, Raes J et al, Nature 2010;4;464:59-65
Kingdom
Phylum
Class
Order
Genus
Family
Species

7. Neurotransmitters
Acetate
Butyrate
Propionate
Bacteriocins
Galactosidases
…
Genetic
repertoire
Bile salt hydrolases
cell wall peptides
metabolites
Microbiota-Host Interactions

8. Microbiota-Host Communication
Gut Epithelial & Vascular Barriers
Spadoni I et al., Science 2015; 350:830-4
PV1 plasmalemma
vesicle–associated protein-1
Turner JR. Nat Rev Immunol. 2009;9:799-809
Epithelial Barrier
Vascular Barrier

9. Our Microbiome Varies Over Time
Origins of
Health and
Disease
Aagaard K et al., EMBO 2016;17:1679–1684

10. Microbiota Diversity Around the World
Faith’sPhylogeneticDiversity
Clemente J et al., Sci Adv 2015;347:911-20
Autoimmunity
Allergy

11. Stecher B et al. Nat Rev Microbiol 2013;11:277-84
The Dysbiosis Concept

12. Diseases Associated to Dysbiosis
Goldszmid RS et al., Nat Immunol, 2012;13:932-8

13. Effect of Antibiotics on Hypertension
Calesnick B et al., The Am J Med Sci 1958;236:736-41

14. Reduced Microbiota Diversity in Hypertension
Yang T et al., Hypertension 2015;65:1331-1340

15. Tang W et al., NEJM 2013;368:1575-84
Trimethylamine
(TMAO)
plasma levelsRisk of major CV events

16. Microbiota and Metabolic Disorders
Delzenne NM & Cani PD. Ann Rev Nutr 2011;31:15-31

17. Obesity and Microbiota
Conventionalized
(i.e. with microbiota)
High fat diet
Germ free
(i.e. no microbiota)
 Bacteroidetes
 Firmicutes
 Energy extraction
Obesity is a
transmissible trait
Fecal transplantation
(i.e. introduction of microbiota
of obese mouse to germ free
lean mouse)
2 weeks
Turnbaugh PJ et al., Nature 2006;444:1027-31

18. Fecal Transplantation and Insulin
Sensitivity in Human Metabolic Syndrome
Vrieze et al., Gastroenterology 2012;143:913-16
6 weeks after
Insulin sensitivity
Fecal transplantation
lean
obese

19. Microbiota-Brain Crosstalk
Clinical scenarios

20. Hepatic Encephalopaty
Bajaj GS. Aliment Pharmacol Ther 2016;43(S1):11–26

21. Tillish K et al., Gastroenterology 2013;144:1394-1401
Probiotics modulate brain activity
Reduced activity in the intervention group vs. placebo
• Bifidobacterium animalis subsp Lactis
• Streptococcus thermophiles
• Lactobacillus Bulgaricus
• Lactococcus lactis subsp Lactis

22. • ↓ depression <2 pts on HADS at
wk 6; P = 0.04)
• ↑ QoL
• No effect on anxiety or IBS
symptoms
↓ Responses to negative
emotional stimuli on brain MRI

23. Microbiota-Brain Crosstalk
What are the mechanisms?

24. Gut Bacteria Possess Major Enzymes Involved
in the Production of Neurochemical Messangers
Iyer LM et al, Trends Genet 2004;20:292-9

25. Collins SM et al. Nature Reviews Microbiol 2012;10:735-42
The Microbiota – Brain Axis

26. Bloating
Pain
Distension
IBSM
C
D
FC
FDr
FC: Functional constipation
FDr: Functional diarrhea
IBS-C: Irritable bowel syndrome with predominant constipation
IBS-D: Irritable bowel syndrome with predominant diarrhea
IBS-M: Irritable bowel syndrome with mixed bowel habits (D and C)
Type 1
Type 2
Type 3
Type 7
Type 5
Type 6
Type 4
Constipation
The Spectrum of FBD in Rome IV
Lacy BE et al. Gastroenterology 2016;150:1393–1407.e5

27. IBS Microenvironment
Barbara G et al. Gastroenterology 2016;150:1305–1318

28. Pan A et al., Clin Microbiol Infection 2011;17:1698–1703

29. Prevalence of C. difficile
Lessa F C et al. Clin Infect Dis. 2012;55:S65-S70
85+ yrs
65-84 yrs
<18 yrs
18-44 yrs
45-64 yrs
Age
Increase in ribotypes: 027 (US), 001, 053, 106

30. Fecal transplantation in C.difficile infection
Van Nood et al., NEJM 2013;368:407-15

31. Inflammatory Bowel Disease
CD + UC prevalence = 0,4%
1.4 million people in USA
2.2 million people in Europe
Crohn’s Disease - Ulcerative Colitis
Dysbiosis ?

32. Abnormal Gut Microbiota in IBD
Sokol H et al., Gut 2017;66:1039-48
Beta diversity

33. Fecalibacterium prausnitzii
A commensal with anti-inflammatory properties
Sokol et al., PNAS 2008;105:16731-6
Colitisseverityscore
Protection in TNBS colitis
Low FP levels predict Crohn’s Disease
post-operative recurrence

34. Microbiota, Inflammation and
Diverticular Disease
“colonic pouch”
– Fecal entrapment
– Bacterial translocation
– Mucosal inflammation
Smooth Muscle
ENS
Barbara G et al., J Clin Gastroenterol 2016;50 S60-3

35. Kingdom
Phylum
Class
Order
Genus
Family
Species
Gut Ecosystem
(Phylum Level)

36. Shift in Bacterial Phyla Abundance in
Colonic Diverticular Disease
Lopetruso et al., UEG J 2014;3(Suppl 1):A60

37. Bacterial Phyla in Patients with Diverticulitis
Daniels et al., Eur J Clin Microbiol Infect Dis 2014;33:1927-36
Diverticulitis
All Bacterial Phyla
Proteobacteria (Gram -)
INFLAMMATION
All phyla Bacteroidetes Firmicutes Proteobacteria
*
**
ShannonIndex

38. Microbiota in Diverticular Disease
Barbara et al. Gut 2017;66:1252–1261
Healthy Controls
Diverticulosis
SUDD
Bacterial 16S rRNA
HTF-Microbi.Array

39. Microbiota Composition in DD
CONTROL DIVERTICULOSIS SUDD
 Clostridium cluster IX
 Fusobacterium
 Lactobacillaceae
Barbara et al. Gut 2017;66:1252–1261
 Akkermansia
(in diverticular
vs. distant site)**
** Negative correlation with macrophage inflammation
Anti-inflammatory; SCFA producers
Comprise mucus degrading bacteria
 Clostridium cluster IV
↑ Bacteroides / Prevotella

40. Dysbiosis in Diverticular Disease
Barbara et al. Gut 2017;66:1252–1261
 Bacterioides
 Prevotella
 Clostridium cl IV & IX
 Fusobacterium
 Lactobacillaceae
Pathogenetic potential
eg, proinflammatory
Beneficial
eg, anti-inflammatory

41. Metabolomics
The Science of Small Molecules
Measurable in body fluids
Compound classes:
• Sugars
• Amino acids
• Steroids
• Fatty acids
• Lipids
• Phospholipids
• Organic acids
Study of the set of
metabolites
present within an
organism, cell, or
tissue
Results of the metabolic activity of
the host and microbiome
Influenced by the
environment and genetic
repertoire

42. Urinary Metabolomics in DD
(H1 nuclear magnetic resonance)
Barbara et al. Gut 2017;66:1252–1261
X=unidentified molecule
mM/L(E)
**
*
*
**
** * P<0.05 vs HC
** P<0.05 vs HC

43. Urinary and Fecal Metabolomics in DD
(H1 nuclear magnetic resonance)
• Hippurate ( in SUDD)
– Result of bacterial metabolism of benzoic acid
– Similarly decreased in Crohn’s disease
– Correlated to changes in Bacteroidaceae
• Kynurenine & Quinolate ( in SUDD)
– Catabolic pathway of tryptophan
– Similarly increased in IBD, IBS, celiac disease
– Impact gut function and inflammation
Barbara et al. Gut 2017;66:1252–1261

44. Dysbiosis
Therapeutic Approaches for Dysbiosis
Diet & Prebiotics Probiotics FMT Antibiotics

45. Key messages
 The field of microbiota is moving fast and taking
center stage in clinical medicine
 Still in the learning phase
 Microbiota participates in the pathophysiology of
the main GI diseases
 An opportunity for therapeutic approaches