El lunes 23 de octubre de 2017 celebramos una jornada en la Fundación Ramón Areces sobre Microbiota Intestinal: Implicaciones en la Salud y Enfermedad.

1. Jornada de Microbiota Intestinal
Implicaciones en la Salud y Enfermedad
Madrid, 23 de octubre de 2017

2. Guarner & Malagelada, Lancet 2003

3. http://www.hmdb.ca
Fluid Total
Microbial
origin
% Microbial origin
All fluids 3821 129 3,4
Blood 2273 102 4,5
Urine 1741 101 5,8
Saliva 1233 59 4,8
CSF 440 36 8,2
Number of Metabolites Detected in Human Fluids

4. ILEO-CECAL DYSBIOSIS IN CHRONIC LIVER DISEASE
Guarner C & Runyon BA. Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites. J
Hepatol 1997
Pardo A, et al. Effect of cisapride on intestinal bacterial overgrowth and bacterial translocation in cirrhosis.
Hepatology 2000
Francés R, et al. Bacterial translocation is downregulated by anti-TNF-alpha monoclonal antibody administration
in rats with cirrhosis and ascites. J Hepatol 2007

5. SERUM MICROBIOME IN CHRONIC LIVER DISEASE
Santiago et al. Scientific Reports 2016

6. MICROBIOTA-INDUCED PROGRESSION TO CHRONIC LIVER DISEASE
Schnabl & Brenner, Gastroenterology 2015

7. Decision making in the adaptive (acquired) immune system is
instructed by the microbial impact on APCs and T cells
CD4
TCR
APC
CD4
Th1, Th17
Treg
Foxp3+
Th2
TNF-, IFN- IL-17
IL-10
IL-4, IL-5, IL-13
CD4
CD4
+
–
–
–
–
PRR
Foreign antigen
(Ag)
Naive T-cell
activation
Cytokines
+
TGF-b
Signatures via pattern
recognition receptors
(PRRs): TLRs & NLRs
(NOD+LRR)
Ligation
MHC II
T
+
By Per Brandtzaeg in Guarner et al, Nature Clin Practice 2006

8. F
F
FAE
Gut-Associated Lymphoid Tissue structures are strategically situated in relation to the
greatest concentration of microbiota
• Peyer’s patches:
distal ileum (nos. 100-250)
• Isolated lymphoid follicles (ILFs):
large bowel (nos. ~ 30 000)
Brandtzaeg, Immunological Investigations 2010

9. HUMAN BLOOD REGULATORY CELLS INDUCED BY
Faecalibacterium prausnitzii
Sarrabayrouse et al, PLoS Biol 2014

10. Commensal microbiota affects ischemic stroke outcome
Benakis et al, Nat Med 2016

11. Anticancer Immunotherapy and Microbiota
Vetizou et al, Science 2015

12. Anticancer immunotherapy and microbiota
Vetizou et al, Science 2015

13. THE ENEMY IS WITHIN THE FAECAL STREAM
Rutgeerts P, Goboes K, Peeters M, Hiele M, Penninckx F, Aerts R, Kerremans R,
Vantrappen G.
Effect of faecal stream diversion on recurrence of Crohn's disease in the neoterminal
ileum. Lancet 1991;338:771-4.
Winslet MC, Allan A, Poxon V, Youngs D, Keighley MR.
Faecal diversion for Crohn's colitis: a model to study the role of the faecal stream in the
inflammatory process. Gut 1994;35:236-42.
D’Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P.
Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in
excluded ileum. Gastroenterology 1998;114:262–267.

14. Immuno-
suppression
Drug
Mucosal
healing
Mild
Aminosalicylate
Budesonide
Low
Moderate
Azathioprine
Methotrexate
Corticosteroids
Medium
Strong
Anti-TNF
Anti-integrins
High
Mucosal lesions are caused by an aggressive immune response against
gut bacteria

15. Adapted from Holtmann et al. Z Gastroenterol 2002
Cell detachment
Macrophage
TNF-
TNF-
Severe tissue injury by inflammation: role of TNF-
enderetal,JImmunol1998

16. Modern life style Traditional lifestye
Birth in the hospital; increasing rate of caesarean delivery Vaginal delivery at home
Small family size Large family size, crowding
Life on concrete Life in contact with soil microorganisms
Sanitation of living spaces: environment colonized by
resistant micro-organisms (including resistant bacteria,
fungii, acari)
Ancestral colonization of the living environment
Antibiotic usage early in life No antibiotics in infant life
Daily body wash with hot water and soap Limited access to hot water and soap
Low rate of H. pylori colonization High rate of H. pylori colonization
Decline in endemic parasitism Common carriage of parasitic worms
Food conserved by refrigeration Food conserved by microbial fermentation
Consumption of processed foods Consumption of natural foods
IBD risk factors are linked with altered microbial colonization
Manichanh et al, Nature Reviews Gastroenterology 2012

17. Blaser & Falkow, Nature Rev Microbiol 2009

18. Clemente et al, Science Advances 2015

19. Clemente et al, Science Advances 2015

20. Manichanh et al, Nat Rev GH 2012
Profiling the Human Microbiome

21. Dysbiosis in IBD
Pascal et al, Gut 2017

22. Meta-Genomic Species
Nielsen et al, Nature Biotechnology 2014

23. Gene Richness and Species Diversity
Nielsen et al, Nature Biotechnology 2014

24. • Richness is greatly altered in Crohn’s
Disease
•* • *
•Gene Count •Species count
•Genes,N°
•MGS,N°
•050000010000001500000
•0100200300400
500
•p = 4.3e-10 (wilcox. test) • p = 4.9e-9 (wilcox. test)
•Healthy, n = 52 •CD, n = 73 •Healthy, n = 52 •CD, n = 73
•24

25. Richness is less altered in Ulcerative Colitis
*
MGS,N°
Genes,N°
p = 0.15 (wilcox. test)
Gene Count Species count
p = 0.019 (wilcox. test)
Healthy, n = 56 Healthy, n = 56UC, n = 65 UC, n = 65
2000006000001000000
100200300400500
•25Maziers et al, IHMC 2016

26. •26
Strong Species signal in CD Healthy, n = 52 CD, n = 73
Healthy
CD
Richness
Numerous Faecalibacterium spp
Maziers et al, IHMC 2016

27. Less strong Species signal associated with UC Healthy, n = 28 HR, n = 28 UC -1, n = 34 UC-2, n = 31
Healthy
UC
Richness •27
Maziers et al, IHMC 2016

28. • Reduction of SCFA producing bacteria (butyrate producers such as
Faecalibacterium, Roseburia, Lachnospiraceae, Eubacterium, Subdoligranulum).
• Increased mucus degradation potential by abnormal mucin degraders that
displace Akkermansia.
• Reduced hydrogen and methane production potential combined with increased
hydrogen sulphide formation potential. Hydrogen sulphide is toxic for the
epithelium.
• Increase in abundance of bacteria with LPS endotoxins (Proteobacteria) that
can drive inflammation.
• Increased potential to manage oxidative stress, i.e. microbes become able to
proliferate in close vicinity to the epithelium.

29. Conclusiones
• En pacientes con EII, hay una distorsión permanente del ecosistema microbiano
intestinal, incluso durante períodos de remisión, caracterizada por reducción de
riqueza de genes microbianos, reducción de la diversidad de especies e
inestabilidad de la comunidad.
• CD y UC tienen firmas microbianas distintas a nivel taxonómico, pero las
alteraciones funcionales son parecidas.
• Los cambios son más intensos en pacientes con CD, mientras que los pacientes
UC presentan mejor recuperación durante los períodos de remisión.

30. Acknowledgments
MetaHIT
Consortium
HUVH: V. Robles, N. Borruel, F. Casellas,
F. Guarner
INRA: E. Le Chatelier, N. Maziers, D.
Ehrlich
La Fe (Valencia) : B. Beltrán, P. Nos
Parc Tauli (Sabadell) : A. Villoria, X. Calvet